Welcometothe26thInternationalMammalianGenomeConferenc ...imgs.org/Archive/abstracts/2012abstracts/IMGC_2012...FinalProgram&BookofAbstracts –7– IMGCP ROGRAM Saturday,October20,2012

Final Program & Book of Abstracts

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Welcome to the 26th International Mammalian Genome ConferenceTradewinds ResortSt. Pete Beach, October 21 – 24, 2012

Welcome to the 26th Annual Conference of the International Mammalian Genome Society, returning to the site of the 11th Annual Conference, The Tradewinds Resort on St. Pete Beach, Florida. We have planned an exciting meeting that emphasizes cutting edge research in mammalian genetics and genomics, but we have also left you some free time to network with your colleagues and enjoy the recreational opportunities of the Tampa/St. Pete Beach area!

The meeting will begin with a Bioinformatics Workshop that was very popular at the last conference and will be led by investigators actively involved in developing tools for large-scale genomics analysis. The Bioinformatics Workshop will be followed by the Student Satellite Symposium, which offers budding scientists an opportunity to hone their presentation skills and compete for presentation slots in the main meeting sessions.

The main conference will feature multiple exciting sessions including: Large-scale Resources;; Advances in Genome Manipulation;; Stem cells and Development;; Human Disease Models;; Comparative Genomics;; Aging and Adult-onset Disease Modeling, sponsored by the Ellison Foundation;; and two poster sessions. The mentoring dinner on Tuesday will provide an opportunity

Attendees will have some free time to enjoy the amenities offered by the Tradewinds Resort and the St. Pete Beach area. Located on Florida’s west coast, the Tradewinds Resort is a family friendly locale that has direct beach access to the tranquil, warm waters of the Gulf of Mexico. Conference

available at the resort as well. For those desiring more sedate relaxation, nearby St. Petersburg, nick-named “The City of the Arts”, is home to six major museums (including the Salvadore Dali and Chihuly Museums) as well as many shops and restaurants.

We welcome you “Back to the Beach” for the 26th IMGC.

Local Organizing Committee

26th International Mammalian Genome Conference

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CONTENTS

Page

Part 1 – Program and General Information

Program at a Glance 3

Social Program 6

Full Conference Program Sunday, October 21 7 Monday, October 22 9 Tuesday, October 23 11 Wednesday, October 24 13 Committees 16

General Information 17

Awards 18

Exhibitors/Sponsors List 19

Part 2 – Book of Abstracts

Student Symposium Oral Presentation Abstracts 20Oral Presentation Abstracts 31Poster Presentation Abstracts 57

Author Index 97

Part 3 – Attendee List 103

Conference Organisers In Conference Ltd, 4-6 Oak Lane, Edinburgh, EH12 6XH, Scotland, UK

Tel: +44 (0) 131 339 9235 Fax: +44 (0) 131 339 9798 Email: imgc@in-conference.org.uk


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PROGRAM AT A GLANCE

Saturday, October 20, 2012

2:00 pm – 6:00 pm Secretariat Meeting Chart Room

Sunday October 21, 2012 8:00 am – 7:00 pm Registration Open Registration Desk

9:00 am – 12:00 pm Bioinformatics Workshop Tarpon

1:00 pm – 3:15 pm Student Satellite Symposium Session 1 Tarpon

3:15 pm – 3:45 pm Tea & Coffee Grand Palm Colonnade

3:45 pm – 6:30 pm Student Satellite Symposium Session 2 Tarpon

6:30 pm – 8:30 pm Welcome Reception and Buffet Dinner Garden Courtyard

Monday October 22, 2012

8:00 am – 6:30 pm Registration Open Registration Desk 7:00 am – 8:30 am Continental Breakfast Grand Palm Colonnade 8:30 am – 8:45 am Welcome and Opening Comments Tarpon / Sawyer 8:45 am – 10:30 am Plenary Session: Large Scale Resources I Tarpon / Sawyer 10:30 am – 11:00 am Tea & Coffee, Exhibition & Posters Banyan Breezeway

11:00 am – 12:30 pm Plenary Session: Comparative Genomics Tarpon / Sawyer

11.00 am – 11.30 am Genetics of Color Variation: Model Organisms in a Post-Genome World

Greg Barsh, HudsonAlpha Institute & Standford University, Huntsville, AL, USA Tarpon / Sawyer

11:30 am – 12:30 pm Comparative Genomics Tarpon / Sawyer

12:30 pm – 1:30 pm Lunch, Exhibition & Posters Garden Courtyard & Banyan Breezeway

12:30 pm – 1:30 pm Mammalian Genome Editorial Board Lunch Royal Tern

1:30 pm – 3:00 pm Plenary Session: Advances in Genome Manipulation Tarpon / Sawyer


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2:15 pm – 3:00 pm Selected Student Talks x 3 (15 min each) Tarpon / Sawyer

3:00 pm – 5:00 pm Poster Session I & Refreshments (Odd Numbers) Banyan Breezeway 5:00 pm – 6:00 pm Plenary Session: Human Disease Modeling I Tarpon / Sawyer

6:30 pm – Dinner & Free Evening Garden Courtyard

Tuesday October 23, 2012

8:00 am – 6:30 pm Registration Open Registration Desk

7:00 am – 9:00 am Continental Breakfast Grand Palm Colonnade

9:00 am – 10:30 am Plenary Session: Stem Cells & Development I Tarpon / Sawyer

9:00 am – 9:30 am Stem Cell-Based Models for Cardiovascular Development and Regeneration

Stephen Dalton, University of Georgia, Athens, GA, USA Tarpon / Sawyer

9:30 am – 10:30 am Stem Cells & Development I Tarpon / Sawyer

10:30 am – 11:00 am Tea & Coffee, Exhibition & Posters Banyan Breezeway

11:00 am – 12:00 pm Plenary Session: Stem Cells & Development II Tarpon / Sawyer

12:00 pm – 1:00 pm Lunch, Exhibition & Posters Garden Courtyard & Banyan Breezeway

12:00 pm – 1:00 pm Nomenclature Committee Meeting & Lunch Royal Tern

1:00 pm – 5:30 pm Free Time

5:30 pm – 6:30 pm Verne Chapman Lecture Why did C57BL/6J Win the Race and

How did it Facilitate Gonad Development Research

Bar Harbor, Maine, ME, USA Tarpon / Sawyer

6:30 pm – 8:00 pm Dinner and “Mentoring Dinner” Garden Courtyard

8:00 pm – 10:00 pm Poster Session II (Even Numbers) Banyan Breezeway


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Wednesday October 24, 2012

8:00 am – 5:30 pm Registration Open Registration Desk

7:00 am – 9:00 am Continental Breakfast Grand Palm Colonnade

9:00 am – 10:00 am Plenary Session: Large Scale Resources II Tarpon / Sawyer

10:00 am – 10:30 am Plenary Session: Aging & Adult-onset Disease Modeling Understanding Aging Through Genome Analysis Vadim Gladshev, Brigham & Women’s Hospital, Harvard Medical School

Tarpon / Sawyer

10:30 am – 11:00 am Tea & Coffee, Exhibition & Posters Banyan Breezeway

11:00 am – 11:30 am Plenary Session: Aging & Adult-onset Disease Modeling

Drugs that Slow Aging in Mice Rich Miller, University of Michigen,

Ann Arbor, MI, USA Tarpon / Sawyer

11:30 am – 12:30 pm Aging & Adult-onset Disease Modeling Tarpon / Sawyer 12:30 pm – 1:30 pm Lunch, Exhibition & Posters Garden Courtyard

& Banyan Breezeway

12:30 pm – 1:30 pm Secretariat Meeting Royal Tern

1:30 pm – 3:00 pm Plenary Session: Human Disease Modeling II Tarpon / Sawyer 3:00 pm – 4:00 pm IMGS Business Meeting Tarpon / Sawyer

4:00 pm – 4:30 pm Tea & Coffee, Exhibition & Posters Grand Palm Colonnade

4:30 pm – 5:30 pm Plenary Session: Human Disease Modeling III Tarpon / Sawyer

5:30 pm – 7:00 pm Free Time

7:00 pm – 11:00 pm Banquet and Awards Ceremony Breckenridge Pool Deck North


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SOCIAL PROGRAM

Welcome Reception and Dinner – TradeWinds Island Grand Resort, Garden CourtyardSunday October 21, 6.30pm – 8.30pm

The Welcome Reception & Dinner will be held at the meeting venue, theTradeWinds Island Grand Resort. The event is open to all delegates and is included in the registration fee.

Dress Code: Smart / Casual

Conference Dinner & Award Ceremony- TradeWinds Island Grand Resort, Breckenridge Pool Deck North Wednesday October 24, 7.00pm – 11.00pm

The conference farewell dinner will be an buffet dinner which will be held at TradeWinds Island Grand Resort. The event is open to all delegates and is included in the registration fee.

Dress Code: Smart / Casual


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IMGC PROGRAMSaturday, October 20, 20122.00pm - 6.00pm

IMGS Secretariat Meeting Chart Room

Sunday, October 21, 20128.00am - 7.00pm

Registration Open Registration Desk

9.00am - 12.00pm

Bioinformatics Workshop Tarpon

1.00pm - 3.15pm 1.00pm - 1.15pm 1.15pm - 1.30pm

1.30pm - 1.45pm 1.45pm - 2.00pm 2.00pm - 2.15pm

2.15pm - 2.30pm

2.30pm - 2.45pm 2.45pm - 3.00pm

Student Satellite Symposium Session 1 Chairs: David Beier and David Threadgill SO-1

Elizabeth Adams, University of Michigan, Ann Arbor, MI, USA SO-2 Characterizing the Role of the Ubiquitin Ligase Itch in C57BL/6J-ApcMin/+/J Gut Homeostasis and Intestinal Tumorigenesis Heather Mentrup, University of South Carolina, Columbia, SC, USA SO-3 Functional Analysis of the Opioid Receptor, Delta on Alcohol Metabolism Christine Rubinshteyn, North Carolina State University, Raleigh, NC, USA SO-4 Treatment of Ts65Dn Mice with Epigallocatechin Gallate Ameliorates the Abnormal Appendicular Skeletal Phenotype Caused by Trisomy

SO-5 Altered Enteric Neural Crest Cell Differentiation in the Postnatal Ganglionated Bowel of Sox10Dom/+ Hirschsprung Mouse Mutants Melissa Musser, Vanderbilt University, Division of Genetic Medicine and Center for Human Genetics Research, Nashville, TN USA SO-6 Characterization of an Allelic Variant of the Mechanistic Target of Rapamycin (Mtor), a Susceptibility Allele for Plasmacytoma Formation in BALB/cAnPt Mice

Lansing, MI, USA SO-7 Analysis of delta-like 1 (DLL1) in Adult Murine Islets Davide Cavanna, Institute of Experimental Genetics & German Center for Diabetes Research, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany SO-8

Mouse Strains Chen-Ping Fu, University of North Carolina, Chapel Hill, NC

Tarpon


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3.00pm - 3.15pm

SO-9 Collateral Damage: Spontaneous Mutations from a Targeted Knockout Programme Morag Lewis, Wellcome Trust Sanger Institute, Cambridge, UK

Tarpon

3.15pm - 3.45pm

Tea & Coffee Break Grand Palm Colonnade

3.45pm - 6.30pm 3.45pm - 4.00pm 4.00pm - 4.15pm

4.15pm - 4.30pm 4.30pm - 4.45pm 4.45pm - 5.00pm

5.00pm - 5.15pm

5.15pm - 5.30pm

5.30pm - 5.45pm

5.45pm - 6.00pm

Student Satellite Symposium Session 2 Chairs: David Threadgill and David Beier SO-10 In Silico Predictions of the Genomic Structure for Extant CC Lines Catherine Welsh, University of North Carolina, Chapel Hill, NC, USA SO-11

CDCA7L in Astrocytoma Min-Hyung Lee, Mouse Cancer Genetics Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA SO-12 Impaired Maternal Cardiovascular Adaptation to Pregnancy in HcB8 Mice

SO-13 Variation in Sperm Quality in Collaborative Cross Founder Strains and Extinct Lines Wenqi Pan, University of North Carolina, Chapel Hill, NC, USA SO-14 High Incidence of Skewed X Inactivation in Laboratory Mouse is a Byproduct of Domestication and Speciation

SO-15 Molecular and Histological Comparison of Pancreata from Adult Pax6leca2 Mutant Mice of Different Ages Daniel Gradinger, Institute of Experimental Genetics & German Center for Diabetes Research, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg/München, Germany SO-16 Serotonin Signaling in Neural Crest-Derived Progenitors in the Lower Urinary Tract Elaine Ritter, Division of Genetic Medicine, Vanderbilt University & Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA SO-17 The First Inbred Pig Line works as a New Large Mammal Model for Human Rong Zeng, University of Missouri, Columbia,MO, USA SO-18 Incompatibilities of the Prdm9 (Hst1) Gene in Mouse Hybrid Sterility Petr Flachs, Department of Mouse Molecular Genetics;; Institute of Molecular Genetics, Academy of Sciences CR, Prague, Czech Republic

Tarpon


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6.00pm - 6.15pm

6.15pm - 6.30pm

SO-19 The Collaborative Cross Mouse Population for Dissecting Host Susceptibility to Mixed Infection Inducing Alveolar Bone Loss Aysar Nashef, Department of Prosthodontics, Hadassah Medical Center,

University, Ramat Aviv, Israel SO-20 Transcriptomes of Mouse Olfactory Epithelium Reveal Sexual Differences in Odorant Detection Meng-Shin Shiao, Academia Sinica, Taipei, Taiwan

Tarpon

6.30pm – 8.30pm

Welcome Reception and Buffet Dinner Garden Courtyard

Monday, October 22, 20128.00am - 6.30pm


7.00am - 8.30am

Continental Breakfast Grand Palm Colonnade

8.30am - 8.45am

Welcome and Opening Comments Tarpon / Sawyer

8.45am - 10.30am

8.45am - 9.00am

9.00am - 9.15am

9.15am - 9.30am 9.30am - 9.45am 9.45am - 10.00am 10.00am - 10.15am

Plenary Session: Large Scale Resources 1 Chairs: Tim Wiltshire & Karlyne Reilly O-1 An Update from the Mouse Genomes Project Thomas Keane, Wellcome Trust Sanger Institute, Cambridge, UK O-2 Modernizing the Mouse Reference Assembly Deanna Church, Genome Reference Consortium, Bethesda, MD, USA O-3 Expression QTL mapping in the Diversity Outbread Mouse Population

O-4 The FANTOM5 Project - A Promoter Level Expression Atlas Alistair Forrest O-5 Optimizing High Throughput Sequencing Approaches for Spontaneous Mutation Discovery

O-6Genome-Wide Prediction of Copy Number Variation (CNV) in 162 Strains of Laboratory Mice and Large Scale Validation Using Sequence Capture and Massively Parallel Sequencing

Tarpon / Sawyer


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10.15am - 10.30am

O-7 The Mouse Mutant Resource: Genetic, Genomic and Phenotypic Characterization of Spontaneous Mutant Mice Arising at the Jackson Laboratory

Tarpon / Sawyer

10.30am - 11.00am

Tea & Coffee, Exhibition & Posters Banyan Breezeway

11.00am - 12.30pm 11.00am - 11.30am 11.30am - 11.45am 11.45am - 12.00pm

12.00pm - 12.15pm

12.15pm - 12.30pm

Plenary Session: Comparative Genomics Chairs: Steven Munger & Fernando Pardo-Manuel de Villena O-8 Genetics of Color Variation: Model Organisms in a Post-Genome World Greg Barsh, HudsonAlpha Institute & Stanford University, Huntsville, AL, USA O-9 The Role of X Chromosome in Regulation of Meiotic Recombination Rate

O-10 A High Precision Link Age Map of the Mouse: Sex, Strain and Prdm9 effects on Overall Recombination, Hotspots and Cold Regions

O-11 Genetic Reproductive Incompatibility on the Mouse Collaborative Cross David Aylor, University of North Carolina, NC, USA O-12 The Genetic and Transcriptomic Complexity of Olfaction in Mice Darren Logan, Wellcome Trust Sanger Institute, Cambridge, UK

Tarpon / Sawyer

12.30pm - 1.30pm

Lunch, Exhibition & Posters Garden Courtyard & Banyan Breezeway

12.30pm - 1.30pm

Mammalian Genome Editorial Board Lunch Royal Tern

1.30pm - 3.00pm 1.30pm - 1.45pm

1.45pm - 2.00pm

2.00pm - 2.15pm

Plenary Session: Advances in Genome Manipulation Chairs: Deanna Church & Yoichi Gondo O-13 Analysis of Mouse Whole exome Sequencing for mapping ENU Induced Single Nucleotide Variations (SNVs) Kart Tomberg, University of Michigan, Ann Arbor, MI, USA O-14

Application to inbred Mutagenized Mice

O-15 Informing Conditional Mutagenesis: The CrePortal

Tarpon / Sawyer

2.15pm - 3.00pm

Selected Student Talks x 3 (15 min) Tarpon / Sawyer


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3.00pm - 5.00pm

Poster Session I & Refreshments (Odd Numbers) Banyan Breezeway

5.00pm - 6.00pm 5.00pm - 5.15pm

5.15pm - 5.30pm

5.30pm - 5.45pm 5.45pm - 6.00pm

Plenary Session: Human Disease Modeling l Chairs: Karen Steel & Randall Roper O-16

Actr2 mutation as a novel suppressor of lethal thrombosis in the Factor V Leiden mouse Randal Westrick, University of Michigan, Ann Arbor, MI, USA O-17 The Ubiquitin Ligase WWP1 Impacts GJA1 turnover in the Heart Potentially Contributing to Sudden Cardiac Death Lydia Matesic, University of South Carolina, Columbia, SC, USA O-18 Lrp1 Plays an Essential Role in Craniofacial, Skeletal and Ventral Body Wall Development

O-19 A Focused Forward Genetic Screen for Abnormal Cortical Patterning

Lrp2 Mutant with Axon Guidance Defect Seungshin Ha, Brigham and Women’s Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA

Tarpon / Sawyer

6.30pm Dinner & Free Evening Garden Courtyard

Tuesday, October 23, 20128.00am - 6.30pm


7.00am - 9.00am


9.00am - 10.30am 9.00am - 9.30am 9.30am - 9.45am

9.45am - 10.00am

Plenary Session: Stem Cells & Development l Chairs: Xavier Montagutelli & Amy Lossie O-20 Stem Call-Based Models for Cardiovascular Development and Regeneration Stephen Dalton, University of Georgia, Athens, GA, USA O-21 Reversal of Female Infertility by Mutation of Chek2Meiotic DNA Damage Checkpoint

O-22 Transgenerational Epigenetic Effects of Apobec1 on Inherited Susceptibility to Testicular Germ Cell Tumors

Tarpon / Sawyer


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10.00am - 10.15am

10.15am - 10.30am

O-23 Epithelial Organizations were Defected during Seminal Vesicle and Vaginal Formation in a new Ctnnb1 Infertile Model Mouse

O-24 Differential Expression of Phox2b Marks Distinct Progenitor Populations in Enteric Nervous System Ontogeny Michelle Southard-Smith, Vanderbilt University, Nashville, TN, USA

Tarpon / Sawyer

10.30am - 11.00am

Tea & Coffee, Exhibition & Posters Banyan Breezeway

11.00am - 12.00pm 11.00am - 11.15am

11.15am - 11.30am

11.30am - 11.45am

11.45am - 12.00pm

Plenary Session: Stem Cells & Development ll Chairs: Teresa Gunn & Elena de la Casa-Esperon O-25 A Chromatin Remodeling Complex Member, Actl6aof Sox10 Neurocristopathy William Pavan, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA O-26 A Novel Rab18 Mouse Model of Warburg Micro SyndromeSarah Carpanini, MRC Human Genetics Unit, Edinburgh, UK O-27 Notchless Homolog 1 (Drosophila) Impacts Multiple Signaling Pathways During Pre-Implantation Development Chiao-Ling Lo, Purdue University, West Lafayette, IN, USA O-28 A Genetic Approach To Identifying Genes Regulating Gestation Time

Tarpon / Sawyer

12.00pm - 1.00pm


12:00pm – 1:00pm

Nomenclature Committee Meeting & Lunch Royal Tern

1.00pm - 5.30pm

Free Time

5.30pm - 6.30pm

Verne Chapman Lecture Chair: David ThreadgillWhy did C57BL/6J Win the Race and How Did it Facilitate Gonad Development Research?

Tarpon / Sawyer

6.30pm - 8.00pm

Dinner and Mentoring Dinner Garden Courtyard

8.00pm - 10.00pm

Poster Session ll (Even Numbers) Banyan Breezeway


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Wednesday, October 24, 20128.00am – 5.30pm


7.00am - 9.00am


9.00am - 10.00am 9.00am - 9.15am

9.15am - 9.30am

9.30am - 9.45am

9.45am - 10.00am

Plenary Session: Large Scale Resources ll Chairs: David Aylor & Darren Logan O-29 High-throughput Mutant Mouse Phenotyping is a Powerful Tool to Generate Novel Hypotheses

O-30 Moving Drug Development Forward: Validating in Vitro Assays Developed Using Genetically Diverse Mouse Inbred Cell Lines Tim Wiltshire, University of North Carolina, Chapel Hill, NC, USA

O-31 Systemic Analysis of Mouse Mutants at the German Mouse Clinic for Detecting Biomarkers of Human Diseases Martin Hrabé de Angelis, Chair of Experimental Genetics, Technische Universität München, Freising-Weihenstephan, Germany O-32 Case Studies of Metabolic Syndrome in the Diversity Outbred Mouse Population: A Gateway to Individualized Medicine?

Tarpon / Sawyer

10.00am - 10.30am

Plenary Session: Aging & Adult-onset Disease Modeling Chairs: David Beier & Linda Siracusa O-33 Understanding Aging Through Genome Analysis Vadim Gladshev, Brigham & Women’s Hospital, Harvard Medical School, Boston, USA

Tarpon / Sawyer

10.30am - 11.00am

Tea & Coffee, Exhibition & Poster Banyan Breezeway

11.00am - 12.30pm 11.00am - 11.30am 11.30am - 11.45am 11.45am - 12.00pm

Plenary Session: Aging & Adult-onset Disease Modeling Chairs: David Beier & Linda Siracusa O-34 Drugs That Slow Aging in Mice Rich Miller, University of Michigen, Ann Arbor, MI, USA O-35 The Harwell Ageing Mutant Screen Paul Potter, Mammalian Genetics Unit, MRC Harwell, Oxfordshire, UK O-36 Multi-scale Congenic Analysis Provides Insight into the Complex Genetic Architecture of Diet-Induced Obesity David Buchner, Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA

Tarpon / Sawyer


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12.00pm - 12.15pm 12.15pm - 12.30pm

O-37 Germline Genetic Variation Modulates Tumor Progression and Metastasis in a Mouse Model of Neuroendocrine Prostate Carcinoma Nigel Crawford, NHGRI/NIH, Bethesda, MD, USA O-38

Dissemination in Human Breast Cancer Patients Kent Hunter, National Cancer Institute, NIH, Bethesda, MD, USA

Tarpon / Sawyer

12.30pm - 1.30pm


12.30pm - 1.30pm

Secretariat Meeting Royal Tern

1.30pm - 3.00pm 1.30pm - 1.45pm

Plenary Session: Human Disease Modeling ll Chairs: Nigel Crawford & Klaus Schugart O-39 Mouse Disease Models and Functional Evaluation of Human Variants Miriam Meisler, University of Michigan, Ann Arbor, MI, USA

Tarpon / Sawyer

1.45pm - 2.00pm

2.00pm - 2.15pm 2.15pm - 2.30pm 2.30pm - 2.45pm 2.45pm - 3.00pm

O-40 A Mouse Genetics Approach to Understanding the Pathogenesis of Spongiform Encephalopathy Teresa Gunn, McLaughlin Research Institute, Great Falls, MT, USA O-41 Icst is a Dominant Negative Mutation of Lmx1b Sally Cross, MRC Human Genetics Unit, Edinburgh University, Edinburgh, UK O-42 Multiple Phase Analysis Revealed Different QTL Associated with Host Response During Klebsiella pneumonaie Infection in Collaborative Cross Mouse Reference Population Fuad Iraqi, Tel-Aviv University, Israel O-43

Karlyne Reilly, National Cancer Institute, Frederick, MD, USA O-44 Hypothyroidism Induces Deafness in Susceptible Strains: Hunt for the Protective Gene Sally Camper, University of Michigan, Ann Arbor, MI, USA

3.00pm - 4.00pm

IMGS Business Meeting (ALL encouraged to participate) Tarpon / Sawyer

4.00pm - 4.30pm

Tea & Coffee, Exhibition & Posters Grand Palm Colonnade


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4.30pm - 5.30pm 4.30pm - 4.45pm

4.45pm - 5.00pm 5.00pm - 5.15pm

5.15pm - 5.30pm

Plenary Session: Human Disease Modeling lll Chairs: Linda Siracusa & Klaus Schugart O-45 MtorProduction and Humoral Response to Bacterial Infection Beverly Mock, NCI, NIH, Bethesda, MD, USA O-46 Susceptibility and Resistance Loci for Benzene Genotoxicity

O-47 Resistance to Plague of Mus spretus SEG/Pas Mice Requires the Combined Action of at Least Four Genetic Factors Xavier Montagutelli, Institut Pasteur, Paris, France O-48 Host Directed Therapy Against the Malarial Parasite Gaetan Burgio, Macquarie University and Menzies Research Institute Tasmania, University of Tasmania, Australia

Tarpon / Sawyer

5.30pm - 7.00pm

Free Time

7.00pm Conference Banquet & Awards Dinner Breckenridge Pool Deck North


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COMMITTEES

Local OrganizersTeresa M. GunnMichelle Southard-Smith

David Threadgill - President Karen Steel - Past President David Beier - Vice-President

Terms through 2012 meeting: Simon Foote Xavier Montagutelli

Terms through 2013 meeting: Piero Carninci Teresa Gunn Steven Munger (VM Chapman Award Winner)

Terms through 2014 meeting: Klaus Schughart Linda Siracusa TBD (VM Chapman Award Winner)

IMGC Business ManagerDarla Miller

Nomination and Election CommitteeMorag LewisAmy LossieTim WiltshireSally CrossBruce HerronWilliam Pavan

Committee on Standardized Genetic Nomenclature for Mice

Ruth ArkellPiero CarninciSally CrossDeanna Church

Simon Foote

Teresa GunnMonica McAndrewsAmy Moser

David Threadgill

Tim WiltshireWolfgang Wurst


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GENERAL INFORMATION

Insurance The Conference Organisers cannot accept any liability for personal injuries or for loss or damage to property belonging to delegates, either during, or as a result of the meeting. Please check the validity of your own personal insurance before travelling.

Meeting EtiquetteDelegates are advised that they are not allowed to take photographs of any posters or presentations without the author’s/presenters consent. Delegates should also obtain consent from an author before citing any of their work that was presented at the conference

Cell phones should be switched off or placed on ‘silent’ during sessions. Please also respect speakers and other delegates and refrain from talking during presentations. Thank you for your co-orperation.

Internet Access

organised for free access in both the meeting rooms and exhibition areas exclusively for all delegates. Please see the notice board for login details.

CateringTea and coffee will be served in the Banyan Breezeway during which you will have the time to view the posters and exhibition. Lunch will be served in the Garden Courtyard.

If you have requested a special diet at the time of registering (other than vegetarian), then your name badge will have a sticker on the back which you should show to the catering staff who will bring you your pre-ordered food.

Please note no lunch will be provided for the Student Satellite Symposium on Sunday. Exhibition Opening HoursMonday October 22 08.00hrs – 18.30hrsTuesday October 23 08.00hrs – 18.30hrsWednesday October 24 08.00hrs – 16.30hrs

Posters Posters will be available for viewing from 9.00am on Monday October 22 and for the remainder of the meeting during normal opening hours. Posters can be removed from 4.30pm on Wednesday October 24. Authors will be by their boards to discuss their poster at the following times.

Poster TimesOdd Poster Numbers Poster Session 1 Monday, October 22 3pm – 5pmEven Poster Numbers Poster Session 2 Tuesday, October 23 8pm – 10pm

Registration/Information DesksAll delegates will receive their name badge, meeting documents and all relevant meeting information upon arrival at the registration desk at TradeWinds.

The Registration and Information Desks will be open at the following times:

Sunday October 21 08.00hrs – 19.00hrsMonday October 22 08.00hrs – 18.30hrsTuesday October 23 08.00hrs – 18.30hrsWednesday October 24 08.00hrs – 17.30hrs

Speaker Presentation Check In Presenters must bring their presentation on a USB to the conference.

Presenters do not need to bring a laptop as presentations will be loaded onto a main computer in the session room.


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AWARDS

The Secretariat and members of The International Mammalian Genome Society are proud of the students, postdoctoral fellows and junior faculty who present oral and poster presentations at the annual meeting. The outstanding contributions of these young scientists are recognized through several awards.

presentation from a postdoctoral fellow or student. This is a monetary award of $500 and a two year position on the IMGS secretariat year by The Genetics Society of America.

A selection of publishing companies have sponsored this year’s presentation prizes, which are a one year subscription to their journal. genesis is donating 5 books. These awards are given to the most outstanding poster or oral presentations by graduate students and postdoctoral fellows, and are chosen by members of the IMGS Secretariat and other judges during the course of the meeting. This year the sponsors are:

Genetics Research from: Nature, Nature Genetics and Nature Reviews Genetics from:

Mammalian Genome from:

Genetics from:

STUDENT SCHOLARSHIPSFunding for student scholarships was made possible by: 2R13HG002394 from NHGRI and NICHD at NIH and from Mouse News Letter, Ltd.

Student Satellite Symposium Oral Presentation Abstracts

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EXHIBITORS/ SPONSORS

The international Mammalian Genome Society would like to thank the following exhibitors and sponsors for their support:


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Sunday October 21Student Satellite Symposium Oral Presentation

Abstracts


– 21 –

SO-1/P-2

DEFINING THE ROLES OF MOUSE COPII COMPONENTS SEC24C AND SEC24D

Elizabeth Adams1, David Ginsburg1 ,2, Andrea Baines1 1University of Michigan, Ann Arbor, MI, USA, 2Howard Hughes Medical Institute, Ann Arbor, MI, USA

SEC24 is the COPII component thought to be primarily responsible for the recruitment of transmembrane cargoes or cargo adaptors into newly forming COPII vesicles on the ER membrane. Mammalian genomes encode four Sec24 paralogs (Sec24a-d)sequence, SEC24A/B are more closely related to one another than they are to SEC24C/D. All four paralogs are broadly expressed, and co-immunoprecipitations indicate that all four SEC24 paralogs interact with both paralogs of the SEC24 binding partner SEC23 (SEC23A/B) at relatively equivalent ratios.

To address the in vivo

gene-trap allele exhibit early embryonic lethality. Embryonic lethality in Sec24d gene-trap homozygotes is rescued by the introduction of a BAC transgene spanning the Sec24d gene.

An allele for murine Sec24cgene-trap cassette insertion in intron 2, as well as LoxP sites around exon 3. Mice homozygous for the gene-trap allele exhibit early embryonic lethality. Removal of exon 3 by Cre creates a null allele. A detailed characterization of mice homozygous for the null allele (Sec24c-/-) is ongoing.

It is evident from our experiments that SEC24C and SEC24D are critical for survival;; current studies are also underway examining the potential overlap in function between SEC24C/D by transgenic rescue experiments.

SO-2/P-38

CHARACTERIZING THE ROLE OF THE UBIQUITIN LIGASE Itch IN C57BL/6J-APCMIN/+/J GUT HOMEOSTASIS AND INTESTINAL TUMORIGENESIS

Heather Mentrup, Elizabeth Thames, Wassim Basheer, Margeaux Wetendorf, Lydia E. Matesic University of South Carolina, Columbia, SC, USA

The importance of HECT-family E3 ubiquitin ligases in the initiation and progression of cancer is emphasized by the numerous tumor suppressor proteins regulated by this family. One member in particular, Itch, has been implicated in carcinogenesis. Various cancer cell lines have altered ITCH expression, and its down regulation in cells sensitizes them to chemotherapeutic agents. ITCH expression is also upregulated in anaplastic thyroid carcinoma, as well as in bladder, breast, and colorectal cancer. This led us to hypothesize that Itch may be important in normal gut homeostasis and its dysregulation contributes to altered tumor suppressor half life, changes in the cell cycle, and colorectal tumorigenesis. In

ApcMin/+ ApcMin/+) mice, we detected elevated Itch expression. Treatment of ApcMin/+ Itch expression. Animals lacking Itch and carrying the ApcMin/+ mutation had a 70-80% reduction in tumor burden as compared to ApcMin/+ littermates with wild type levels of Itch Itcha18h/a18h/Ncif (Itch-/-) and Itch-/-;; Apc Min/+ animals suggested increased proliferation primarily in the lamina propria. These animals also had increased differentiation of secretory cell lineages, most notably goblet cells. Future experimentation will be directed toward elucidating the molecular mechanism underlying how precise levels of Itch regulate epithelial homestasis in the gut. Increased expression of Itch in tumor tissue as well as its transcriptional downregulation by 5-FU suggest that this ligase may be a potential therapeutic target in the treatment of colorectal cancer.


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SO-3/P-54

FUNCTIONAL ANALYSIS OF THE OPIOID RECEPTOR, DELTA 1 ON ALCOHOL METABOLISM

Christine Rubinshteyn1, David Aylor2, Wendy Foulds-Mathes2, Darla Miller2, Daniel Pomp2, Fernando Pardo-Manuel de Villena2, David Threadgill1 1North Carolina State University, Raleigh, NC, USA, 2University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Identifying genetic variants that contribute to differential rates of alcohol clearance is fundamental to understanding how one may respond to ethanol’s action on the body and one’s inherit risk for alcohol abuse. We have analyzed pre-

trait analysis, to identify functional candidate genes for blood alcohol clearance (BAC) rates. Alcohol concentrations were measured in serial blood draws from which BAC rates were calculated for males from both the preCC population and founder strains. Phenotypic distribution for BAC rates in preCC mice (0-677 mg/kg/hr;; n = 192) combined with that from founder strains (10-239 mg/kg/hr) provided a continuous trait distribution. Genome-wide association mapping

receptor, delta 1 (Oprd1alcoholism. In Oprd1-/-

same mice. The functional data implicates Oprd1 as a QTL with an unexpected metabolic role in alcohol metabolism. Initial mechanistic investigation of Oprd1 on hepatic alcohol metabolism suggests that decreases in cellular antioxidant capacity may play a role.

SO-4/P-7

TREATMENT OF Ts65Dn MICE WITH EPIGALLOCATECHIN GALLATE AMELIORATES THE ABNORMAL APPENDICULAR SKELETAL PHENOTYPE CAUSED BY TRISOMY

Indiana University Purdue University Indianapolis, Indianapolis, IN, USA

Down syndrome (DS), caused by trisomy 21, results in abnormal skeletal phenotypes including altered adolescent growth, shortened stature, reduced bone mineral density and increased incidence of osteoporosis. The Ts(1716)65Dn aka Ts65Dn mouse model of DS has segmental trisomy of mouse Chromosome 16, containing homologs to nearly half of the genes on human chromosome 21. Ts65Dn mice exhibit skeletal abnormalities including lower BMD, altered trabecular bone microstructure, and reduced bone formation. DYRK1A, found in three copies in humans with DS and Ts65Dn mice, is a kinase critical in the activation of several developmental pathways and is hypothesized to be involved in the abnormal DS skeletal phenotype. Dyrk1a overexpressing transgenic mice exhibit severe bone abnormalities similar to those observed in Ts65Dn mice. Epigallocatechin Gallate (EGCG), the most prevalent green tea polyphenol, is a potent inhibitor of DYRK1A and treatment with EGCG corrects neurological function in Dyrk1a overexpressing transgenic mice. We hypothesize that the inhibition of excess DYRK1A activity will ameliorate the Ts65Dn appendicular skeletal phenotype. Treatment of Ts65Dn mice with EGCG positively impacted the trisomic femoral phenotype including

compared to untreated Ts65Dn mice. Furthermore, EGCG treated Ts65Dn mice exhibited similar percent trabecular bone volume and trabecular thickness, number, and separation when compared to untreated euploid mice. These results suggest that increased Dyrk1a expression contributes to the abnormal Ts65Dn femoral phenotype and treatment with a


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SO-5/P-41

ALTERED ENTERIC NEURAL CREST CELL DIFFERENTIATION IN THE POSTNATAL GANGLIONATED BOWEL OF Sox10DOM/+ HIRSCHSPRUNG MOUSE MUTANTS

Melissa Musser1 ,2 2, E. Michelle Southard-Smith2 ,3 1Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA, 2Genetic Medicine, Vanderbilt University, Nashville, TN, USA, 3Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA

length of distal intestine. In humans, mutations in SOX10, GDNF, RET, EDNRB, and EDN3 have been associated with this disease. First line of treatment for patients with HSCR is surgical removal of the aganglionic portion of the bowel followed by reanastomosis of ganglionated bowel to the anus. Unfortunately, many patients suffer from post-surgical complications that do not appear iatrogenic, such as enterocolitis and chronic constipation. These observations in patients suggest that HSCR may alter the enteric nervous system (ENS) in the ganglionated, proximal bowel. In vitro and in vivo studies in various strains of the Sox10Dom/+ HSCR mouse model also suggest that neural crest cells (NCC) in this HSCR mutant undergo inappropriate differentiation. We therefore hypothesize that aberrant lineage segregation and differentiation of NCC in the ganglionated intestine contribute to the chronic disease suffered by HSCR patients. To test this hypothesis, we have begun fate-mapping NC-derived lineages in postnatal (P17-P20) Sox10Dom/+ mutants. Our

more prevalent in Sox10Dom/+ mutants compared to wild type littermates. Additionally, aberrant expression of glial cell

percentages of neuronal subtypes within Sox10Dom/+ enteric ganglia in the proximal intestine. Disruption of neural crest derived lineages in Sox10Dom/+ mutants could readily explain altered gut motility.

SO-6/P-22

CHARACTERIZATION OF AN ALLELIC VARIANT OF THE MECHANISTIC TARGET OF RAPAMYCIN (Mtor), A SUSCEPTIBILITY ALLELE FOR PLASMACYTOMA FORMATION IN BALB/cAnPT MICE

1 ,2, Shuling Zhang1, Ke Zhang1, Dena Tran1, Aleksandra Michalowski1, Beverly Mock1 1CCR, NCI, NIH, Bethesda, MD, USA, 2Michigan State University, East Lansing, MI, USA

The PI3K/AKT/MTOR pathway is frequently dysregulated in cancer and often involves activation of growth factor receptor pathways, mutations, Pten loss, and Akt Mtor are relatively rare. Our lab discovered an allelic variant of Mtor (C1977T) in BALB/cAnPt mice, which predisposes these mice to the development of pristane-induced plasmacytomas (PNAS 100:14982), serving as a model of B-cell carcinogenesis. We recently developed a knock-in (KI) mouse by homologous recombination that carries the BALB/c allele (Mtortm1.1Lgm) of Mtor (Blood 117:1228). To explore the possible mechanisms for plasmacytoma susceptibility associated with this allele, we compared microRNA and mRNA expression in B220+ splenocytes from wild-type (WT) and Mtortm1.1Lgm/ Mtortm1.1Lgm KI mice using Nanostring and Affymetrix arrays, respectively. mRNA expression in bone marrow was also compared between

compared to WT, including Mir30a (2-fold), Mir101a-c (3-fold), and Mir423 (1.5-fold). Each of these miRs are associated with the Mtor pathway. In the Affymetrix array, 181 genes were differentially expressed in B220+ splenocytes of KI mice,

differentially expressed genes overlapped between B220+ splenocytes and bone marrow. Several overlapping genes are in functional categories involving hematological system development, hematopoiesis, and PI3K signaling.


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SO-7/P-15

ANALYSIS OF DELTA-LIKE 1 (DLL1) IN ADULT MURINE ISLETS

Davide Cavanna1 ,2, Daniel Gradinger1 ,2, Gerhard K. H. Przemeck1 ,2, Martin Hrabé de Angelis1 ,2 1Institute of Experimental Genetics, Neuherberg, Germany, 2German Center for Diabetes Research, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany, 3Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany

The Notch signaling pathway is a key player in a wide range of evolutionarily conserved developmental processes.

in mammals) with a transmembrane receptor on another cell (NOTCH 1-4), followed by receptor proteolysis and the consequent release of a soluble fragment that participates directly in transcriptional regulation. While the Notch pathway is an established major player in pancreatic endocrine development, its role in the adult organ is less clear.

We analyzed the expression of all pathway components in the murine pancreas via qRT-PCR on isolated islets and extensive immunohistological analysis, hereby identifying a clear localization of DLL1 to the insulin-producing beta-cells.

Dll1 ) was bred and inspected. Isolated islets from these mice were examined ex vivo in a whole genome transcriptomics approach and revealed differences in the gene expression network compared to wildtype controls. Furthermore, the islet physiology of the Dll1-bKO appeared altered in immunohistological analyses. The metabolic phenotype was analyzed in vivo both on a standard diet and on a high fat diet.

Taken together, a role for Dll1 in adult pancreatic beta-cell homeostasis is hypothesized.

SO-8/P-21

AN ONLINE RESOURCE FOR CERTIFICATION OF GENOMIC COMPOSITION OF MUTANT MOUSE STRAINS

Chen-Ping Fu University of North Carolina, Chapel Hill, NC, USA

We have developed an online tool for assessing the genomic composition of mutant mouse strains distributed by the Mutant Mouse Regional Resource Centers (MMRRC). Using genotypes from the 7.5K Mouse Universal Genotyping

- typically the original strain carrying the genetically engineered construct or mutation and an additional backcross strain. Our approach compares the target sample’s genotyping probe intensities to a cluster model derived from intensities of the background strains, pooling information from multiple replicates when available. A unique contribution of our approach is that when only one sample of a background strain is available, we pool other MUGA samples locally to construct a more robust statistical model. Using a dynamic programming algorithm, we assign the most probable background strain at each locus with the aim of minimizing the difference in target and background strain intensities. Regions where the target

contamination from non-background strains. Using the Mouse Genome Informatics database, we locate and indicate the target locus, as well as the genomic segment most likely to contain the engineered construct or mutation. We plan to extend our tool to MUGA’s successor, the medium density genotyping array MegaMUGA. The ten-fold density increase


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SO-9/P-35

COLLATERAL DAMAGE: SPONTANEOUS MUTATIONS FROM A TARGETED KNOCKOUT PROGRAMME

Morag Lewis

Wellcome Trust Sanger Institute, Cambridge, UK

The Sanger Institute’s Mouse Genetics Project (MGP) aims to generate knockout mice and characterise the effect of the null allele using a broad spectrum of phenotyping tests. One of these is the Auditory Brainstem Response, a sensitive test capable of detecting subtle hearing defects. During standard phenotyping, several mice were found which displayed a variety of hearing defects which did not segregate with the knockout allele, and were probably due to spontaneous mutations. DNA from four of these lines was sent for array CGH and whole exome sequencing, along with DNA from the embryonic stem cell lines used to make the knockout alleles. The mutations from two of the lines have also been mapped using a backcross.

The results show a background of mutations present in ES cells, many common to both cell lines. Mapping has proven effective in identifying which of the mutations was responsible for the rapid progressive hearing loss seen in one of the

S1pr2, a gene known to be important for hearing. We are currently

to several MGP mouse lines.

The Mouse Genetics Project has proven to be a highly informative resource, combining the advantages of reverse and forward genetics to discover new disease genes. These mutations, with their intriguing phenotypes, are an unexpected

SO-10/P-68

IN SILICO PREDICTIONS OF THE GENOMIC STRUCTURE FOR EXTANT CC LINES

Catherine Welsh1, Darla Miller1, Kenneth Manly1 1, Leonard McMillan1, David Threadgill2, Fernando Pardo-Manuel de Villena1 1University of North Carolina, Chapel Hill, NC, USA, 2North Carolina State University, Raleigh, NC, USA

Extant strains from the Collaborative Cross (CC) panel of recombinant inbred lines are nearing completion and are now

their development. We have created a novel set of tools and online resources that characterize the genomes of each available CC line. This is in contrast to previous analyses that we have presented, which characterized the genome of a

and derived haplotype reconstructions of this obligate ancestor set are jointly considered to establish an upper bound on the residual heterozygosity of a developing line. If lines satisfy the required thresholds for distribution, we generate

still segregating. As the CC line continues to develop via imposed breeding bottlenecks and subsequent genotyping

genotypes, and other pertinent information about each distributable lines are available at http://csbio.unc.edu/CCstatus/. Also available at this website are tools for ordering lines, downloading genotypes, and viewing the genomes. We also provide tools for analyzing the genomes of other publicly available CC samples.


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SO-11/P-34

THE POTENTIAL MALE-SPECIFIC ONCOGENIC FUNCTION OF CDCA7L IN ASTROCYTOMA

Min-Hyung Lee1 1, Karl Broman2, Karlyne Reilly1 1Mouse Cancer Genetics Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA, 2Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA

The most common types of primary CNS tumors, astrocytoma and glioblastoma multiforme (GBM), are currently incurable. Both astrocytoma and GBM show male predominance, with a male-to-female ratio of 1.31:1 and 1.26:1, respectively. Previously, our lab demonstrated that astrocytoma/GBM tumorigenesis in the Nf1-/+ Trp53-/+cis (NPcis) mouse model shows gender bias in certain genetic contexts. Using linkage analysis in the NPcis mouse, we have

Arlm1. We used combinatorial bioinformatic approaches and cross-species comparisons to identify CDCA7L/Cdca7l as a strong candidate for a male-

CDCA7L in astrocytoma/GBM, we analyzed CDCA7L/Cdca7l in both human and mouse astrocytoma cell lines in both genders. CDCA7L expression was up-regulated in astrocytoma cells compared to normal brain, with males showing higher levels than females in astrocytoma cells. shRNA-mediated CDCA7L/Cdca7l depletion in male-derived astrocytoma cells led to decreased growth and viability in both human and mouse. Further mechanistic studies showed that CDCA7L depletion in male-derived astrocytoma cells led to the induction of caspase 3 activation and reduction of cyclin D1 expression, suggesting the oncogenic role of CDCA7L in astrocytoma/GBM. On the other hand, CDCA7L overexpression in female-derived astrocytoma cells showed less of an effect on proliferation and viability. Strikingly, CDCA7L depletion in human female U87MG cells caused increase of both growth and viability opposite to what is seen in male cells. These data highlight the importance of CDCA7L in

SO-12/P-32

IMPAIRED MATERNAL CARDIOVASCULAR ADAPTATION TO PREGNANCY IN HcB8 MICE

University of Wisconsin-Madison, Madison, WI, USA

Preeclampsia, fetal loss and intrauterine growth restriction (IUGR) are common pregnancy complications Recombinant congenic mice HcB8 (aka HcB-8) and HcB23 (aka HcB-23) have differences in BP, litter size, birth weight, and frequency of fetal loss. Non-pregnant HcB8 females have higher blood pressure than HcB23 (116 ± 7/90 ± 4 v 103 ± 3/75 ± 3, p =0.016 (systolic)/p= 0.007 (diastolic)). This disparity of blood pressure is similar to that seen in males. HcB8 litters are smaller than HcB23 litters (4.4 + 1.8 v -3) and HcB8 pups are lighter at birth (1.2 + 0.2 g v 1.5 + 0.2 g, p

-20). Furthermore, HcB8 females experience higher rate of pregnancy loss (PL) (5 PL/7 dams v 1 PL/8 dams, p= 0.04)

may be the contributing factor. Pregnant HcB8 females harvested at 17.5 dpc have smaller placental weight than HcB23 17.5 dpc females (0.085 ± 0.006 v 0.10 ± 0.010, p =0.010) but HcB8 have larger fetal to placental ratio than HcB23 (9 ± 1 v 6 ± 0.5, p = 0.009). Pregnant HcB8 females also have larger fractional heart sizes than HcB23 (0.006 ± 0.0007 v 0.004 ± 0.0003, p=0.001). Non-pregnant HcB8 females expressed nearly ~5 fold higher brain natriuretic peptide, a marker for


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SO-13/P-45

VARIATION IN SPERM QUALITY IN COLLABORATIVE CROSS FOUNDER STRAINS AND EXTINCT LINES

Wenqi PanFernando Pardo-Manuel de Villena, Deborah O’Brien University of North Carolina at Chapel Hill, Chapel Hill,NC, USA

To assess contributions of male reproductive parameters to the extinction of 85% of Collaborative Cross (CC) lines initiated as part of the US population, we phenotyped a representative male from the last generation of 348 extinct lines and determined their fertility, reproductive organ weights, testis histology, sperm counts, sperm morphology and

have higher percentages of sperm with normal morphology and more vigorous motility than other founder strains

slow and weak motility immediately after isolation. Males from extinct CC lines (184 fertile, 164 infertile) displayed a much broader distribution of sperm morphology and motility parameters than founder males. The median percentage of progressive motility was higher in fertile males from extinct lines, while the median percentage of weak motility was higher in the infertile males. QTL analysis based on the genotypes of these 348 males indicated that VCL is associated

associated with higher sperm velocities.

SO-14/P-12

HIGH INCIDENCE OF SKEWED X INACTIVATION IN LABORATORY MOUSE IS A BYPRODUCT OF DOMESTICATION AND SPECIATION

1, Alan B Lenarcic1 1 2, William Valdar1, Fernando Pardo-Manuel de Villena1 1University of North Carolina, Chapel Hill, NC, USA, 2Cornell University, Ithaca, NY, USA

X-chromosome inactivation (XCI) is the mammalian mechanism of dosage compensation that balances X-linked gene expression between the sexes. During early female embryogenesis, each epiblast cell independently chooses to transcriptionally inactivate one parental X-chromosome. In mouse, X-inactivation choice is affected by the genotype of a cis-acting locus, the X chromosome controlling element (Xce). Xce has been localized to a 1.9Mb interval within the X-inactivation center (Xic), yet its molecular identity and mechanism of action remain a mystery. We have leveraged recently released genotype and sequence data for mouse stocks with Xce phenotyping information and developed a statistical model that incorporates phenotype data from multiple genes and tissues to disentangle sources of XCI phenotypic variance in natural female populations. We reduced the Xce candidate interval to a 200kb region located ~500kb proximal to Xist Xceheterozygous females. Phylogenetic analysis of 290 inbred strains and wild mice revealed three Xce haplotypes in the M. m. domesticus subspecies. One haplotype is only associated with the Xcea allele and exclusive to classical inbred strains, while the other haplotypes are found both in the wild and in inbred strains. We conclude that Xcea is a derived allele and arose concurrent or shortly after the domestication of fancy mice in the early 20th century. Furthermore, we discovered an evolutionary paradox where each mouse taxon has a different functional Xce allele, yet there is no evidence of intra-taxa functional variation in the wild.


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SO-15/P-24

MOLECULAR AND HISTOLOGICAL COMPARISON OF PANCREATA FROM ADULT PAX6LECA2 MUTANT MICE OF DIFFERENT AGES

Daniel Gradinger1 ,2, Davide Cavanna1 ,2, Gerhard K.H. Przemeck1 ,2, Martin Hrabé de Angelis1 ,2 1Institute of Experimental Genetics, Neuherberg/München, Germany, 2German Center for Diabetes Research, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg/München, Germany, 3Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany

The transcription factor PAX6 contains two DNA-binding domains, a homeodomain and a paired-box domain, and plays

of differentiated endocrine cells in the pancreas. Mutations in the human PAX6 gene were reported to be associated with early onset diabetes. Pax6Leca2 (mouse strain C3H;;C-Pax6Leca2/H) mice, containing an amino-acid substitution in the paired-box domain (a highly conserved arginine is substituted by a cysteine), are homozygous viable and survive to adulthood, which allows us to dissect the role of PAX6 binding domains in development and maintenance of the pancreas.

SO-16/P-53

SEROTONIN SIGNALING IN NEURAL CREST-DERIVED PROGENITORS IN THE LOWER URINARY TRACT

Elaine Ritter2 ,3, Dennis Buehler1 ,2, Sara Ireland1 ,2, Michelle Southard-Smith1 ,2 1Department of Medicine, Vanderbilt University, Nashville, TN, USA, 2Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA, 3Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA

Serotonin (5-HT) signaling is critical for development of the peripheral nervous system. Signaling through 5-HT receptors is required for multipotent progenitors to migrate from the neural crest (NC) and form enteric neurons and glia of the fetal intestine. NC-derived progenitors also give rise to the autonomic innervation of the lower urinary tract (LUT), but there is

in pelvic ganglia of the mouse, but the role of 5-HT in the development and function of the LUT remains unknown. We

detect exonic sequences of each Htr gene family member. Reverse-transcription PCR from fetal mouse urogenital tract cDNA harvested at 15 days post coitus

Htr gene expression is being pursued via in situ hybridization and immunohistochemical approaches. Overall, these experiments will shed light on the role of 5-HT signaling in the neural development and function of the bladder and LUT in mice.


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SO-17/P-75

THE FIRST INBRED PIG LINE WORKS AS A NEW LARGE MAMMAL MODEL FOR HUMAN

Rong Zeng1, Yangzhi Zeng1 ,2 1 ,2, Weirong Pan1 1University of Missouri, Columbia,MO, USA, 2Yunnan Agriculture University, Kunming,Yunnan, China

who set off in 1980 to produce 20 consecutive brother-sister and/or parent-offspring matings, similar to the strategy used

99.6%. To date, more than 30 substrains with different phenotypes and genetic disorders have been formed. Due to the high homozygosity of the genetic background and diversity of phenotypes in the various substrains, BMI has become a

genomics and species evolution. In addition, to provide novel inbred pig lines for bimedical and biomaterial research

SO-18/P-20

INCOMPATIBILITIES OF THE Prdm9 (Hst1) GENE IN MOUSE HYBRID STERILITY

Petr Flachs1, Ondrej Mihola1, Yasuhisa Matsui2 3, Frédéric Baudat4, Bernard de Massy4Piálek5 1, Zdenek Trachtulec1 1Department of Mouse Molecular Genetics;; Institute of Molecular Genetics, Academy of Sciences CR, Prague, Czech Republic, 2Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan, 3Center for Vertebrate Genomics, Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, USA, 4Institut de Genetique Humaine, CNRS UPR 1142, Montpellier, France, 5Institute of Vertebrate Biology, Academy of Sciences CR, Brno and Studenec, Czech Republic

Disturbed gametogenesis in the progeny of two fertile parental forms is called hybrid sterility;; it is an important part of reproductive barriers between species. The Dobzhansky-Muller model of incompatibilities explains reproductive isolation between species by incorrect interactions between genes. Although the mechanisms of speciation are of great interest, no incompatibility has been characterized at the gene level in mammals. Hybrid sterility 1 (Hst1) is one of the genes causing meiotic arrest in F1 male hybrids between certain Mus musculus musculus (e.g., the PWD strain) and M. m. domesticus Hst1

Prdm9, but the mechanism causing sterility has remained unknown. While the F1 male offspring of B6 males and PWD females produce no sperm, the males from the reciprocal cross using PWD males and B6 females yield progeny. To characterize hybrid sterility, we phenotyped reproductive and meiotic markers

Prdm9. The meiotic progress and fertility of hybrid males from both reciprocal F1 crosses improved by removal as well as overexpression of the B6 allele of Prdm9, suggesting that dominant-negative Prdm9B6 interactions not present in the parental species (incompatibilities) play a role in hybrid sterility. Incompatibility(ies) not involving Prdm9B6 also acts in the (PWD x B6)F1 hybrids, because the rescue of hybrid fertility by Prdm9B6 deletion was not complete.


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SO-19/P-42

THE COLLABORATIVE CROSS MOUSE POPULATION FOR DISSECTING HOST SUSCEPTIBILITY TO MIXED INFECTION INDUCING ALVEOLAR BONE LOSS

Aysar Nashef1 ,2, Yaser Salaymeh2, Ariel Shusterman1, Richard Mott3, Caroline Durrant3, Ervin Weiss1, Yael Houri-Haddad1, Fuad A. Iraqi2 1Department of Prosthodontics, Hadassah Medical Center, Jerusalem, Israel, 2Departmentof Clinical Microbiology and Immunology, Tel Aviv University, Ramat Aviv, Israel, 3Wellcome Trust Human Genome Centre, Oxford University, Oxford, UK

environmental factors. Here, we initiated study aimed at mapping and subsequently identifying the host susceptibility genes to experimental periodontitis in a high genetically diverse mouse resource population, the Collaborative-cross (CC). In total, 1021 mice of 111 lines were tested. (On average, 5 mice per line used for challenge and 5 for control).

Porphyromonas gingivalis and Fusobacterium nucleatum. 42 days

Currently, we have completed the phenotype analysis of 618 mice (74 lines). ANOVA results showed some lines out of

sense heritability of the bone volume trait of naïve mice and bone loss volume of mice due to infections was estimated and found to be 0.84 and 0.77, respectively. Initial QTL mapping was conducted on 54 lines using HAPPY software, and number of QTL associated with naïve, residual (differences between naïve and infected) and proportion (residual/

periodontitis is a complex trait and controlled by polygenetic factors and CC population is a powerful tool for dissecting this trait.

SO-20/P-58

TRANSCRIPTOMES OF MOUSE OLFACTORY EPITHELIUM REVEAL SEXUAL DIFFERENCES IN ODORANT DETECTION

Meng-Shin Shiao1, Andrew Ying-Fei Chang2, Yung-Hao Ching3, Ben-Yang Liao2 1, Stella Maris Chen1, Wen-Hsiung Li1 ,4 1Academia Sinica, Taipei, Taiwan, 2National Health Research Institutes, Miaoli County, Taiwan, 3Tzu Chi University, Hualien, Taiwan, 4The University of Chicago, Chicago, USA

To sense numerous odorants and chemicals, animals have evolved a large number of olfactory receptor genes (Olfrs) in their genome. In particular, the house mouse has ~1,100 genes in the Olfr gene family. This makes the mouse a good model organism to study Olfr genes and olfaction-related genes. To date, whether male and female mice possess the same ability in detecting environmental odorants is still unknown. Using the next generation sequencing technology (paired-end mRNA-seq), we detected 1,088 expressed Olfr genes in both male and female olfactory epithelium (OE). We found that not only Olfr genes but also odorant binding protein (Obp) genes have evolved rapidly in the mouse lineage. Interestingly, Olfr genes tend to express at a higher level in males than in females, whereas the Obp genes clustered

system in females, whereas a more active Olfr gene expressing system in males. In addition, we detected the expression of two genes encoding major urinary proteins, which have been proposed to bind and transport pheromones or act as pheromones in mouse urine. This observation suggests a role of main olfactory system (MOS) in pheromone detection, contrary to the view that only accessory olfactory system (AOS) is involved in pheromone detection. This study suggests the sexual differences in detecting environmental odorants in MOS and demonstrates that mRNA-seq provides a powerful tool for detecting genes with low expression levels and with high sequence similarities.

Oral Presenters Abstracts

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Oral Presentation Abstracts

0-1 - 0-48


– 32 –

O-1

AN UPDATE FROM THE MOUSE GENOMES PROJECT

Thomas Keane1, Kim Wong1, Petr Danecek1, Binnaz Yalcin1 ,2 1 ,2, David Adams1, Mouse Genomes Consortium Mouse Genomes Consortium1 ,2 1Wellcome Trust Sanger Institute, Cambridge, UK, 2Wellcome Trust Centre for Human Genetics, Oxford, UK

The Mouse Genomes Project is an ongoing effort to sequence the genomes of common laboratory mouse strains, catalog all forms of molecular variation, and produce genome sequences of each strain. In 2011, we completed our

and 0.28M structural variants including 0.07M transposable element insertion sites.

variants (Wong et al., Genome Biology, 13:R72). We have catalogued new forms of sequence variation such as RNA-

completed a detailed view of transposable element variation across the mouse strains and their effects on selection and phenotypes (Nellaker et al., Genome Biology, 13:R45). Our goal is to produce high quality genome sequences of each strain and with this in mind we have recently resequenced the entire set of strains to ~40x coverage on the newer HiSeq platform. Finally, we present our second release of the sequence variants from this higher quality dataset including new

O-2

MODERNIZING THE MOUSE REFERENCE ASSEMBLY

Deanna M. Church Genome Reference Consortium, Bethesda, MD, USA

community but did not mark the end of work on the mouse reference assembly. The mouse and human reference

(Church et al., 2011;; http://genomereference.org).

Over the past two years the GRC has analyzed and improved the mouse assembly. Over 1000 ‘issues’ representing over 450 regions of the genome have been entered into our curation database. Over half of these represent gaps or clone problems, whereas 47 represent regions containing a misassembly and 104 involve sequence missing from the assembly.

reference assembly. Over 83 Mb of sequence was added and 200 gaps were closed. Additionally, several misassembled regions were corrected. Notably, a partial representation of the pseudo-autosomal region (PAR) was added to both the X and Y Chromosomes. A more complete representation of the Y Chromosome is included with chromosome length increasing from 15Mb to over 91Mb. By adopting the new assembly model developed for human we have been able to provide over 55 Mb of sequence from other strains as part of GRCm38, with more than two-thirds of this placed in a


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O-3

EXPRESSION QTL MAPPING IN THE DIVERSITY OUTBRED MOUSE POPULATION

Steven Munger, Karen Svenson, Dan Gatti, Narayanan Raghupathy, Gary Churchill The Jackson Laboratory, Bar Harbor, Maine, USA

The Diversity Outbred (DO) panel is a new heterogeneous stock derived from the same eight founder strains as the Collaborative Cross (CC) recombinant inbred strains. These resources capture a uniform high level of genetic variation, and together provide powerful, complimentary toolsets for QTL mapping and gene discovery. Here we report results

seq in 286 liver samples from 26-week old male and female DO mice that were genotyped at 7,854 SNPs across the genome. Alignment of genetically heterogeneous RNA-seq reads is challenging, due to high levels of founder strain-

associations. Local eQTLs are highly abundant and most localize to within 0.5 Mb of the controlled transcript. We

CC are evidenced by the high concordance in reported eQTLs and strain effect patterns in the current analysis and an earlier eQTL mapping study in pre-CC strains. We show that allele effect patterns of local eQTLs in the DO match those observed in liver RNA-seq data from the founder strains. The eight strain allele effect patterns are particularly powerful for predicting genes with local eQTLs that may be causative for phenotypic QTLs.

O-4

THE FANTOM5 PROJECT – A PROMOTER LEVEL EXPRESSION ATLAS USING SINGLE MOLECULE SEQUENCING

Piero Carninci, Alistair ForrestMasayoshi Itoh, Fantom5 Consortium, Yoshihide Hayashizaki Riken Yokohama Institute, Yokohama, Japan

organs necessary to survive outside the womb as an adult and reproduce. The instructions must also specify the number, location and differentiative pathway for all cells created during our lifetime and their potential for renewal and response to stimuli. There is a complex set of extracellular and intracellular signals used to achieve this and ultimately each cell

DNA binding activity. Using the Heliscope single molecule sequencing platform we have surveyed transcription initiation

sites used in each cellular state and concurrently measure gene expression. We have sequenced thousands of libraries and produced an unprecedented coverage of transcription starting sites (TSSs) for mouse and human, identifying more

characterize a given cell type, for each cell type/tissue analyzed.


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O-5

OPTIMIZING HIGH THROUGHPUT SEQUENCING APPROACHES FOR SPONTANEOUS MUTATION DISCOVERY

Laura Reinholdt The Jackson Laboratory, Bar Harbor, ME, USA

Phenotype driven screens are powerful approaches for discovery of novel genes and/or novel functions of known genes. However, the process of mutation discovery has slowed the pace of forward genetics. Over the last few years,

spontaneous mutant mouse models of genetic disease for 50 years. We’ve found that whole exome high throughput

mutants using a standard DNA Seq analysis pipeline (Burrows Wheeler Aligner and mpileup), increasing our rate of mutation discovery by nearly 10 fold. In an effort to further improve our discovery rate, we are now focusing our efforts on the mutations (42%) that have proven recalcitrant to whole exome sequencing and standard DNA Seq analysis. Here we present a number of examples of new mutations that failed to be discovered by whole exome sequencing either because they do not reside in coding sequence or are structural or both. Using these data, we have optimized our process of mutation discovery by expanding our DNA Seq analysis pipeline to accommodate structural lesions and by introducing additional technologies, including mate pair libraries and RNA Seq where possible.

O-6

GENOME-WIDE PREDICTION OF COPY NUMBER VARIATION (CNV) IN 162 STRAINS OF LABORATORY MICE AND LARGE SCALE VALIDATION USING SEQUENCE CAPTURE AND MASSIVELY PARALLEL SEQUENCING

1, Timothy Bell1 1 1, Hyuna Yang2, Leonard McMillian1, Gary Churchill2, Fernando Pardo-Manuel de Villena1, Patrick Sullivan1 1University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2The Jackson Laboratory, Bar Harbor, ME, USA

CNV is a major source of genetic diversity and plays an important role in the etiology of human diseases. Laboratory mice are important tools for understanding mutational mechanisms of CNV and its effects on behavior. However, relatively little is understood about the extent and consequences of CNV in mouse. We conducted a genome-wide CNV survey in 162 strains of laboratory mice, selected to canvass four subspecies of Mus musculus. For CNV discovery, we used the Affymetrix MDA and developed an analysis protocol that combined microarray data with computational algorithms and genomic resources. For high-throughput experimental validation, we used targeted capture with Agilent SureSelect enrichment followed by massively parallel sequencing. We developed an analysis protocol to verify CNV status by comparing read-depths. Additional small-scale validation was conducted using PCR, breakpoint sequencing, and gene

genes whose deletion in other inbred strains are embryonic lethal, suggesting a strain background effect. For the high-throughput validation, we achieved ~700 fold of enrichment and ~100x coverage. Initial analysis for the Glo1 duplication,

there was complete concordance between our predictions and the validation results. As the most comprehensive survey of CNV in mouse, this catalog provides insights into the genetics of complex traits and genome evolution and speciation.


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O-7THE MOUSE MUTANT RESOURCE: GENETIC, GENOMIC AND PHENOTYPIC CHARACTERIZATION OF SPONTANEOUS MUTANT MICE ARISING AT THE JACKSON LABORATORY David Bergstrom, Laura Reinholdt, Muriel Davisson-Fahey, Cat Lutz, Michael Sasner, Stephen Murray, Stephen Rockwood, Leah Rae Donahue The Jackson Laboratory, Bar Harbor, Maine, USAThe application of high-throughput sequencing technologies is revolutionizing the process of mutation detection. By

the mission of the MMR (and its predecessors) has been to provide mouse models of human genetic illness to the

the originating strain, but also provides a pool of potential spontaneous mutant mice for further characterization. After colonies are established, heritability is proven, and the modes of inheritance are determined, subchromosomal locations for each mutant locus are established by backcross or intercross in conjunction with SNP genotyping. In place of Sanger-based sequencing of promising candidate genes from select mutant strains, Illumina GAIIx-based high-throughput whole-exome sequencing (DNASeq), transcriptome sequencing (RNASeq), and array-comparative genome hybridization are now being incorporated to broaden the scope of mutation detection and dramatically shorten the time to causative gene

the MMR website at http://mousemutant.jax.org/. The presentation will enumerate the many advantages of studying spontaneous mutant mice and summarize current resource offerings and metrics.

O-8GENETICS OF COLOR VARIATION: MODEL ORGANISMS IN A POST-GENOME WORLDChris Kaelin a,b, Lewis Hong b, Xiao Xu c, Kelly McGowan a,b Victor David c, Anne Schmidt-Kuentzel c, Marilyn Menotti-Raymond c, and Greg Barsh a,b a HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA;; b Departments of Genetics, Stanford University School of Medicine, Stanford, CA, USA;; c Laboratory for Genomic Diversity, NCI Frederick, MD, USAFor more than 100 years, mouse coat color mutations have provided a model system to understand gene action and interaction. The availability of mammalian genome sequences together with the advent of massively parallel sequencing offers the opportunity to study color variation in “non-model” organisms, probing basic questions in developmental biology and evolution that are not represented in laboratory mice.I will describe recent work from our laboratory on the genetic and developmental basis for mammalian color patterns, including stochastic patterns such as brindling, and periodic patterns such as cheetah spots and zebra stripes. Periodic

among the 36 extant wild cat species.We demonstrate the utility of a forward genetics approach in domestic cats that takes advantage of emergent genomic

function in a gene conserved among all vertebrates, and whose identity is consistent with a theoretical reaction-diffusion

felid phenotype.We also have developed a highly sensitive and robust methodology—EcoP15I-tagged Detection of Gene Expression, or EDGE—that is suitable for detecting and comparing gene expression among tissues from animals for whom fully assembled and annotated genomes do not yet exist. We carried out an EDGE analysis of patterned skin from cheetahs (yellow and black spots), and zebras (white and black stripes). Our results provide a conceptual framework for understanding periodic patterns in terms of three phases: (1) establishment via a self-organizing system during fetal development;; (2) maintenance via an epigenetic mechanism during subsequent somatic growth;; and (3) implementation via paracrine mechanisms that intersect with well-known signalling pathways apparent from mouse coat color genetics.

Organisms. Genome Res 21: 1905-1915, 2011.Kaelin, CB et al. Specifying and Sustaining Pigmentation Patterns in Domestic and Wild Cats. Science 337: 1536-1541, 2012.


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O-9THE ROLE OF X CHROMOSOME IN REGULATION OF MEIOTIC RECOMBINATION RATE AND MEIOTIC FAILURE OF MOUSE INTER-SUBSPECIFIC HYBRIDS

Tanmoy Bhattacharyya, Sona Gregorova, Corinna Knopf, Maria Dzur-Gejdosova, Radka Reifova, Petr Simecek, Forejt Institute of Molecular Genetics AS CR, Prague, Czech Republic

When PWD females (Mus m. musculus Mus m. domesticus origin) males, all F1 male progeny are sterile due to massive asynapsis and meiotic arrest at mid-late pachynema. QTL analysis of this model

major hybrid sterility loci: Hst1/Prdm9 on Chromosome 17 and Hstx2heterozygosity of a portion of F1 genetic background1. Prdm9 2, was later shown to be a major regulator of recombination hotspots in mice and other mammals. Here we report high resolution mapping of Hstx2dominace theory of Haldane’s rule. The meiotic recombination is under strict genetic control, both locally by controlling genomic position of recombination hotspots by Prdm9 gene, and genome-wide by determining the overall recombination

Hstx2 in the 4.5 Mb interval on Chromosome X. Future studies will decide whether the association of Hstx2 with recombination rate

1. Dzur-Gejdošová M. et al. 2012. Genetic architecture of hybrid sterility in the house mouse. Evolution, DOI: 10.1111/j.1558-5646.2012.01684.x

2. Mihola O et al. 2009. A mouse speciation gene encodes a meiotic Histone H3 methyltransferase. Science, 323:373—375.

O-10

A HIGH PRECISION LINKAGE MAP OF THE MOUSE:SEX, STRAIN AND Prdm9 EFFECTS ON OVERALL RECOMBINATION, HOTSPOTS AND COLD REGIONS

Eric Yi Lin1, Gary A Churchill3, Elissa Chesler3, Wei Wang1, Fernando Pardo-Manuel de Villena2 1Department of Computer Science, University of North Carolina, USA, 2Department of Genetics, University of North Carolina, USA, 3The Jackson Laboratory, Bar Harbor, ME, USA

We have generated a new linkage map of the laboratory mouse genome by genotyping 237 male---female sib pairs with the high---density Mouse Diversity genotyping Array. These pairs are the result of the two generations of outcrossing that precede the inbreeding each Collaborative Cross (CC) line (i.e., the G2F1 generation of the CC). In each pair we can assign recombination events to one of eight meioses and determine the location of each event with great precision. Here we exploit the number of recombination events (n-22,000), the precision at which we can map each event (-35kb) and the unique characteristics of the CC to provide a new and powerful look at the effects of sex, strain and genotypes at polymorphic loci of interest (for example Prdm9) on recombination. In addition to an extended catalog of sex and

characteristics.


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O-11

GENETIC REPRODUCTIVE INCOMPATIBILITY IN THE MOUSE COLLABORATIVE CROSS

David Aylor1, Timothy Bell1, Chen-Ping Fu1, Fanny Odet1, Wenqi Pan1, Mark Calaway1, Darla Miller1, Elissa Chesler2, Leonard McMillan1, Deborah O’Brien1, Fernando Pardo-Manuel de Villena1 1University of North Carolina, Chapel Hill, NC, USA, 2The Jackson Laboratory, Bar Harbor, ME, USA

The Collaborative Cross (CC) project is creating a large multi-parental recombinant inbred panel of laboratory mice. Over

mice are descended from highly diverse inbred strains, we expect this observation to be explained by Dobzhansky-Muller epistasis. To assess the genetic basis and mechanism of these incompatibilities, we measured fertility and reproductive parameters in male mice from 358 independent extinct CC lines. Our fertility testing results indicated multiple causes of extinction, with male infertility accounting for almost half (46%). We mapped novel loci associated with fertility, sperm count variation, variation in testis weight, and sperm quality.

O-12

THE GENETIC AND TRANSCRIPTOMIC COMPLEXITY OF OLFACTION IN MICE

Ximena Ibarra-Soria1, Elizabeth Wynn1, Maria Levitin1 ,2, Carla Daniela Robles-Espinoza1, Ruben Bautista1, David Adams1, Gabriela Sánchez-Andrade1, Darren Logan1 1Wellcome Trust Sanger Institute, Cambridge, UK, 2Imperial College, London, UK

in mammals. Variation in genes encoding olfactory receptors (ORs) and vomeronasal receptors (VRs), and their selective expression in sensory neurons, are likely to underpin individual differences in both olfactory perception and pheromone response. We have analysed the entire OR and VR repertoire of 17 mouse strains: over 24,000 receptor alleles. We identify unusually high amounts of sequence variation, non-randomly distributed between receptor gene clusters. We

Mus subspecies and species, suggesting some VRs may play a role in mediating behavioural adaptation while others are highly conserved within the genus. In parallel we characterised the VNO and MOE transcriptomes of one mouse strain by RNAseq, quantifying expression of almost

both tissues. Both receptor classes are unequally expressed across a surprisingly large dynamic range, but individual receptor abundances are consistent between different mice of the same strain, suggesting a non-stochastic mechanism

in the MOE, revealing a potential mechanism for functional overlap between the organs. We also characterized some

these data publically available to encourage further community investigation into the consequences of genomic and transcriptomic diversity on olfaction.


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O-13

ANALYSIS OF MOUSE WHOLE EXOME SEQUENCING FOR MAPPING ENU INDUCED SINGLE NUCLEOTIDE VARIATIONS (SNVs)

Kärt Tomberg1, Randal Westrick1, David Siemieniak1 ,2, David Ginsburg1 ,2 1University of Michigan, Ann Arbor, MI, USA, 2Howard Hughes Medical Institute, Ann Arbor, MI, USA

A sensitized screen of N-ethyl-N-nitrosourea (ENU) mutagenized mice was applied to identity dominant thrombosis

coding region, totaling 49.6 Mb of DNA sequence from 8 descendants of ENU treated mice was captured using the Agilent SureSelect mouse exome capture system. Whole-exome sequencing using the Illumina HiSeq high-throughput sequencer yielded 12-15 gigabases of sequence data per sample, corresponding to an average of ~100 fold sequencing

background) were removed. Also, variants that were called in more than one mouse were removed because it is very unlikely that the exact same position was changed in 8 different ENU treatments. Less than 20 candidate ENU induced

O-14

MUTATION MAPPING AND IDENTIFICATION BY WHOLE GENOME SEQUENCING: APPLICATION TO INBRED MUTAGENIZED MICE

, Ignaty Leshchiner, Wolfram Goessling, Shamil Sunyaev, David Beier Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USA

biological processes, including human diseases. However, this approach has historically required the prior characterization of informative markers. We have developed a fast and cost-effective method for genetic mapping using Next Generation

causal sequence variants (Leshchiner et al., Genome Research, 2012). In contrast to prior approaches, we have utilized

in the mutant pool. In addition, we created an interactive online software resource to facilitate automated analysis

snptrack/). Importantly, this approach can potentially be applied to mutagenized mice that have not been outcrossed, using the ENU-induced variants as SNP markers. This will enable the possibility of doing both primary screens and


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O-15

INFORMING CONDITIONAL MUTAGENESIS: THE CREPORTAL (WWW.CREPORTAL.ORG)

The Jackson Laboratory, Bar Harbor, ME, USA

The International Mouse Knockout Consortium (IKMC, www.knockoutmouse.org) produced myriad conditional-

the construct and driver in the cre-driver parent. To capitalize on the IKMC conditional-ready resource, cre-driver lines with well-characterized cre activity for the intended target tissues, and any off-target sites, must be available. Without

creportal.org), a free publicly accessible site, provides critical data about cre alleles and transgenes, the driver/promoter contained, whether they are inducible (and by what), availability through public repositories, and links to data describing the conditional mutagenesis work done using them. Annotations and images of tissues, anatomical structures, and

investigator submissions, and direct integration of data from large-scale projects producing new cre-bearing strains, including Pleiades, GENSAT, Allen Institute, EUCOMMTOOLS, NIH Neuro-Blueprint, ICS MouseCre and CanEuCre.

the Allen Institute, and these data are being incorporated as available. We will present the current status and content of CrePortal, examples of cre target and off-target activity, and plans for further developing this critical research tool. Supported by NIH grants RR032656, HD062499, HG00330;; EU grant HEALTH-F4-2009-223487.

O-16

A SENSITIZED WHOLE GENOME ENU MUTAGENESIS SCREEN IDENTIFIES AN Actr2 MUTATION AS A NOVEL SUPPRESSOR OF LETHAL THROMBOSIS IN THE FACTOR V LEIDEN MOUSE

Randal Westrick1, Guojing Zhu1, Kart Tomberg1, Sara Haynes1, David Siemieniak2, David Ginsburg1 ,2 1University of Michigan, Ann Arbor, MI, USA, 2Howard Hughes Medical Institute, Ann Arbor, MI, USA

Only ~10% of individuals carrying the common venous thrombosis risk factor, Factor V Leiden (FVL) will develop venous

screen based on the perinatal synthetic lethal thrombosis observed in mice homozygous for FVL (F5tm2Dgi/F5tm2Dgi aka Tfpi+/-). The screen was performed by crossing

F5tm2Dgi/F5tm2Dgi mice with F5tm2Dgi/+ Tfpi+/-females. Surviving G1 offspring were analyzed to identify survivors with the lethal F5tm2Dgi/F5tm2Dgi Tfpi+/- genotype. Analysis of 7,128 G1 offspring (~2X genome coverage)

F5tm2Dgi/F5tm2Dgi Tfpi+/- mice that survived to weaning. Fourteen F5tm2Dgi/F5tm2Dgi Tfpi+/- G1 mice exhibited successful transmission of a putative suppressor mutation to two or more F5tm2Dgi/F5tm2Dgi Tfpi+/- G2 offspring. Whole exome sequencing was performed on a progeny tested member of 8 of the 14 lines using the Agilent SureSelect mouse

heterozygous (dominant) variants in each sample. Sanger re-sequencing of additional mice from one of the lines Actr2 Actr2

gene codes for the ACTR2 aka ARP2 protein, which is essential for intracellular actin branching and polymerization. Additional studies are underway to determine the mechanism by which the novel R286G ENU induced mutation in Actr2

F5tm2Dgi/F5tm2Dgi Tfpi+/- lethal phenotype.


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O-17

THE UBIQUITIN LIGASE WWP1 IMPACTS GJA1 TURNOVER IN THE HEART, POTENTIALLY CONTRIBUTING TO SUDDEN CARDIAC DEATH

Wassim Basheer1, Brett Harris2, Measho Abreha1, Robert Price3, Lydia Matesic1 1University of South Carolina, Columbia, SC, USA, 2Medical University of South Carolina, Charleston, SC, USA, 3University of South Carolina School of Medicine, Columbia, SC, USA

results in sudden cardiac death, which affects upwards of 300,000 in the US alone each year. The main constituent of gap

this process remains elusive. Here we demonstrate that the ubiquitin ligase WWP1 co-immunoprecipitates with and Wwp1 in mice resulted in a 90% reduction in

and this phenotype was completely penetrant in two independent founder lines. Interestingly, increased expression of Wwp1

previously unappreciated role in arrhythmogenesis when dysregulated. This mechanistic insight opens new avenues for

O-18

Lrp1 PLAYS AN ESSENTIAL ROLE IN CRANIOFACIAL, SKELETAL AND VENTRAL BODY WALL DEVELOPMENT

Brianna Caddle, Michelle Curtain, Dennis Maddox, Polyxeni Guidus, Caleb Heffner, Stephanie Siegmund, Leah Rae Donahue, Stephen Murray The Jackson Laboratory, Bar Harbor, ME, USA

The low-density lipoprotein receptor-related protein 1 (LRP1) is a widely expressed transmembrane receptor that binds to at least 40 different ligands, including growth factors and receptors known to play a role in craniofacial development. LRP1 is thought to regulate the activity of growth factor signaling through modulation of both endocytosis and activation of receptor signal transduction, although its function in embryonic development is poorly understood. We have recently

clfp4, which displays cleft secondary palate due to failure of palate shelf elevation, omphalocele, and skeletal malformations at high penetrance. Traditional genetic mapping, coupled with

the Lrp1 gene, producing a non-synonymous transition in a highly conserved “YWTD” putative ligand binding motif. Using strain and a conditional allele of Lrp1, we are able to interrogate the

mechanism by which Lrp1 regulates craniofacial development, including its impact on the Tgfb, Pdgf and Wnt signaling pathways. Transcriptome analysis of E13.5 palate shelves in these mutants reveal novel pathways involved in palate growth and elevation. While simultaneous presentation of orofacial clefting and body wall defects is observed in human syndromes, there are few mouse models that recapitulate these phenotypes. Thus, Lrp1clfp4 represents a new model of craniofacial/body wall birth defects and our analysis will provide new insight into the critical role of Lrp1 in the regulation of signaling pathways that dictate craniofacial development. Supported by NIH grants: DE019451 and DE020052.


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O-19

A FOCUSED FORWARD GENETIC SCREEN FOR ABNORMAL CORTICAL PATTERNING IDENTIFIED HYPOMORPHIC Reln MUTANT WITHOUT ATAXIA AND Lrp2 MUTANT WITH AXON GUIDANCE DEFECT

Seungshin Ha1 ,4, Rolf Stottmann1 ,2 3 ,4, Christopher Walsh3 ,4, David Beier1 ,4 1Brigham and Women’s Hospital, Boston, MA, USA, 2Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, 3Children’s Hospital Boston, Boston, MA, USA, 4Harvard Medical School, Boston, MA, USA

Formation of a six-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers 2/3 and 5 of the cortex (B6;;129P2-Rgs4tm1Dgen Cntn2tm1Furl ). Four lines with abnormal cortical

Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. This Reln mutant, named Reln CTRdel, is a hypomorphic allele with lamination defect but not cerebellar malformation. This suggests that Reln

Lrp2, a causal gene for Donnai-Barrow syndrome in human. This focused screen highlighted axon guidance defect in Lrp2

demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is

O-20

STEM CELL-BASED MODELS FOR CARDIOVASCULAR DEVELOPMENT AND REGENERATION Stephen DaltonPaul D. Coverdell Center for Biomedical and Health Sciences, University of Georgia, Athens, GA, USA

In this talk I will discuss approaches where human pluripotent stem cells (hPSCs) are used to model various aspects of

that plays critical roles in cardiac development, homeostasis and repair. By marker analysis, epicardium cells (EpiCs) generated from hPSCs are indistinguishable from their in vivo counterparts and like authentic epicardium, are derived from an Isl1+ Nkx2.5+ splanchnic mesoderm progenitor population. hPSC-derived EpiCs respond to signaling molecules

major implications for our understanding of human cardiovascular development, for the generation of cell therapies and drug discovery.


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O-21

REVERSAL OF FEMALE INFERTILITY BY MUTATION OF CHEK2 IDENTIFIES THE MAMMALIAN MEIOTIC DNA DAMAGE CHECKPOINT

Ewelina Bolcun-Filas, Michelle White, Vera Rinaldi, Cornell University, Ithaca, NY, USA

Errors in meiosis such as aneuploidy, chromosome aberrations, or gene mutations can lead to birth defects. The vast majority of spontaneous abortions due to aneuploidy are traceable to Meiosis I defects that occur during oogenesis. Checkpoint mechanisms exist to eliminate defective oocytes, and mutant mice with genetic defects in meiotic chromosome metabolism experience complete oocyte elimination and infertility. However, the molecular identities, exact functions,

meiotic mutants to identify checkpoint kinase 2 (Chek2) as being essential for culling oocytes with unrepaired, genetically-programmed DNA double strand breaks (DSBs). Startlingly, females bearing a mutant allele of Trip13 that causes complete oocyte loss due to defective DSB repair have their fertility restored by concurrent mutation of Chek2. They remain fertile for many months, yielding offspring without any visible defects. Additional genetic experiments indicate that in response to double strand breaks (DSBs) caused by defect recombination genes or ionizing radiation, CHEK2 signals primarily to TRP63 rather than TRP53 in diplotene oocytes. These data thus establish CHEK2 as essential for DNA damage surveillance in female meiosis.

O-22

TRANSGENERATIONAL EPIGENETIC EFFECTS OF Apobec1 ON INHERITED SUSCEPTIBILITY TO TESTICULAR GERM CELL TUMORS

1 ,3, Vicki Nelson1 1, Paul Tesar1, Nicholas Davidson2 1 2Washington University School of Medicine, St.Louis, Missouri, USA, 3

Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes

(Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically A1cf, the RNA-binding subunit of

the ApoB editing complex, raises the possibility that the function of Dnd1 is related to APOBEC1 activity as a cytidine Apobec1 on the TGCT-

susceptible 129/Sv inbred background to determine whether dosage of Apobec1 mutation susceptibility, either alone or in combination with Dnd1, and either in a conventional or a transgenerational manner. In the paternal germ-lineage, Apobec1subsequent transgenerational effects, showing that increased TGCT risk resulting from partial loss of Apobec1 function

among wild-type offspring. These heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage. These results suggest that Apobec1 plays a central role in controlling TGCT susceptibility in both a conventional as well as a transgenerational manner.


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O-23

EPITHELIAL ORGANIZATIONS WERE DEFECTED DURING SEMINAL VESICLE AND VAGINAL FORMATION IN A NEW Ctnnb1 INFERTILE MODEL MOUSE

Takuya Murata1, Hideaki Toki2, Yuichi Ishitsuka1, Hideki Kaneda3, Shigeru Makino1, Ryutaro Fukumura1, Shigeharu Wakana3, Tetsuo Noda2, Yoichi Gondo1 1Mutagenesis and Genomics Team, RIKEN BRC, Tsukuba, Japan, 2Team for advanced development and Evaluation of Human Disease Models, RIKEN BRC, Tsukuba, Japan, 3Japan Mouse Clinic, RIKEN BRC, Tsukuba, Japan

We have presented a new infertile model mouse carrying a mutation of catenin (cadherin associated protein), beta 1, Ctnnb1, C429S. This mutant line was discovered by RIKEN ENU-based mutagenesis, “next-generation reverse genetics.” The mutant mouse was infertile, while other defects have not been found yet. Gross morphological defects were solely restricted in seminal vesicle and vagina, in male and female, respectively. In male, seminal vesicle was formed as duplicated. As a result, sperm transportation route was affected. Sperms were found ectopically in seminal vesicle. In female, vaginal atresia resulted in hydrometrocolpos. Both sperms and oocytes were functionally normal, from in vitro fertilization and subsequent embryonic transfer experiments (reported by Murata et al. 2010, at 24th IMGC).

Detailed histological analyses revealed that abnormal organization of epithelia was found in forming seminal vesicle in male. This abnormality coincided with local up-regulation of Wnt/ß-catenin signal indicated by a TOPGAL transgene. In female, vaginal atresia resulted from loss of vaginal extension toward surface vulva. In rudiment vagina, keratinized squamous epithelial cells were not found, but some columnar epithelial cells, atypical for cervix, were observed.

CTNNB1 protein has two distinct functions with ubiquitous expression;; one is a transcriptional cofactor in Wnt/ß-catenin signal, the other is a cytoplasmic component of cadherin complex in tight junction in the case of epithelium. This mutant mouse may reveal a dynamic integrative mechanism of the dual function. In addition, how the Ctnnb1 C429S mutation only affects to a very restricted tissue on a limited developmental time is of another interest.

O-24

DIFFERENTIAL EXPRESSION OF Phox2B MARKS DISTINCT PROGENITOR POPULATIONS IN ENTERIC NERVOUS SYSTEM ONTOGENY

Michelle Southard-Smith1, Dennis Buehler1, Stephanie Skelton1 1, Nripesh Prasad2, Shawn Levy2, Travis Clark1 1Vanderbilt University, Nashville, TN, USA, 2Hudson Alpha Research Institute, Huntsville, AL, USA

Normal gastrointestinal motility relies upon formation of a balanced complement of cell types from enteric neural crest-derived progenitors (ENPs) that populate the fetal intestine and form the enteric nervous system (ENS). Regulatory processes that control generation of cellular diversity within the ENS have previously been elusive. Phox2b is an essential transcription factor that is required for normal ENS development. Heterogeneous expression of Phox2b

stages with higher levels in enteric neurons and lower levels in enteric glia. The B6C3Fe.Tg(Phox2b-HIST2H2BE/Cerulean)1Sout transgene line (Phox2b-CFP) recapitulates this heterogeneous expression and facilitates capture of multi-potent progenitors during ENS. In this study we test the hypothesis that differential Phox2b expression coincides

distinct levels of Phox2b. These progenitors maintained differential expression of Phox2b even over extended periods based on live cell imaging. Our studies show that differential expression of Phox2b coincides with differences in vitro developmental potential. Finally we identify multiple pathways that exhibit differential expression in Phox2b-CFP high and low populations by next-generation sequencing. These pathways are ideal therapeutic targets for production of


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O-25

A CHROMATIN REMODELING COMPLEX MEMBER, Actl6a, IDENTIFIED AS A MODIFIER OF Sox10 NEUROCRISTOPATHY

Dawn Watkins-Chow, Raymond Mullen, Temesgen Fufa, William Pavan National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Neurocristopathies arise from disruption in neural crest development and can present with altered pigmentation in skin and/or hair and are associated with debilitating diseases including deafness, blindness, cleft lip, congenital megacolon, and albinism. We established an enhancer screen to identify mutations increasing the phenotypic severity of Sox10 (C57BL/6-Sox10tm1Weg/+ aka Sox10LacZ/+) a well-characterized mouse model

hedgehog, neuregulin, and semaphorin signaling as well as ribosomal and RNA binding proteins. Most recently, we have characterized a Sox10-dependent, semi-dominant phenotype resulting from a mutation in Actl6a, a member of the BAF chromatin remodeling complex. Homozygote Actl6a mutants exhibit embryonic lethality, and Actl6a/+ heterozygotes appear indistinguishable from their wild type littermates. However, on a Sox10LacZ/+ background, heterozygosity for the Actl6a mutation increases the severity of Sox10LacZ/+ belly spotting and causes additional white head spotting that is never observed in Sox10LacZ/+ mice. Embryonic analysis shows that Actl6a causes a synergistic reduction in cranial crest-derived melanoblasts (E12.5), before a synergistic reduction in trunk melanoblasts is observed. Actl6a loss in vitro disrupts melanocyte growth and alters the normal expression of well-characterized Sox10 target genes. Collectively, our data suggests that Actl6a more severely affects the cranial crest than other spotting mutants and reveals a novel pathway affecting melanoblast development. Further analysis of the interaction between Sox10 and Actl6a will contribute

melanoma progression.

O-26

A NOVEL Rab18 MOUSE MODEL OF WARBURG MICRO SYNDROME

Sarah Carpanini1, Lisa McKie1, Derek Thomson2, Ann Wright2, Sarah Gordon2, Sarah Roche2, Mark Handley1, David Brownstein3, Thomas Gillingwater2, Irene Aligianis1 1 1MRC Human Genetics Unit, Edinburgh, UK, 2Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK, 3Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK

Warburg Micro syndrome is a heterogeneous autosomal recessive disorder associated with ocular (congenital cataracts, optic atrophy, micropthalmia, microcornea, atonic pupils and cortical blindness) and neurological abnormalities (postnatal microcephaly, severe global developmental delay, progressive spastic paraplegia, frontal polymicrogyria and

mutations within RAB3GAP1, RAB3GAP2 and RAB18 resulting in clinically indistinguishable conditions. RAB3GAP1 and RAB3GAP2 for the RAB3 family. RAB3 functions in modulating the regulated exocytosis of hormones and neurotransmitters. The role

Little is known about the pathology underlying Warburg Micro syndrome, so to enable a deeper understanding of the disease we have generated a novel Rab18 null mutant mouse model from embryonic stem cells and begun its characterisation. Rab18 mutant mice present with congenital nuclear cataracts, atonic pupils and progressive hindlimb muscle weakness, recapitulating the Warburg Micro syndrome phenotype. We have examined in detail the nature of the

mice.


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O-27

NOTCHLESS HOMOLOG 1 (DROSOPHILA) IMPACTS MULTIPLE SIGNALING PATHWAYS DURING PRE-IMPLANTATION DEVELOPMENT

Chiao-Ling Lo1 ,2 3, Amy Lossie1 ,4 1Department of Animal Science, Purdue University, West Lafayette, IN, USA, 2PULSe Graduate Program, Purdue Univeristy, West Lafayette, IN, USA, 3Department of Biological Sciences, Purdue University, West Lafayette, IN, USA, 4Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Our interests lie in determining the genes and genetic pathways that are important for establishing and maintaining maternal-fetal interactions during pregnancy. Through positional cloning, we discovered that mutations in notchless homolog 1 (Drosophila) (Nle1) lead to embryonic lethality during peri-implantation in mice. NLE1 is a member of the WD40-repeat protein family, and is thought to signal via the canonical Notch pathway. In invertebrates and lower vertebrates, the Notch pathway directs cell fate prior to gastrulation. However, gene targeting studies demonstrate that Notch signaling is dispensable for gastrulation in mice. The phenotype of Nle1 mutant embryos is much more severe than single Notch receptor mutations or even in animals where Notch signaling is blocked. To test the hypothesis that Nle1 functions in multiple signaling pathways during pre-implantation development, we examined expression of NOTCH downstream target genes, as well as select members of the Wnt pathway in wild-type and mutant embryos. We saw no indication that the Notch pathway is disrupted in mutant embryos;; Notch receptors, ligands and downstream targets showed normal expression levels. Instead, we found that members of the Wnt pathway are downregulated in Nle1 mutants, while Cdkn1a was upregulated. Our data implicate NLE1 in WNT signaling and cell cycle arrest via CDKN1A-mediated apoptosis. Intriguingly, WNT signaling is critical for gastrulation in mice. Deletion of Wnt3 leads to failure prior to primitive streak formation, and multiple ligands and receptors are detected in blastocysts and the uterus during peri-implantation. These pathways could provide novel targets for the design of therapeutic interventions for infertility.

O-28

A GENETIC APPROACH TO IDENTIFYING GENES REGULATING GESTATION TIME

Leah Rae Donahue The Jackson Laboratory, Bar Harbor, Maine, USA

Our goal is to use the mouse to understand the genetic basis of preterm birth. In our previous collaborative study with the March of Dimes, we determined the gestation time for 15 inbred strains. The results revealed striking differences in gestation time between strains, with over 42 hours separating the shortest and longest strains. In order to better understand the genetic basis of these differences, we have used powerful genetic tools derived from the two strains that

gestation time. Building upon that information, we are using a combination of mouse genetic tools including nested congenics, diverse inbred strains, and diversity outcross mice to identify genetic loci responsible for differences in gestation time.

When combined with data from large-scale human genetic association studies, this work will greatly facilitate the

and mouse genetics, this work will have an important impact on screening and subsequent treatment of those at risk for preterm delivery.


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Verne Chapman Lecture

WHY DID C57BL/6J WIN THE RACE AND HOW DID IT FACILITATE GONAD DEVELOPMENT RESEARCE?

Eva Eicher The Jackson Laboratory, Bar Harbor, Maine, ME, USA Rarely does a scientist get to tell the behind-the-scenes story about how a discovery occurred. What I am going to do is

inbred strain? Why were wild-derived inbred strains developed and how did they advance our knowledge of the mouse genome? And, why did the use of B6 lead to uncovering genes involved in primary (gonad) sex determination?

O-29

HIGH-THROUGHPUT MUTANT MOUSE PHENOTYPING IS A POWERFUL TOOL TO GENERATE NOVEL HYPOTHESES


As part of the Sanger Mouse Genetics Project we have generated over 600 knockout mouse lines. Viability and fertility of each line are assessed during colony expansion;; 28% of lines have been found to be embryonic lethal at postnatal day 14, with a further 12% classed as sub-viable, and 5.7% of lines homozygous for the targeted allele present with fertility issues. Following expansion, dedicated groups of mice are phenotyped through an extensive and standardised

line. For homozygous lethal lines, heterozygous animals are phenotyped. Whilst lines homozygous for the targeted

3.9 hits per line), lines assessed in the heterozygous state were still remarkably informative (42% of lines assessed in the heterozygous state were classed as pheno-deviant with an average of 1 hit per line) and represent a rich source of information, which is openly available on the Sanger Mouse Portal (http://www.sanger.ac.uk/mouseportal/).

Many genes have been selected based on the absence of available mutant mouse phenotypic information. We will present some of the hypothesis-generating mouse lines that have resulted, including mice with metabolic abnormalities (Kptn, Dusp3), skeletal changes (Zc3hc1), haematological alterations (Crlf3) and developmental defects (Psat1). Our data shows that high-throughput phenotyping is a powerful tool to generate novel hypotheses and that most knockouts have robust phenotypes, few of which could be predicted a priori.


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O-30

MOVING DRUG DEVELOPMENT FORWARD: VALIDATING IN VITRO ASSAYS DEVELOPED USING GENETICALLY DIVERSE MOUSE INBRED CELL LINES

Cristina Benton1, Suzuki Oscar1, Frick Amber1, Chan Emmanuel1, McQuaid Patricia1 2, Parks Bethany2, Thomas Rusty2, Tim Wiltshire1 1University of North Carolina, Chapel Hill, NC, USA, 2Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA

Cell-based toxicogenomic assays provide a global and systematic way to identify genetic determinants of drug response and toxicity. Results from high-throughput cell-based toxicogenomic screens can guide clinical trial design, subject selection, and dosing, leading to an accelerated and more cost-effective drug discovery and development process.

32 inbred mouse strains and screened them against 69 different drugs and environmental toxicants. To assess inter-strain cellular responses to xenobiotics, we measured eight multiplexed cell health parameters, including cell loss, mitochondrial membrane potential, and cytochrome c immunostaining using high-content imaging of cell populations at 24 and 72 hours post-treatment. Using genome-wide association analysis, we found a 1.2 Mb locus on Chr X that was

putative locus is cytochrome b-245, beta polypeptide (Cybb) gene, which encodes for a voltage-gated H(+) channel that mediates pH in the mitochondria. Given that mitochondrial dysfunction has been shown to underlie idiosyncratic adverse drug reactions such as drug-induced liver injury and rhabdomyolysis, we conducted a series of experiments to examine the role of Cybb in mediating toxic responses to rotenone in vivo. Our study demonstrates that cell-based toxicogenomic assay using MEFs is an effective tool for identifying genes underlying drug response. Importantly, this approach could be used to assess and predict drug response phenotypes in humans at the early stage of drug development.

O-31

SYSTEMIC ANALYSIS OF MOUSE MUTANTS AT THE GERMAN MOUSE CLINIC FOR DETECTING BIOMARKERS OF HUMAN DISEASES

Valérie Gailus-Durner1, Helmut Fuchs1, and the GMC consortium1 2, Larissa Haliw2, Sunita Biswas2, Diane E. Brown2, Sylvie Breton2, Susan Cotman2, Oliver Puk3 3 1 ,4, Martin Klingenspor4, Pawel Olszewski5, Helgi Schiöth5, Martin Hrabé de Angelis6 1German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Munich, Germany, 2Massachusetts General Hospital, Boston, MA, USA, 3German Mouse Clinic, Institute of Developmental Genetics, Helmholtz Zentrum München, Munich, Germany, 4Molecular Nutritional Medicine, Else Kröner-Fresenius Center and ZIEL Research Center for Nutrition and Food Sciences, Technische Universität München, Freising-Weihenstephan, Germany, 5University of Uppsala, Uppsala, Sweden, 6Chair of Experimental Genetics, Technische Universität München, Freising-Weihenstephan, Germany

Since its establishment, more than 290 mutant mouse lines have been systemically phenotyped at the German Mouse Clinic (GMC). The GMC is a pillar of Infrafrontier, a pan European research infrastructure for phenotyping and archiving mouse models and participates in the long-term task to generate and systematically phenotype knockout mouse lines for every gene in the mouse genome within the International Mouse Phenotyping Consortium (IMPC).

Systemic phenotyping of mutant mouse lines leads to the detection of unexpected phenotypes - thereby uncovering new functions of genes involved in the development of human diseases. For example, we showed for neurobeachin, a regulator of synaptic protein targeting and associated with autism, a function in body fat mass regulation and feeding behavior in mice. Furthermore, phenotyping of young animals of the C57BL/6N-Cln3tm1.1Mem aka Cln3 mouse line,

peripheral blood that may be exploited for biomarker development.

In addition, we constantly test new methods for its usability in high-throughput phenotyping. We will show our progress

the mouse lens or Fourier transform infrared spectroscopy (FTIR) for analysis of feces composition.


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O-32

CASE STUDIES OF METABOLIC SYNDROME IN THE DIVERSITY OUTBRED MOUSE POPULATION: A GATEWAY TO INDIVIDUALIZED MEDICINE?

Karen Svenson, Nicole Savignac, Daniel Gatti, Gary Churchill The Jackson Laboratory, Bar Harbor, Maine, USA

The Diversity Outbred (DO) mouse population is a newly available resource for investigating the genetics of complex traits. This heterogeneous population was created from partially inbred lines of the Collaborative Cross (CC) and therefore shares its eight founder alleles. Hence, DO mice provide an opportunity to predict phenotypic outcomes from

metabolic traits in 550 DO animals fed chow or high-fat diet to evaluate genetic variants driving Metabolic Syndrome (MetSyn) disorders, including diabetes and obesity, and to better understand how these complications are related. Initial

While more than half of the mice in this study became obese, no QTL were found for percent body fat, indicating that multiple loci contribute to obesity and that identifying them requires additional animals. Obese mice varied widely in their susceptibility to other traits associated with MetSyn, namely elevated glucose and elevated triglycerides. These “case studies”, for which there were too few to achieve adequate statistical power, provide an important opportunity to develop strategies for interrogating genotype-phenotype outcomes in complex disease. We used phenotypic subgrouping to reveal additional loci driving coincident features of MetSyn. The development of an algorithm to identify genetic loci with interactive effects as well as those with main-effects in this population is needed and will be an important primer towards realizing individualized medicine approaches in humans.

O-33

UNDERSTANDING AGING THROUGH GENOME ANALYSIS

Vadim GladshevBrigham & Women’s Hospital, Harvard Medical School, Boston, USA

Mammals differ more than 100 fold in lifespan. Understanding genetic changes that are responsible for this difference may uncover the molecular basis for the processes that lead to an increase in species lifespan. To address this

its maximum lifespan exceeds 30 years, making this animal the longest-living rodent. Naked mole rats show negligible senescence, no age-related increase in mortality, and high fecundity until death. We sequenced and analyzed the naked mole rat genome and transcriptome, which revealed unique genome features and molecular adaptations consistent with cancer resistance, poikilothermy, and insensitivity to hypoxia. This information provides insights into the naked mole

the regulation of mammalian lifespan may help develop approaches that target these pathways in organisms, including humans, thereby extending their lifespan.


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O-34

DRUGS THAT SLOW AGING IN MICE

Richard Miller University of Michigan, Ann Arbor, USA

The NIA Interventions Testing Program (“ITP”) is a multi-institutional collaboration that tests drugs thought likely to extend mouse lifespan by slowing the aging process. We reported in 2009 that rapamycin, an inhibitor of the TOR kinase, could extend mouse lifespan when given late in life, but lifespan data by themselves cannot show whether the improved survival represented deceleration of the aging process, or merely of the forms of neoplastic disease most likely to kill mice. We now have new results showing that rapamycin does indeed retard multiple aspects of aging in several tissues, including liver, heart muscle, endometrium, adrenals, and tendon, and also slows the age-dependent loss of spontaneous activity. These data strongly support the hypothesis that rapamycin slows aging in mice, although they do not exclude the idea that the lifespan extension might represent a more direct effect on neoplastic cells themselves. Rapamycin also led to several undesirable side effects, including cataracts and testicular degeneration. New data also show that rapamycin also induces expression, in the liver, of a set of genes encoding enzymes involved in xenobiotic metabolism. These mRNAs are also induced by anti-aging mutations, by dietary restriction, and by a crowded litter manipulation that also leads to longer lifespan.

Studies now nearing their conclusion provide preliminary data for improved survival from two agents not previously studied. One of these is acarbose, which interferes with absorption of carbohydrates from the intestine and is in clinical use as a treatment for some forms of diabetes. The other is 17-a-estradiol, a non-feminizing estradiol that works largely through pathways independent of the classical estrogen receptor. Unlike rapamycin, whose effects are stronger in female mice, both acarbose and 17-a-estradiol seem to have much stronger effects on male mice.

Support: National Institute on Aging, Ellison Medical Foundation

O-35

THE HARWELL AGEING MUTANT SCREEN

Paul Potter1, Laura Wisby1, Andrew Haynes1, Andrew Blease1, Thomas Nicol1, Michelle Simon1, Gareth Banks1, Pat Nolan1, Abraham Acevedo1, Mike Bowl1, Andy Parker1, Prasshy Shanthakumar1 3, Becky Starbuck1, Raj Thakker2, Michelle Goldsworthy1, Roger Cox1, Anne-Marie Mallon1, Sara Wells1, Steve Brown1 1Mammalian Genetics Unit, MRC Harwell, Oxfordshire, UK, 2Oxford Centre for Diabetes, Endrocrinology and Metabolism, University of Oxford, Oxfordshire, UK, 3MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine University of Edinburgh, Edinburgh, UK

investigate the interaction between genetic variation and the pleiotropic effects of ageing to generate new models of late onset or age-related disease. This resource will allow us to;; identify genes and pathways involved in age related disease, screen for biomarkers of age related disease, and provide better platforms for pre-clinical assessment of new therapies. Pedigrees are being aged to 18 months and undergo phenotyping across a wide range of disease areas including diabetes and metabolism, neurobehaviour, bone analysis, renal function, cardiac disease, liver function,

hearing loss, cardiovascular disease, impaired renal function, impaired liver function, and bone disease which are being mapped and characterised in detail. The age challenged mice are an important resource for many research groups, identifying novel genes and pathways resulting in age-related phenotypes.

We are capitalising on the power of the whole genome sequencing by pre-emptively sequencing G1 founder males

community, and secondly allow the combination of gene-driven and phenotype-driven screens in a single pipeline by

to a large-scale, high throughput screen.


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O-36

MULTI-SCALE CONGENIC ANALYSIS PROVIDES INSIGHT INTO THE COMPLEX GENETIC ARCHITECTURE OF DIET-INDUCED OBESITY

David Buchner1 ,2, Soha Yazbek1 ,3, Colleen Croniger1 1 ,4 1Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA, 2Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA, 3Faculty of Health Sciences, American University of Beirut, Beirut, Raid El-Solh, Lebanon, 4Institute for Systems Biology, Seattle, WA, USA

To study the genetic architecture of metabolic disease we analyzed multiple scales of congenic strains, with congenic intervals ranging from individual genes to entire chromosomes. The results suggested that hundreds of quantitative trait loci (QTLs) with large effects regulate obesity and glucose homeostasis with surprisingly consistent effect sizes

QTLs over 3000-fold, the average phenotypic effect on body weight was reduced less than 3-fold. Additionally, many Obrq2a QTL

transgenerationally regulates body weight and food intake through the paternal, but not maternal lineage;; with effects of equal strength lasting at least three generations. Two of the four additional body weight QTLs tested also demonstrated parental effects suggesting the importance of this inheritance mechanism in regulating obesity. Despite the complexity,

Slc35b4 and the neurexin superfamily member Cntnap2 that regulates the localization of voltage-gated potassium channels in myelinated neurons. Cntnap2 both increased and decreased obesity-susceptibility depending on the genomic context. Collectively, this work highlights the complex genetic basis of metabolic disease yet demonstrates that this mapping strategy is able to identify novel disease genes.

O-37

GERMLINE GENETIC VARIATION MODULATES TUMOR PROGRESSION AND METASTASIS IN A MOUSE MODEL OF NEUROENDOCRINE PROSTATE CARCINOMA

Shashank Patel1, Alfredo Molinolo2, Silvio Gutkind2, Nigel Crawford1 1NHGRI/NIH, Bethesda, MD, USA, 2NIDCR/NIH, Bethesda, MD, USA

Neuroendocrine (NE) differentiation has gained increased attention as a prostate cancer (PC) prognostic marker.

the eight progenitor strains of the Collaborative Cross recombinant inbred panel. Tumor growth and metastasis were

pulmonary metastasis tended to follow those of local dissemination in each of the strains. All tumors and metastases displayed positive staining for NE markers, synaptophysin and FOXA2. These experiments conclusively demonstrate that the introduction of germline variation by breeding modulates tumor growth, local metastasis burden, and distant

QTLs on distal Chromosome 6 and proximal Chromosome 12 are associated with tumor growth in the TRAMPxNOD/

forms of PC.


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O-38

METASTASIS SUSCEPTIBILITY GENES DEFINE MULTIPLE MECHANISMS FOR TUMOR DISSEMINATION IN HUMAN BREAST CANCER PATIENTS

Ying Hu1, Maxime Look1 ,2 1 ,2, Kent Hunter1 1National Cancer Institute, NIH, Bethesda, Maryland, USA, 2Josephine Nefkins Cancer Center, Rotterdam, The Netherlands

Previously, using a highly metastatic transgene-induced model of mammary tumors we demonstrated the presence of inherited alleles that predispose animals to developing distant visceral metastases. Further transcriptional and epidemiological analysis validated that metastasis susceptibility genes exist in humans, and likely contribute to the

from the majority of these crosses predict metastatic outcome in estrogen receptor (ER) positive breast cancer, the

appear to assemble into a either a single nuclear complex or a set of highly related nuclear structures. Unexpectedly,

presence of tumor cells in sentinel lymph nodes indicate that function more broadly than originally thought, but switch

is associated with tumor non-autonomous affects suggest that multiple metastatic mechanisms exist for breast cancer.

O-39

MOUSE DISEASE MODELS AND FUNCTIONAL EVALUATION OF HUMAN VARIANTS

Miriam Meisler University of Michigan, Ann Arbor, MI, USA

variants in human patients with rare disorders. In addition to inherited variants, each human genome contains, on average, one new de novo mutation that changes protein sequence. It is now imperative to distinguish between causal variants with altered gene function and ‘neutral’ non-pathogenic variants on the other hand. The functional analyses of mouse mutants that has been carried out in the laboratories of IMGS members for several decades is contributing to

can provide evidence for causality of a human mutation. Cell-based assays developed in the context of mouse genetic studies can also be of value for evaluating novel human mutations. We will discuss new human mutations in two genes, FIG4 and SCN8Aevaluated using tools from mouse genetics.


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O-40

A MOUSE GENETICS APPROACH TO UNDERSTANDING THE PATHOGENESIS OF SPONGIFORM ENCEPHALOPATHY

Sarah Anderson, Kelsey Schweitzer, George Carlson, Teresa Gunn McLaughlin Research Institute, Great Falls, MT, USA

Spongiform encephalopathy is a form of neurodegeneration characterized by the presence of vacuoles throughout the central nervous system (CNS). This pathology is most commonly associated with prion diseases, but can also be caused by infection of the brain with some retroviruses (including HIV), or mitochondrial disease. While the general cause of disease is known (presence of the aberrant conformer of the prion protein, viral infection or mitochondrial dysfunction), the cellular mechanism(s) that cause this pathology remain unknown. Several mouse mutants exist that develop spongiform encephalopathy, providing an opportunity to better understand the pathogenesis of CNS vacuolation. Here, we report that a unique, spontaneous missense mutation in the gene encoding the Sox10 transcription factor causes spongiform encephalopathy. A cross to Sox10 null mutant mice indicates that this mutation is hypomorphic.

and anatomically, mirrors the onset of CNS myelination. Unlike the null mutant mice, these Sox10 hypomorphs generate mature oligodendrocytes capable of forming myelin, although they do show hypo- and/or demyelination. Since Sox10 is expressed exclusively in oligodendrocytes within the CNS, these data suggest a connection between myelination and vacuole formation. These mice represent a new model that will provide insight into the development of neurological variant Waardenburg-Shah syndrome, which is caused by mutations in human SOX10, as well as the pathogenesis of spongiform encephalopathies.

O-41Icst IS A DOMINANT NEGATIVE MUTATION OF Lmx1b

Sally Cross1, Lisa Mckie1, Margaret Keighren1, Lorraine Rose2, Dan Macalinao3, Alison Kearney3, Rob van ‘t Hof2, 3 ,4 1

1MRC Human Genetics Unit, Edinburgh University, Edinburgh, UK, 2Molecular Medicine Centre, Edinburgh University, Edinburgh, UK, 3The Jackson Laboratory, Bar Harbor, Maine, USA, 4The Howard Hughes Medical Institute, Bar Harbor, Maine, USA

Mutations in LMX1B underlie the dominant human disorder nail-patella syndrome (NPS). This is characterised by nail and joint dysplasia sometimes accompanied by kidney defects and glaucoma. It is thought to be caused by

a missense mutation in mouse Lmx1b, Iris-corneal strands, (Icst) which causes raised intraocular pressure and anterior segment scarring when heterozygous. Furthermore, 30% of heterozygotes die between birth and weaning probably due to kidney failure. Icst homozygotes have a similar lethal phenotype to Lmx1b KO mice, with kidney, limb and skull abnormalities and absent cerebellum, but KO mice have no heterozygous phenotype. The LIM-homeodomain mutation in Icst prevents binding to DNA targets, and we hypothesise that Icst mutant LMX1B protein acts in a dominant negative fashion and that ratio of wild-type to mutant protein would be crucial.

We made a BAC transgenic line expressing Lmx1b at 65-70% the level of the endogenous gene. One copy of the transgene rescues the dominant Icst eye phenotype and two copies rescue the homozygous lethality but not the limb

still have abnormal limbs. It has previously been suggested in humans that mutant LMX1B Icst acts in a dominant-negative fashion raises the possibility that some cases of NPS

may be due this mechanism.


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O-42

MULTIPLE PHASE ANALYSIS REVEALED DIFFERENT QTL ASSOCIATED WITH HOST RESPONSE DURING KLEBSIELLA PNEUMONAIE INFECTION IN COLLABORATIVE CROSS MOUSE REFERENCE POPULATION

Fuad Iraqi1, Karin Vered1, Caroline Durrant2, Richard Mott2 1Tel-Aviv University, Tel-Aviv University, Israel, 2Wellcome Trust Human Genome Center (WTHGC), University of Oxford, Oxford, UK

Klebsiella pneumonaie (Kp) is a common pulmonary pathogen causing severe pneumonia in immunocompromised hosts and often associated with sepsis. Here, we initiated studies aimed of mapping and subsequently identifying the host susceptibility genes to Kp infection in a high genetically diverse mouse population, the Collaborative cross (CC). In total, 434 mice of 73 CC lines were challenged by intraperitoneally (IP) with 104 CFU of strain K2 (KP-2) and mean survival time post infection were monitored for 15 days duration the challenge. Survival analysis has shown that the different

sense” heritability of this trait in the CC mouse population was high as of 0.45. QTL mapping results have shown that different QTL were mapped at different time points during the challenge and not consistent across the whole course of the challenge. For instance, QTLs on Chromosomes 4, 17 and 12 were mapped on days 2, 3 and 6, respectively, but not across the whole infection period. Two QTL were mapped on Chromosomes 8 and 18 on day 8 of infection. These two QTL on additional to a third QTL mapped in Chromosome 2, were consistent during the infection from day 10 of infection

Klebsiella pneumonia is a complex trait and controlled by multiple genetic factors, which acts sequentially during the course of infection.

O-43

MODIFIERS OF NEUROFIBROMATOSIS-ASSOCIATED ASTROCYTOMA DEMONSTRATE THE TISSUE SPECIFICITY AND SEX SPECIFICITY OF CANCER SUSCEPTIBILITY

1 ,2, Min-Hyung Lee1, Christina DiFabio1, Sungjin Kim3 ,4, Yanhong Liu5, Melissa Bondy5, Karl Broman3, Karlyne Reilly1 1National Cancer Institute, Frederick, MD, USA, 2George Washington University, Washington, DC, USA, 3University of Wisconsin, Madison, WI, USA, 4Emory University, Atlanta, GA, USA, 5Baylor College of Medicine, Houston, TX, USA

Many oncogene and tumor suppressor pathways are mutated across a wide variety of cancers, suggesting that common pathways are used by many (if not all) cancers. In contrast, many of the familial cancer syndromes in which these pathways are mutated show an increased susceptibility for a limited panel of cancer types. One example is the disease

NF1 gene that has been shown to be mutated in many cancers, including brain, colon, lung, and ovarian cancers. NF1 patients are at increased risk for astrocytoma, malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, myeloid leukemia, and rhabdomyosarcoma.

an individual’s risk for developing astrocytoma in the central nervous system, compared to MPNSTs in the peripheral , et al. (2012) Neuro

Oncol , et al. (2012) Mamm Genome , et al. (2006) Cancer Res 66(1):62-68) and

Arlm1, shows an epistatic interaction with the

astrocytoma from these loci.


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O-44

HYPOTHYROIDISM INDUCES DEAFNESS IN SUSCEPTIBLE STRAINS: HUNT FOR THE PROTECTIVE GENE

Sally Camper1, Qing Fang1 2 1, Michelle Fleming1, Mirna Mustpaha3 1University of Michigan, Ann Arbor, MI, USA, 2The Jackson Laboratory, Bar Harbor, ME, USA, 3Stanford University, Palo Alto, CA, USA

Hypothyroidism during gestation or in newborns can cause permanent deafness and intellectual disability, although individuals vary in susceptibility. The fetal genetic background is responsible for the susceptibility to this birth defect

development of hearing suggested that the susceptibility would be genetically complex (2, 3). Surprisingly, a QTL Pou1f1dw/dw mutants that have profound,

congenital deafness, with CAST/Ei, suggested that a single locus on Chr 2, named Mdwh

hormone in the cochlea, and 10 map to the Mdwh region. We are comparing expression of these genes in susceptible and resistant strains to identify Mdwh. Knowledge of a gene that can protect against the pleiotropic effects of thyroid

to thyroid hormone supplementation.

March of Dimes (SAC), NIH (DFD, MM).

1. Mamm Genome 19:596, 2007

4. Genetics 189:665, 2011

O-45

Mtor DEFICIENCY IN MICE IMPAIRS GERMINAL CENTER FORMATION, ANTIBODY PRODUCTION AND HUMORAL RESPONSE TO BACTERIAL INFECTION

Beverly Mock1, Shuling Zhang1, Margaret Pruitt1, Dena Tran1, Wendy DuBois1, Mark Simpson1, Clifford Snapper2, Rafael Casellas1 1NCI, NIH, Bethesda, MD, USA, 2Uniformed Services University of Health Sciences, Bethesda, MD, USA

Bacterial infection is a common complication of immunosuppression in both organ transplantation and cancer treatment regimens. B cell maturation and antibody responses to bacterial infection require immunoglobulin (Ig) somatic

Mtor

CSR. Mtor Streptococcus pneumoniae had a high mortality rate (40%) compared to no lethality in wild-type littermates. SHM frequency within the Igh H4) intron was lower in sorted germinal center B cells from Mtor Ighg1/Ighg3 CSR and Ighlower in their ex vivo activated B cells. In wild type cells, pharmacologic inhibition of MTOR with rapamycin, frequently used as an immunosuppressant following organ transplantation, resulted in decreased ex vivo CSR at doses that did not impair cell cycle or induce apoptosis. RNA and protein levels of activation-induced cytidine deaminase (Aicda) were lower in Mtorincreasing Aicda expression restored CSR levels to that of wild-type B cells. Thus, Mtormodel for rapamycin treatment, and Mtor plays an important immunoregulatory role in the germinal center, through


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O-46

SUSCEPTIBILITY AND RESISTANCE LOCI FOR BENZENE GENOTOXICITY

Daniel Gatti1, Kristine Witt2, Daniel Morgan2, Kim Shepard3, Herman Price4, Grace Kissling2, Keith Shockley2, Leslie Recio3, Gary Churchill1 2 1The Jackson Laboratory, Bar Harbor, ME, USA, 2National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 3ILS, Inc., Research Triangle Park, NC, USA, 4Alion, Research Triangle Park, NC, USA

Workplace benzene exposure is a serious health hazard which, among other effects, disrupts the hematopoietic system. There is a wide variation in individual response to exposure and these differences may be due to individual genetic variation. Model organisms like the mouse allow us to control environmental factors and focus our attention on genetic factors. New genetic resources like the Diversity Outbred mice (derived from eight inbred founders) allow us to incorporate

crosses. In order to study the effect of genetics on benzene genotoxicity, we exposed ~600 male Diversity Outbred mice to a range of benzene concentrations and collected peripheral blood and bone marrow. We measured several traits related to red blood cell production and DNA damage. One such measure is the proportion of micronucleated

fact, this locus was important for many DNA damage traits in both reticulocytes and mature red blood cells. We found several other loci with a complex mixture of founder effects. This study shows the utility of the Diversity Outbred for furthering our understanding of the genetic basis of toxicology.

O-47

RESISTANCE TO PLAGUE OF Mus spretus SEG/Pas MICE REQUIRES THE COMBINED ACTION OF AT LEAST FOUR GENETIC FACTORS

Lucie Chevallier1 ,2, Charlène Blanchet1 ,2 1 ,2, Emilia Pachulec3, Christian Demeure3, Elisabeth Carniel3, 1 ,2, Xavier Montagutelli1 ,2

1Institut Pasteur, Mouse Functional Genetics Unit, Paris, France, 2CNRS, URA2578, Paris, France, 3Institut Pasteur, Yersinia Unit, Paris, France

Plague is an acute bacterial infection caused by the Gram-negative bacterium Yersinia pestis, which can develop in several forms, bubonic, septicaemic, or pulmonary. The rapid multiplication of the bacteria from the entry point and the

Y. pestis can escape host innate immune responses are responsible for very high mortality rate in the absence of effective antibiotherapy.

Y. pestis Yprl1, Yprl2 and Yprl3 as three QTLs controlling this exceptional phenotype in females from a backcross between SEG/Pas and C57BL/6 strains. We have now developed congenic strains to further characterize the

in males and females, while the third one may well be a spurious association. We show that no genomic region alone is able to increase the survival of C57BL/6 mice but that C57BL/6 mice carrying both Yprl2 and Yprl3 exhibit intermediate resistance. Each of these two QTLs contains at least two sub-regions which are required to increase survival. Finally, through the analysis of congenic strains in an F1 background, we establish the mode of inheritance of the SEG-derived

resistance to plague in SEG/Pas mice.


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O-48

HOST DIRECTED THERAPY AGAINST THE MALARIAL PARASITE

Clare Smith2, Gaetan Burgio1 ,2, Andreas Greth1 ,2, Pat Lelliott1 ,2, Elinor Hortle1 ,2, Meredith Roberts-Thomson2, Brendan McMorran1 ,2, Simon Foote1 ,2 1Macquarie University, Sydney NSW, Australia, 2Menzies Research Institute Tasmania, University of Tasmania, Tasmania, Australia

Malarial parasite resistance to all known antimalarial drugs is now the norm. Parasites develop resistance through

therapies that will bypass both these mechanisms of resistance. ENU mutagenesis is used to introduce mutations into the germline of mice that are otherwise susceptible to murine malaria. Mice carrying protective mutations will survive a

infection and have 40 resistant lines. Several of these mutations will be discussed. These include structural proteins as well as enzymes. Extensive analysis of the accompanying phenotypic changes will also be discussed. Strategies for

Poster Presentation Abstracts

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Poster Presentation AbstractsP-1 – P-75


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P-1

GENETIC MOUSE MODELS OF HUMAN CONGENITAL DIAPHRAGMATIC DEFECTS

Nian Zhang, Kate Ackerman University of Rochester, Rochester, USA

Progress towards understanding pathogenesis is limited due to embryonic lethality of mouse embryos carrying null mutations of diaphragm development genes. Association of mouse pathogenesis with human disease is limited by the complex genetic nature of the disease in humans and limited phenotyping data. It is unknown whether mutations in a

Our lab is currently investigating many different diaphragmatic defect models. We used Zfpm2multitype 2, previously known as friend of Gata, 2) and Gata4 models to investigate phenotypes observed with variable gene dosage and to develop conditional gene models for investigation of this and other developmental pathways. Six mutant alleles of Zfpm2 and Gata4 Wt1 (Wilms tumor 1) Cre recombinase lines.

Mutations were associated with both communicating (frank herniation with abdominal to thoracic communication) and noncommunicating (membrane intact) phenotypes. All mutant embryos derived from Zfpm2 crosses had muscularization defects, while many also displayed posterior communicating defects. Adult Zfpm2 mutation carriers develop anterior noncommunicating defects similar to human Morgagni hernias. Gata4produce earlier embryonic lethality. Gata4defects.

These studies address an unanswered question in medicine, that is, whether mutations in a single gene can cause or contribute to multiple diaphragmatic phenotypes.

P-2

DEFINING THE ROLES OF MOUSE COPII COMPONENTS SEC24C AND SEC24D

Elizabeth Adams1, David Ginsburg1 ,2, Andrea Baines1 1University of Michigan, Ann Arbor, MI, USA, 2Howard Hughes Medical Institute, Ann Arbor, MI, USA

Abstract can be found in the student satellite abstract section on page 21.


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P-3

IDENTIFYING GENETIC FACTORS DETERMINE THE BODY COMPOSITION TRAITS USING THE COLLABORATIVE CROSS MOUSE REFERENCE POPULATION AND DEXA SCAN ANALYSIS

Hanifa Athamni1, Caroline Durrant2, Richard Mott2, Fuad Iraqi1 1Tel-Aviv University, Tel-Aviv, Israel, 2Wellcome Trust Human Genome Center, University of Oxford, Oxford, UK

The Collaborative Cross (CC) is a novel mouse reference population designated for studying system genetics and dissection complex traits. Body composition have been used to study how lean body mass and body fat change during health and disease. In this study, we report a research aiming to determine the genetic factors underlying the body composition using the CC population and the power of the dual X-ray absorptiometry (DEXA) scan technique. The following phenotypes were recorded by the DEXA scan;; bone mineral density (BMD), bone mineral content (BMC), body fat content (BFC) and body fat and lean percentages (%), and will be used in the genome-wide scan analysis for identifying quantitative trait loci associated with these traits. Body length (BL) and weight (BW) for each mouse, the body mass index (BMI= BW/(BL2) were measured, which will also be used as a phenotype for determining the variation between the different CC lines. Finally, the waist circumstance (cM) and hip size (cM) were measured and waist/hip ration calculated. A total of 370 mice of average 4-10 of 18 to 20-week old mice of both sexes of each 37 line, which

using the mouse diversity (MDA) and mouse universal genotype arrays (MUGA). QTL mapping with these traits is ongoing and results will be presented at the conference.

P-4

SEVERAL CLASSICAL MOUSE INBRED STRAINS, INCLUDING DBA/2, NOD/LT, FVB/N, AND SJL, CARRY A PUTATIVE LOSS-OF-FUNCTION ALLELE OF Grp84

Fernando Benavides1, Carlos Perez1 2 1Department of Molecular Carcinogenesis, M. D. Anderson Cancer Center, Smithville, Texas, USA, 2Unité de Génétique Fonctionnelle de la Souris, Institut Pasteur, Paris Cedex 15, France

G protein-coupled receptor 84 (GPR84) is a 7-transmembrane protein expressed on myeloid cells that can bind to medium-chain free fatty acids in vitro. Here, we report the discovery of a 2-bp frame-shift deletion in the second exon of the Gpr84 gene in several classical mouse inbred strains. This deletion generates a premature stop codon predicted to result in a truncated protein lacking the transmembrane domains 4 to 7. We sequenced Gpr84 exon 2 from 50 strains representing different groups in the mouse family tree and found that 14 strains are homozygous for the deletion. Some

wild-derived inbred strains analyzed. Haplotype analysis suggests that the deletion originates from a unique mutation

ostensibly plays a role in the biology of myeloid cells, it could be relevant: (i) to consider the existence of this Gpr84 nonsense mutation in several mouse strains when choosing a mouse model to study immune processes;; and (ii) to re-evaluate previous immunological data obtained using such strains.


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P-5

INFORMATICS FOR THE INTERNATIONAL MOUSE PHENOTYPING CONSORTIUM

Andrew Blake1, Terrence Meehan2, Steve Brown1, Paul Flicek2, Ann-Marie Mallon1, Helen Parkinson2, William Skarnes3, and members of the MPI2 consortium 1MRC Harwell, Harwell, UK, 2EMBL-EBI, Hinxton, UK, 3Wellcome Trust Sanger Institute, Hinxton, UK

The International Mouse Phenotyping Consortium (IMPC) will generate a knockout mouse strain for almost every protein-coding gene in the mouse genome and will characterize each strain using a standardized, broad-based phenotyping pipeline. Phenotype data is being centralized, analysed and integrated by the MPI2 consortium in the IMPC-Data coordinating center. Dedicated ‘data wranglers’ are working with the production centers to ensure proper transfer and quality control of data occurs. An automated statistical analysis pipeline will identify knockout strains whose phenotype parameters have values that lie outside the normal range. Annotation with biomedical ontologies will allow biologists

resources will provide insights into mammalian gene function and human disease. Currently, users can search the

protocols being used by the IMPC production centers. The community is invited to sign up to receive strain production updates and to evaluate the presentation of data as we develop the IMPC web portal: www.mousephenotype.org

P-6

MOUSE FUNCTIONAL ANNOTATIONS EMPOWER ACCESS TO INTERNATIONAL MOUSE PHENOTYPING CONSORTIUM (IMPC) MICE

, Harold Drabkin, Mary Dolan, David Hill, Li Ni, Dmitry Sitnikov The Jackson Laboratory, Bar Harbor, ME, USA

The IMPC project (www.mousephenotype.org/ ) is rapidly generating new mouse resources by phenotyping mice derived from the International Knockout Mouse Consortium (www.knockoutmouse.org). The goal is the generation and phenotyping of mice, each strain of which has a knockout mutation in one of the mouse protein-coding genes. As this project progresses, the incorporation of information about these new mouse resources into comprehensive databases such as the Mouse Genome Database (www.informatics.jax.org) enables access to accumulated knowledge about the molecular functioning of the knocked-out genes. MGI curates over 12,000 articles a year from the biomedical literature that report experimental results from the mouse research system. Using the standardized methodology of the Gene Ontology Consortium (GO, www.geneontology.org ), the MGI curators annotate the functions and processes that protein-coding genes participate in. The MGI resource contains over 280,000 GO annotations to over 23,000 protein-coding genes. In addition to experimentally-based annotations, inferential annotations from experimental data originating in human and rat studies are obtained via ortholog determinations between these organisms. The network graphs of GO

grants HG002273 and HG000330.


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P-7

TREATMENT OF TS65DN MICE WITH EPIGALLOCATECHIN GALLATE AMELIORATES THE ABNORMAL APPENDICULAR SKELETAL PHENOTYPE CAUSED BY TRISOMY

Indiana University Purdue University Indianapolis, Indianapolis, IN, USA


P-8

THE JACKSON LABORATORY REPOSITORY: RESOURCE FOR MOUSE MODELS OF HUMAN DISEASE

Deborah M. Boswell, Stephen F. Rockwood, Cathleen M. Lutz, Michael Sasner, Leah Rae Donahue, the Repository Team The Jackson Laboratory, Bar Harbor, Maine, USA

The success of the mouse as a model organism for studying human disease in recent decades is readily evident in the

as a resource for mouse strains relevant to human disease. Newly developed and acquired models include strains that recapitulate aspects of inherited and complex diseases, tool strains with inducible reporter molecules or conditional

preclinical screening for new therapeutics. In addition to safeguarding each strain by cryopreservation, the Repository

initiative, the Rare and Orphan Disease Center brings mouse resources together with scientists, foundations and other experts to facilitate a comprehensive approach to developing models, optimizing research and enhancing therapeutic treatment discovery (http://research.jax.org/rodc).

Researchers can retrieve information related to strains in the Repository using an on-line resource (www.jax.org).

Researchers wishing to have strains considered for inclusion in the Repository can access the submission form available at: www.jax.org/donate-a-mouse.

Foundation for Parkinson’s Research and other private charitable foundations.


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P-9

A DATABASE OF PATIENT DERIVED XENOGRAFTS (PDX) FOR CANCER RESEARCH

Carol Bult The Jackson Laboratory, Bar Harbor, Maine, USA

of cancer biology and therapeutic intervention. So called “NOD scid gamma” (NSG) mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/

tissue bank, the Patient Derived Xenograft (PDX) resource, contains over 140 engrafted human tumors which are being

(MTB;; http://tumor.informatics.jax.org) database has developed a database of PDX models and their associated data

P-10

NEW QTL RESOURCES AT MGI

Carol Bult The Jackson Laboratory, Bar Harbor, Maine, USA

Supporting access to diverse genetic and genomic data for the laboratory mouse is a primary mission of the Mouse

multiple complex trait mapping studies in a whole genome context, we have developed an interactive QTL viewer that displays QTL studies from the primary literature against a whole genome map of the mouse genome. The QTL Viewer allows users to upload their own annotations to the viewer and to explore the biological attributes of genes and other genome features in the mapped regions. The Viewer is accessed from the Mouse Tumor Biology database home page (MTB;;http://tumor.informatics.jax.org). MGI has also implemented links from QTL detail pages in MGI to the QTL Archive resource (http://www.qtlarchive.org/). The QTL Archive contains phenotype and genotype data used to for QTL mapping. The QTL Viewer and links to the QTL Archive provide rich new functionality for complex trait analysis in MGI. Supported by NCI CA089713 and NHGRI HG000330.


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P-11

PRINCIPLES OF CELLULAR BARCODING, MOLECULAR BARCODES, AND CLONAL ANALYSIS IN COMPLEX TISSUES AND CELL POPULATIONS

Leonid Bystrykh ERIBA / UMCG / University of Groningen, Groningen, The Netherlands

In the last years we develop a methodology for cellular barcoding and clonal analysis of barcoded hematopoietic cells [1, 2]. The barcode is essentially a uniform synthetic DNA fragment inserted within the integrating vector. It serves as a

error-correcting binary codes can be adapted for the use as the DNA barcodes [3]. Compared to other methods, cellular barcoding with retro- or lenti- viral vectors provides an easy, uniform and quantitative tool to create, detect and analyze clonal diversity in cultured cells and mouse blood samples. This tool, however, can be used successfully if several

Since actual sequencing data are noisy and prone to different kinds of errors the detection and analysis of the barcodes in the experimental cell population should be able to discriminate true and false barcode sequences.

barcoding tool for clonal analysis in the hematopoietic system. Blood. 2010 Apr 1;;115(13):2610-8 2. Bystrykh LV, Verovskaya E, Zwart E, Broekhuis M, de Haan G, Counting stem cells: methodological constraints. Nat Methods. 2012, May 30;;9(6):567-74 3. Bystrykh LV. Generalized DNA barcode design based on Hamming codes. PLoS One. 2012;;7(5):e36852.

P-12

HIGH INCIDENCE OF SKEWED X INACTIVATION IN LABORATORY MOUSE IS A BYPRODUCT OF DOMESTICATION AND SPECIATION

1, Alan B Lenarcic1 1 2, William Valdar1, Fernando Pardo-Manuel de Villena1 1University of North Carolina, Chapel Hill, NC, USA, 2Cornell University, Ithaca, NY, USA



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P-13

EXAMINATION OF THE EFFECT OF A DNA REPAIR DEFECT ON THE EFFICIENCY OF ENU MUTAGENESIS

George Carlson1, Delisha Meishery1 1 2, David Beier1 ,2 1McLaughlin Institute, Great Falls, MT, USA, 2Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

ENU mutagenesis is a powerful method for generating novel lines of mice that are informative with respect to both fundamental biological processes and human disease. Rapid developments in genomic technology have made the task

mutation frequency achievable using standard treatment protocols, which currently generate approximately 1 sequence

carrying a mutation in the DNA repair enzyme Msh6 (either as heterozygous or homozygous) are treated using graded

the same method for genome sampling, we will examine whether serial treatment of progeny of mutagenized mice can yield founders carrying large numbers of heterozygous mutations.

P-14

MODELING STRAIN-SPECIFIC RESPONSE TO DIETARY CHALLENGE

Gregory Carter, Gary Churchill, Karen Svenson The Jackson Laboratory, Bar Harbor, ME, USA

Laboratory mice exhibit heritable variation in lean and fat body composition and response to dietary challenge. We propose a framework to link body composition and dietary response based on Forbes theory. The model implements

a simple mechanism to predict fat mass gain due to a high-fat diet. We assessed the model using a genetically diverse panel of the eight inbred founders of the Collaborative Cross. We measured lean and fat masses for the eight strains and nearly all F1 progeny on a standard chow diet. We found a population average consistent with Forbes theory, and performed diallel analysis to model genetic variation in body composition. We used this model to predict fat mass gain from a high-fat diet and validated these predictions with longitudinal body composition data for the eight founders. We found that individual (strain) responses to diet can differ dramatically from population averages. Our results demonstrate

regulation based on energy balance will likely require individualized parameters. Our study also demonstrates the power of hybrid crosses, which have been proposed for future studies using CC mice.


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P-15

ANALYSIS OF DELTA-LIKE 1 (DLL1) IN ADULT MURINE ISLETS

Davide Cavanna1 ,2, Daniel Gradinger1 ,2, Gerhard K. H. Przemeck1 ,2, Martin Hrabé de Angelis1 ,2 1Institute of Experimental Genetics, Neuherberg, Germany, 2German Center for Diabetes Research, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany, 3Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany


P-16

DEPENDENCE OF MOUSE EMBRYONIC DEVELOPMENT ON THE DE NOVO PYRAMIDINE BIOSYNTHESIS GENE Cad

1, Erin Stenson1, Yung-Hao Ching2 1Department of Biomedical Sciences, Ithaca, NY, USA, 22Department of Molecular Biology and Human Genetics, Hualien, Taiwan

Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) is a multi-functional protein that catalyses the ATP-dependent synthesis of de novo synthesis of pyrimidine. Mutations of CAD homolougs in several organisms have been reported, causing various phenotypes including impaired viability, sterility, dysmorphology and

Cad (Cad L5Jcs24 and Cad L5Jcs27) in live Mus musculus. These two N-ethyl-N-nitrosourea (ENU) – induced alleles cause peri-implantation lethality in homozygotes associated with developmental arrested between two-cell and blastocysts stage. Whereas cells bearing the CadL5Jcs24 allele retained carbamoyl phosphate synthetase (CPSase) activity, the activity was refractory to UTP inhibition. These results suggest that the CadL5Jcs24 mutant allele has impaired feedback regulation, and that disruption of this regulation is as critical to ICM growth and embryogenesis.


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P-17

SURVEY OF RNA-EDITING IN 15 LABORATORY MOUSE STRAINS

Petr Danecek1, Christoffer Nellåker2, Rebecca E McIntyre1 1, Suzannah Bumpstead1, Chris P Ponting1 ,2 3, Durbin Durbin1, Thomas M Keane1 1 1Wellcome Trust Sanger Institute, Cambridge, UK, 2MRC, Oxford, UK, 3The Wellcome Trust Centre for Human Genetics, Cambridge, United States Minor Outlying Islands

Adenosine-to-inosine (A-to-I) editing is a site-selective post-transcriptional alteration of double-stranded RNA by ADAR deaminases that is crucial for homeostasis and development. Recently the Mouse Genomes Project used short read sequencing to generate genome sequences for 17 laboratory mouse strains and RNA-seq data from whole brain RNA from 15 of the sequenced strains.

these calls taking into account systematic biases in alignment, single nucleotide variant calling, and sequencing depth to identify RNA editing sites with high accuracy. We applied this approach to our panel of mouse strain transcriptomes identifying 7,389 editing sites with an estimated false-discovery rate of between 2.9 and 10.5%. The overwhelming majority of these edits were of the A-to-I type, with less than 2.4% not of this class, and only three of these edits could not be explained as alignment artifacts. We validated 24 novel RNA editing sites in coding sequence, including two non-synonymous edits in the Cacna1d gene that fell into the IQ domain portion of the Cav1.2 voltage-gated calcium channel, indicating a potential role for editing in the generation of transcript diversity.

We show that despite over two million years of evolutionary divergence, the sites edited and the level of editing at each site is remarkably consistent across the 15 strains. In the Cds2the ancestral transcript sequence despite genomic sequence divergence.

http://genomebiology.com/2012/13/4/r26

P-18

A GENOMIC RESERVOIR FOR Tnfrsf GENES IS DEVELOPMENTALLY REGULATED AND IMPRINTED IN THE MOUSE

Elena de la Casa-Esperon1, Gaelle Cordier1, Nora Engel2 1Albacete Science and Technology Park;; Regional Center for Biomedical Research;; University of Castilla-La Mancha, Albacete, Spain, 2Fels Institute for Cancer Research and Biochemistry;; Temple University School of Medicine, Philadelphia, PA, USA

Imprinted genes are preferentially expressed from the paternal or the maternal allele. These genes often cluster forming imprinted domains, in which discrete imprinting control regions regulate the expression of multiple genes. One of these imprinted regions is the Kcnq1 domain on mouse Chromosome 7. However, imprinting does not necessarily affect to all genes within this region. For instance, three members of the tumor necrosis factor receptor superfamily, Tnfrsf22, 23 and 26, are located close to Kcnq1, but it has been controversial if they have imprinting. In addition, these genes appear to be absent in the human orthologous region. This suggests that these genes might have acquired imprinting due to their insertion in an already imprinted Kcnq1 domain during mammalian evolution.

We explored this hypothesis and found that all three genes are expressed during mouse embryonic development with strong maternal bias, indicating that they may be affected by the Kcnq1 imprinting control region. We also found expression in favor of the maternal allele of an antisense non-coding RNA, AK155734. To determine whether the genes were deleted from the KCNQ1 domain in humans or acquired in the rodent lineage, we performed phylogenetic analyses. We found that Tnfrsf sequences are present in orthologous regions of many vertebrates, while multiple mutations have rendered them undetectable in primates. Our data suggest that Tnfrsf genes were present within the Kcnq1 region before the establishment of imprinting, and were duplicated and/or degenerated or eliminated from the KCNQ1 region several times during the evolution of mammals.


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P-19

PHENOTYPE AND DISEASE MODEL DATA IN MGI: FROM PIPELINE TO PREDICTION

Howard Dene, Anna Anagnostopoulos, Randal Babiuk, Susan M Bello, Donna Burkart, Michelle Knowlton, Hiroaki Onda, Beverly Richards-Smith, Cynthia L Smith, Monika Tomczuk, Linda Washburn, Janan T Eppig The Jackson Laboratory, Bar Harbor, Maine, USA

Large-scale mutagenesis and phenotyping are accelerating discovery by placing new tools in the hands of researchers. The IMPC (International Mouse Phenotyping Consortium) is systematically deriving and phenotyping the plethora of knockout mutations that now exist as mutant ES cell lines. High-throughput sequencing is reviving interest in ENU

QTL are being revealed through studies using the Collaborative Cross and Diversity Outcross, expanding available data relevant to complex and chronic disease. In addition, investigators continue to create new mutations and complex

org) is capturing and integrating this array of phenotypic mutations and data, from single nucleotide changes to complex rearrangements, as well as QTL. Integration relies on the application of standard semantics (including nomenclature for genes, alleles, and strains, Mammalian Phenotype Ontology (MP) terms for phenotype calls, mutant molecular descriptions, and associations with human diseases based on experimental evidence) and brings these data into

annotation, MGI is a treasure for data mining and analyses. MGI makes data available via web browsing, downloadable

candidate human disease genes. Supported by NIH grant HG000330.

P-20

INCOMPATIBILITIES OF THE Prdm9 (Hst1) GENE IN MOUSE HYBRID STERILITY

Petr Flachs1, Ondrej Mihola1, Yasuhisa Matsui2 3, Frédéric Baudat4, Bernard de Massy4Piálek5 1, Zdenek Trachtulec1 1Department of Mouse Molecular Genetics;; Institute of Molecular Genetics, Academy of Sciences CR, Prague, Czech Republic, 2Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan, 3Center for Vertebrate Genomics, Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, USA, 4Institut de Genetique Humaine, CNRS UPR 1142, Montpellier, France, 5Institute of Vertebrate Biology, Academy of Sciences CR, Brno and Studenec, Czech Republic



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P-21

AN ONLINE RESOURCE FOR CERTIFICATION OF GENOMIC COMPOSITION OF MUTANT MOUSE STRAINS

Chen-Ping Fu University of North Carolina, Chapel Hill, NC, USA


P-22

CHARACTERIZATION OF AN ALLELIC VARIANT OF THE MECHANISTIC TARGET OF RAPAMYCIN (Mtor), A SUSCEPTIBILITY ALLELE FOR PLASMACYTOMA FORMATION IN BALB/CANPT MICE

1 ,2, Shuling Zhang1, Ke Zhang1, Dena Tran1, Aleksandra Michalowski1, Beverly Mock1 1CCR, NCI, NIH, Bethesda, MD, USA, 2Michigan State University, East Lansing, MI, USA



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P-23

DIABETES AND AGEING: THE HARWELL METABOLIC AGEING SCREEN

Michelle Goldsworthy, Stuart Noble, Petra Fay, Alison Hough, Laura Wisby, Paul Potter, Steve Brown, Roger Cox MRC Harwell, Oxfordshire, UK

Random ENU mutagenesis followed by comprehensive metabolic phenotyping has previously been used to identify a number of mouse models of obesity and type 2 diabetes (insulin resistance and insulin secretory defects). In order to identify genes involved in late onset metabolic disease and genes involved in diabetic complications that develop with age, male mice from G3 pedigrees are being screened at multiple time points. The screen includes body composition (Echo-MRI at 3, 6, 12 and 18 months) plasma biochemistry (4, 7, 13 and 19 months) including fasting glucose, insulin

glucose and/or insulin also undergo Intra Peritoneal Glucose Tolerance tests (IPGTT) at 5, 8, 14 and 18 months of age to further characterize disease.

(small size/altered body composition), and 3 lines with IGT are currently undergoing SNP mapping. The causative mutation for one of the low cholesterol mutants (Total Cholesterol 0.83±0.21 vs 3.50±1.18 mmol/l, p=0.005) has been

Pla2g12b.

P-24

MOLECULAR AND HISTOLOGICAL COMPARISON OF PANCREATA FROM ADULT Pax6Leca2 MUTANT MICE OF DIFFERENT AGES

Daniel Gradinger1 ,2, Davide Cavanna1 ,2, Gerhard K.H. Przemeck1 ,2, Martin Hrabé de Angelis1 ,2 1Institute of Experimental Genetics, Neuherberg/München, Germany, 2German Center for Diabetes Research, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg/München, Germany, 3Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany



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P-25

THE EUROPEAN MOUSE MUTANT ARCHIVE - EMMA

Michael Hagn6, Glauco Tocchini-Valentini1, Yann Herault2 ,9, Steve Brown3, Urban Lendahl4 5, Martin Hrabé de Angelis6, Paul Flicek7, Ramiro Ramirez-Solis8, Lluis Montoliu10, George Kollias11, Radislav Sedlacek12, Raija Soininen13, Thomas Rülicke14 1CNR Monterotondo, Monterotondo / rome, Italy, 2CNRS-CDTA, Orleans, France, 3MRC Harwell, Harwell, UK, 4Karolinska Institute, Stockholm, Sweden, 5Fundacao Calouste Gulbenkian, Oeiras, Portugal, 6Helmholtz Zentrum München GmbH, München, Germany, 7EMBL-EBI, Hinxton, UK, 8Genome Research Limited, Hinxton, UK, 9GIE-CERBM, Straßbourg, France, 10CNB-CSIC, Madrid, Spain, 11BSRC A. Fleming, Vari / Athens, Greece, 12Institute of Molecular Genetics, Prag, Czech Republic, 13University of Oulu, Oulu, Finland, 14University of Veterinary Medicine, Vienna, Austria

mutant mouse lines and access to a wide range of disease models and other research tools. A full description of these services can be viewed on the EMMA website at http://www.emmanet.org

The EMMA network is comprised of 14 partners who operate as the primary mouse repository in Europe and is funded

free mice for its customers and also hosts courses in cryopreservation.

All applications for archiving and requests for mutant mouse strains are submitted through the EMMA website. Mouse

granted depositors are asked to send mice of breeding age to one of the EMMA partners for embryo or spermatozoa cryopreservation. Strains held under the EMMA umbrella can be provided as frozen materials or re-derived and shipped as live mice depending on the customer’s needs. However, certain strains that are in high demand are maintained as

with the FELASA recommendations.

P-26IDENTIFICATION AND CHARACTERIZATION OF POSITIONAL CANDIDATES FOR Chr15 QUANTITATIVE TRAIT LOCI IN POLYGENIC OBESITY MOUSE MODEL

Simon Horvat1 ,2, Zala Prevorsek1, Gregor Gorjanc1 1, Nicholas Morton3, Mathieu Laplante4 1Biotechnical Faculty, Animal Science Department, University of Ljubljana, Domzale, Slovenia, 2National Institute of Chemistry, Ljubljana, Slovenia, 3University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK, 4Faculté de médecine Université Laval Centre de recherche de l’Institut universitaire de cardiologie et pneumologie de Québec (CRIUCPQ), Québec, Canada

Obesity results from the action of numerous genes and interaction with »obesogenic« environment presenting a severe risk factor for chronic diseases including diabetes, cardiovascular diseases and cancer. Forms of obesity with simple Mendelian inheritance are rare. Therefore, attention has turned to searching for genes of the more common polygenic

obesity QTL on mouse Chr15, Fob3a, Fob3b1 and Fob3b2Fob3a and Fob3b2 QTL using F2 crosses of congenic

identify candidates for Fob3a and Fob3b2 that were differentially expressed by employing microarray, expression and functional studies. Using these approaches, we found only a few positional candidates with demonstrated differential expression in white fat tissue and with additional hits from genomic, bioinformatics analyses in the mouse, as well as

Fob3a QTL, we show that Deptor is the highest-priority candidate most likely causal for the increased adiposity in this model. For Fob3b2 QTL, functional studies are under way for a highest

obesity and related metabolic disorders.


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P-27

DISSECTING HOST SUSCEPTIBILITY TO OBESITY-INDUCED TYPE 2 DIABETES DEVELOPMENT USING COLLABORATIVE CROSS (CC) MOUSE POPULATION

Hanifa Athamni1, Ala Amash1, Ilan Tasarfati1, Galia Tsarfati2, Konstantin Bloch3, Pnina Vardi3, Caroline Durrant4, Richarrd Mostt4, Fuad Iraqi1 1Tel-Aviv University, Tel-Aviv University, Israel, 2Sheba Medical Center (SMC), Sheba Hospital, Tel-Aviv University, Israel, 3Medical Research Center (FMRC), Tel-Aviv University, Israel, 4Wellcome Trust Center for Human Genetics (WTHGC), University of Oxford, Oxford, UK

The prevalence of Type 2 diabetes (T2D), in the past decades, has increased into epidemic proportions, and in year 2000 was 150 million and it is expected to double by the year 2025. Several lines of evidence provide support for the role of genetic variation in the pathogenesis of T2D and insulin resistance. In this context, diabetes can be considered as a disease, where the challenge is the Western diet. In this study, we report the analysis of 371 mice of 48 lines of CC population used for understanding the genetic bases of obesity-induced T2D. On average of 6-8 of 8 week old mice per line were maintained on high fat diet (42% fat) for a period of three months, and subsequently assessed by glucose tolerance test (GTT). We aim to identify the genetic determinants (quantitative trait loci, QTL) that determine susceptibility to challenge by a fat- and cholesterol rich diet, as expressed in of body weight, body composition by DEXA scan, fat accumulation in liver and at other sites of the body by using CT-scan, fasting insulin and proinsulin and Intraperitoneal glucose tolerance test (IPGTT) phenotypes that are acknowledged diabetes. Analyses of the phenotypic results have

was genotyped with high density SNP markers using the mouse diversity (MDA) and mouse universal genotype arrays (MUGA). QTL mapping with these traits is ongoing and results will be presented at the conference.

P-28

MULTIPLE PHASE ANALYSIS UNCOVERED DIFFERENT QTL ASSOCIATED WITH HOST SUSCEPTIBILITY DURING ASPERGILLUS FUMIGATUS INFECTION IN THE COLLABORATIVE CROSS MOUSE REFERENCE POPULATION

Caroline Durrant1, Richard Mott1, Fuad Iraqi2 1Wellcome Trust Human Genome Center (WTHGC), University of Oxford, Oxford, UK, 2Tel-Aviv University, Tel-Aviv University, Israel

Recently, we have mapped seven quantitative trait loci (QTL) associated with host susceptibility to Aspergillus fumigatus

(Durrant et al 2010 Genome Res). Here, we have reanalyzed this data based on multiple phase strategy, taking in account of the numbers of live and dead mice at each time point as a trait of monitoring. In total 413 immune-competent mice from 81 CC lines, at breeding generations 8-14, were challenged by AF. Daily survival rates after infection were recorded. In addition to the seven QTL we previously mapped (on Chromosomes 2, 3, 8, 10 (two QTLs at the proximal

Chromosome 10 was close to, but separate from, the previously mapped proximal QTL. Moreover our new analysis shows that the previously mapped seven QTL have effects at different time points during the challenge and are not

previously mapped QTLs on Chromosome 10 expressed at different time points of the challenge. The different QTL were mapped within small genomic interval regions between 0.47 and 1.2 Mb. A number of candidate genes underlying the QTLs are suggested.


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P-29

MAPPING MODIFIERS OF THE Apc GENE IN INTESTINAL CANCER DEVELOPMENT USING THE COLLABORATIVE CROSS MOUSE REFERENCE POPULATION

Mustafa Mahajne1, Ian Tomlinson2, Richard Mott2, Fuad Iraqi2 1Tel-Aviv University, Tel-Aviv University, Israel, 2Wellcome Trust Human Genome Center (WTHGC), University of Oxford, Oxford, UK

Familial adenomatous polyposis (FAP) is a rare autosomal dominant genetic disease, which is characterized by multiple colorectal adenomatous polyps. It is be caused by a functional mutation in the adenomatous polyposis coli (APC) gene. In order to investigate the syndrome in vivo, ApcMin+/- mice were developed, imitating the polyp phenomenon in humans. In previous studies, Min Apc Apc genes have been mapped (Mom1-10

ApcMin-/+ were mated with female mice from 23 CC lines. The litters carrying Apcmouse diet at conventional facility, and the small intestines and colon were extracted for polyp counts. The size, number

and colon between different CC lines. Broad sense heritability was calculated and found to be 0.45. QTL mapping with these traits is ongoing and results will be presented at the meeting.

P-30

INITIATION OF MEIOTIC RECOMBINATION IN HUMANS BY DIRECT BINDING OF PRDM9A TO HOTSPOTS

Pavlina Ivanova, Christopher Baker, Petko Petkov, Ken Paigen The Jackson Laboratory, Bar Harbor, ME, USA

PRDM9 determines the location of meiotic recombination hotspots in human and mice, with a large tandemly repeated PRDM9A

allele is the most abundant human allele in Caucasians. Modeling the PRDM9A-DNA interaction inferred a 13 bp consensus motif, found in 41% of human hotspots. Population and genomic data suggest that this motif cannot solely explain the activity of PRDM9A, because the presence of PRDM9A is linked to ~70% of recombination activity in Caucasians, and hotspots that do not contain the motif are also activated by PRDM9.

Our study aimed to identify the PRDM9 binding sites within hotspots. Using PRDM9 expressed in E.coli, we detected the binding sites for PRDM9 in several human hotspots by electrophoretic mobility shift assays. We found two binding sites within human hotspot S which is activated by PRDM9A, neither of them having the 13 bp consensus motif, and termed them Sp and Sd. The minimal site lengths are 21 - 24 bp for Sp and 27 bp for Sd. Taking into account that one zinc

A. Transfecting HEK293 cells with a PRDM9A-expressing construct resulted in appearance of

are complex, including the ability to bind at sites lacking the consensus sequence.


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P-31

GENETIC VARIATIONS INFLUENCING HEARING ABILITY IN 6 INBRED MOUSE STRAINS

Yoshiaki Kikkawa1, Yasuhiro Ohshiba1 ,2, Yuki Miyasaka1 ,2, Sari Suzuki1 ,3, Kunie Matsuoka1, Ryo Kominami2 1Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan, 2Niigata University, Niigata, Japan, 3Tokyo University of Agriculture, Abashiri, Japan

Many inbred mouse strains exhibit variability in hearing ability and age-of-onset of age-related hearing loss (AHL). In most case, the Cdh23ahl (Cdh23753A) variant is associated with increased susceptibility to AHL, and the Cdh23Ahl+ (Cdh23753G) variant with enhanced resistance. Here, we report the hearing abilities of the Cdh23ahl strains (including BALB/

Cdh23Ahl+ strains (including C3H/HeN and MSM/Ms) using measurement of the auditory brainstem response (ABR). The Cdh23ahl strains exhibited characteristics typical of early-onset and of late-

elevated ABR thresholds at 4-16-kHz sounds. Interestingly, the time of onset of hearing loss for high-frequency sounds

Cdh23Ahl+ strains retained normal hearing beyond 12-months-of-age;; however, after 12 months, C3H/HeN mice progressively lost the ability to hear low-frequency sounds. In contrast, the MSM/Ms mice remained resistant to AHL until 20 months of age. Analysis of B6-MSM consomic and congenic mice demonstrated an AHL-resistance allele to the MSM mice located within approximately 7-Mb interval on Chromosome 17.

P-32

IMPAIRED MATERNAL CARDIOVASCULAR ADAPTATION TO PREGNANCY IN HcB8 MICE

University of Wisconsin-Madison, Madison, WI, USA



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P-33

IDENTIFICATION OF A MAJOR EFFECT GENE MODULATING INFARCT VOLUME

Han Kyu Lee, Sehoon Keum, Denise Dunn, Donald Lo, Douglas Marchuk Duke University Medical Center, Durham, North Carolina, USA

Although numerous epidemiologic studies have estimated that two-thirds of the population-attributable risk for stroke is

mouse model of infarction, different inbred mouse strains show profound differences in infarct volume, indicating that infarction is under strong genetic control. To identify natural genetic determinants modulating infarct damage, we performed quantitative trait locus (QTL) linkage analysis and a genome-wide association study of cerebral infarct volume using 31 inbred strains. We have mapped a locus on distal Chromosome 7 that contributes over 50% of the observed variation in infarct volume, as well as other loci of smaller effect.

genes. To identify the gene(s) underlying this locus, we determined the transcript levels of all 12 genes in relevant tissues from our original mapping strains. Tissues included P1 and adult brain, and embryonic macrophages due to their importance in the development of the cerebrovascular system. One gene, interleukin 21 receptor (Il21r), showed a

Ex vivo brain slices from different inbred strains and a Chromosome

neuroprotection. Thus, at least some of the effects of this locus may be due to differences in cerebrovascular-independent neuroprotection. We are extending this work to determine whether Il21r or any of the other genes may be responsible for these effects.

P-34

THE POTENTIAL MALE-SPECIFIC ONCOGENIC FUNCTION OF CDCA7L IN ASTROCYTOMA

Min-Hyung Lee1 1, Karl Broman2, Karlyne Reilly1 1Mouse Cancer Genetics Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA, 2Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA



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P-35

COLLATERAL DAMAGE: SPONTANEOUS MUTATIONS FROM A TARGETED KNOCKOUT PROGRAMME

Morag Lewis



P-36

MOUSE GENE NOMENCLATURE AT MOUSE GENOME INFORMATICS (MGI)

Monica McAndrews The Jackson Laboratory, Bar Harbor, ME, USA

Standardization of nomenclature for mouse genes, alleles and strains facilitates the communication and integration of

Mouse Genome Informatics (MGI, www.informatics.jax.org) group maintains the international authoritative resource for the identity and names of mouse genes, genetic markers, alleles, chromosome aberrations, genomic features, and strains. To that end, each of these objects is catalogued in MGI and includes a unique ID and a list of synonyms with

Gene Nomenclature Committee (HGNC) and the Rat Genome Database (RGD) in coordinating mammalian naming conventions and meets annually with the International Committee on Standardized Genetic Nomenclature for Mice to develop international naming guidelines. Nomenclature staff correspond with authors to reserve and release new

databases contact MGI with nomenclature issues and the MGI nomenclature coordinator works with HGNC, RGD, domain experts, and authors to resolve them.

This year we assigned, resolved, and updated nomenclature for many genes and pseudogenes, including ribosomal protein pseudogenes, long intergenic non-protein coding RNAs, microRNA clusters, butyrophilin genes, beta tubulins, and the Bpif genes. We also assisted investigators with naming genetically engineered alleles and markers and continued

This work is supported by NIH grant HG000330.


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P-37

MegaMUGA: A VERSATILE MEDIUM DENSITY MOUSE GENOTYPING PLATFORM

Leonard McMillan University of North Carolina, Chapel Hill, NC, USA

MegaMUGA is a second generation medium density SNP genotyping array optimized for genetic analysis of diverse

66K SNPs were selected to be optimally distributed and highly informative for detecting genetic diversity in the eight founder strains of the Collaborative Cross (CC) and Diversity Outcross (DO) populations. These selected SNPs maximize the number of uniquely distinguishable CC/DO founder haplotype combinations over every 5-SNP sliding window (mean genomic range of 200Kb) and have an overall mean minor allele frequency of 0.32. We spatially distributed these markers according to observed recombination frequencies in the CC population, with an additional increase in density toward the ends of chromosomes. In addition, we included 13.5K SNPs from wild Mus musculus mice, as well as additional markers in the pseudoautosomal region, mitochondria, and Y. Finally, we added markers for tagging constructs common in genetically engineered mice. All informative SNPs from the precursor 7.5K Mouse Universal Genotyping Array (MUGA) are included in MegaMUGA’s design. MegaMUGA will be commercially available and will represent a

for diverse mice.

P-38

CHARACTERIZING THE ROLE OF THE UBIQUITIN LIGASE Itch IN C57BL/6J-APCMIN/+/J GUT HOMEOSTASIS AND INTESTINAL TUMORIGENESIS

Heather Mentrup, Elizabeth Thames, Wassim Basheer, Margeaux Wetendorf, Lydia E. Matesic University of South Carolina, Columbia, SC, USA

Abstract can be found in the student satellite symposium section on page 21.


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P-39

AN UPDATE ON THE DISTRIBUTION CENTER FOR THE COLLABORATIVE CROSS POPULATION AT UNC-CHAPEL HILL

Catherine E Welsh1, Darla R Miller1, Kenneth F Manly1 1, Leonard McMillan1, Grant Morahan2, Richard Mott3, Fuad A Iraqi4, David W Threadgill5, Fernando Pardo-Manuel de Villena1 1UNC at Chapel Hill, Chapel Hill, NC 27599, USA, 2The University of Western Australia, Perth, WA, Australia, 3University of Oxford, Oxford OX3 7BN, UK, 4Tel Aviv University, Ramat Aviv, 69978, Israel, 5North Carolina State University, Raleigh, NC 28695, USA

The Collaborative Cross (CC) is a panel of recombinant inbred lines derived from eight genetically diverse laboratory inbred strains. Recently the genetic architecture of the CC population was reported based on the genotype of a single male per line and other publications report incompletely inbred CC mice that have been used to map a variety of traits. The three breeding sites in the US, Israel and Australia, are actively collaborating to accelerate the inbreeding process through marker-assisted inbreeding and to expedite community access of CC lines deemed to have reached

population through distribution centers. Here we provide a description of the distribution efforts by the University of North Carolina Systems Genetics Core, Tel-Aviv University, Israel and and the University of Western Australia.

P-40

THE JAX KOMP2 PROGRAM: RESOURCES AND OPPORTUNITIES

Stephen Murray, Rick Bedigian, Caleb Heffner, Leslie Goodwin, Laura Reinholdt, Michael Wiles, Mary Ann Handel,

The Jackson Laboratory, Bar Harbor, ME, USA

The overall goal of the KOMP2 (Knockout Mouse Project “2”) program is to annotate gene function and to build mouse models through genome-wide generation and phenotyping of knockout mice. This leverages the massive resource created by the International Knockout Mouse Consortium (IKMC), which has nearly completed a library of targeted

2 Program will generate

discovery while reducing the cost of creating new models. KOMP2 offers an unprecedented opportunity to apply a parallel, standardized set of broad phenotyping modalities to a genome-wide set of knockout strains, eliminating the variability and ascertainment bias intrinsic to analysis in individual labs. In addition to 25 tests comprising over 100 phenotypic parameters for adult mice, we will be assessing embryonic lethal phenotypes, performing both male and female fertility screens and developing an atlas of gene expression through comprehensive analysis of in situ LacZ reporter activity.

2 screen, to expand individual research programs and to provide detailed mechanistic insights into gene function. We will discuss current progress and new developments in the context of the international effort. Supported by NIH grants: OD011185 and HG006332.


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P-41

ALTERED ENTERIC NEURAL CREST CELL DIFFERENTIATION IN THE POSTNATAL GANGLIONATED BOWEL OF Sox10Dom/+ HIRSCHSPRUNG MOUSE MUTANTS

Melissa Musser1 ,2 2, E. Michelle Southard-Smith2 ,3 1Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA, 2Genetic Medicine, Vanderbilt University, Nashville, TN, USA, 3Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA


P-42

THE COLLABORATIVE CROSS MOUSE POPULATION FOR DISSECTING HOST SUSCEPTIBILITY TO MIXED INFECTION INDUCING ALVEOLAR BONE LOSS

Aysar Nashef1 ,2, Yaser Salaymeh2, Ariel Shusterman1, Richard Mott3, Caroline Durrant3, Ervin Weiss1, Yael Houri-Haddad1, Fuad A. Iraqi2 1Department of Prosthodontics, Hadassah Medical Center, Jerusalem, Israel, 2Departmentof Clinical Microbiology and Immunology, Tel Aviv University, Ramat Aviv, Israel, 3Wellcome Trust Human Genome Centre, Oxford University, Oxford, UK



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P-43

SITUS INVERSUS VISCERUM (iv) - A ROBUST AND VIABLE MOUSE MODEL OF PRIMARY CILIARY DYSKINESIA

Dominic P Norris1, Saloni H Patel1, Elizabeth C Adam2, Patricia M Goggin2 1, Martin D. Frey1, Michael T. Cheeseman1 2, Peter M Lackie2 1MRC Harwell, Oxon, UK, 2University of Southampton Faculty of Medicine, Southampton, UK

without additional deleterious defects has been elusive. The situs inversus viscerum (iv) mouse is a long established model for situs inversus, resulting from a spontaneous mutation in the dynein, axonemal, heavy chain 11 gene (Dnahc11). This laterality phenotype is due to immotile cilia in the embryonic node. We have demonstrated immotile tracheal cilia with normal ultrastructure and reduced sperm motility in the Dnahc11iv mouse. This is accompanied by gross rhinitis, sinusitis, and otitis media, all indicators of human PCD. Strikingly, age-related progression of the disease is evident. A

iv mice do show a reduction in sperm count, sperm motility and progressivity, analysis of early post implantation embryos reveals

Dnahc11iv mouse is robust, lacks secondary defects, and requires no

human PCD in which disease progression can be followed from birth into old age.

P-44

IMPACT OF Rint1 KNOCKOUT ON TUMORIGENESIS IN THE ApcMin/+ MOUSE

Karla Otterpohl University of Nebraska Medical Center, Omaha, NE, USA

Colon cancers arise from benign adenomas, which lose the APC tumor suppressor gene by somatic mutation or deletion.

ApcMin/+ mice carry a germline mutation in Apc and spontaneously develop intestinal adenomas. Intestinal tumorigenesis

Mom5, that impacts tumor number in ApcMin/+ mice. At present, the best candidate gene for Rint1, a tumor suppressor that impacts cell proliferation and survival via control of the G2-M checkpoint

and centrosome integrity. Mice heterozygous for a Rint1 knockout allele spontaneously develop tumors in various tissues, whereas homozygosity for this knockout leads to embryonic lethality. To evaluate Rint1in ApcMin/+ Rint1tm1Whl mice with ApcMin/+ mice and evaluated the phenotype.

Rint1+/+;; ApcMin/+ (53.22±7.9) and Rint1+/-;; ApcMin/+ (45.7±5.9) mice. However, the Rint1+/- strain used in this intercross was on a mixed genetic background that

Apc-mediated tumorigenesis. Serial backcrosses have now eliminated most of these regions, which allows us to evaluate tumorigenesis in Rint1+/+ and Rint1+/-;; ApcMin/+ mice on a more uniform background. In addition to evaluating the impact of Rint1 knockout on adenoma number, size and histology, we are also assessing the impact of the Rint1 knockout on adenoma cell proliferation and genome stability.


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P-45

VARIATION IN SPERM QUALITY IN COLLABORATIVE CROSS FOUNDER STRAINS AND EXTINCT LINES

Wenqi PanFernando Pardo-Manuel de Villena, Deborah O’Brien University of North Carolina at Chapel Hill, Chapel Hill,NC, USA

Abstract can be found in te student satellite abstract section on page 27.

P-46

LARGE-SCALE MOUSE GENETICS INFRASTRUCTURES: FROM HIGHLY CUSTOMIZED SCREENS TO INTERNATIONAL PROGRAMS

Guillaume Pavlovic1, Marie-Christine Birling1, Marie Wattenhofer-Donze1 1, Abdelkader Ayadi1, Tania Sorg1, Yann Herault1 ,2 1Institut Clinique de la Souris, ICS, Illkirch, France, 2Institut de Génétique Biologie Moléculaire et Cellulaire, IGBMC, CNRS, INSERM, Université de Strasbourg, UMR7104, UMR964, Illkirch, France

Nowadays, mammalian genetics face 3 main challenges: - Improvement of the knowledge of our genome or understanding the function of protein coding genes and non-coding sequences

- Developing new treatments and improving the drug discovery process

Answers to these challenges are now within reach thanks to the developments in mouse mutagenesis and phenotyping. International major programs will provide mutants ES cells or models, phenotyping data and will develop new tools. The International Knockout Mouse Consortium effort (IKMC) aims to mutate all protein-coding genes and microRNA. Update and recommendations for the use of this resource will be presented. The International Mouse Phenotyping Consortium (IMPC) undertakes a broad-based, systematic genome-wide phenotyping project on knockout mice. The French PHENOMIN initiative started this year. It will enhance the Phenogenomics in mouse models, develop novel tools,

The importance of large-scale infrastructure for supporting mouse genetics is a second key development of the past years. These centers played a major role in the success of these programs and helped scientists in their researches. The French Institut Clinique de la Souris (ICS) combines the capacity of generating mutant mice on a large scale with a high-throughput and comprehensive phenotypic analysis of mice, but also customized protocols to better answer the scientist’s needs. The ICS has also developed resources such as a creERT2 zoo in order to provide to scientists new tools for in-depth studies.


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P-47

DNA BINDING SPECIFICITIES OF THE ZINC FINGER RECOMBINATION PROTEIN PRDM9

Timothy Billings1, Emil D. Parvanov2, Christopher E. Baker1, Michael Walker1, Ken Paigen1, Petko M. Petkov1 1Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA, 2National Centre for Biomolecular Research and Department of Biology, Masaryk University, Brno 625 00, Czech Republic

In many organisms recombination occurs at limited sites, termed hotspots, whose positions in mammals are determined

this we now show that mouse PRDM9 protein expressed in E. coli binds hotspot DNA sequences in a manner that is Prdm9 allele and the haplotype sequence of the binding site, and parallels in vivo biological activity.

Examining four hotspots, three activated by PRDM9Cst and one activated by PRDM9Dom2, each binding site required the

binding sites of the three PRDM9Cstof each position in the Hlx binding site, which is activated by PRDM9Cst, was tested by mutating each nucleotide to its three alternatives;; the 31 positions along the binding site varied considerably in the ability of alternate bases to support

P-48

THE BXH/HXB RAT RECOMBINANT INBRED STRAINS FOR THE ANALYSIS OF COMPLEX TRAITS: THE OMICS APPROACHES

Michal Pravenec1, Edwin Cuppen2, Timothy Aitman3, Norbert Hubner4, Theodore Kurtz5 1Institute of Physiology AS CR, Prague, Czech Republic, 2Hubrecht Institute, Utrecht, The Netherlands, 3Imperial College, London, UK, 4Max-Delbruck-Center for Molecular Medicine, Berlin, Germany, 5University of California, San Francisco, USA

The spontaneously hypertensive rat (SHR) is the most widely studied animal model of human essential hypertension and also displays large numbers of other (patho)physiological phenotypes, including cardiac hypertrophy and failure and features of the human metabolic syndrome. More than 200 QTLs associated with these traits have been reported in the SHR. For genetic and correlation analyses of complex traits, the BXH/HXB recombinant inbred (RI) strains (N=30) were derived from the SHR and BN-Lx progenitors. These RI strains are extremely valuable because of the cumulativeness of multiple data sets, including transcriptomic, proteomic, metabolomic or epigenomic variability, which represent intermediary phenotypes of different levels of complexity between variability at DNA level and complex (patho)physiological traits. These multiple accumulated intermediary phenotypes can be used for linkage and correlation

genome sequences of the SHR and BN-Lx progenitor strains are available to prioritize candidate genes for in vivo

disease phenotypes in the rat. These can then be tested for their relevance to the pathogenesis and treatment of the corresponding human diseases.


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P-49

CONGENIC MOUSE LINES VALIDATE RECIPROCAL ALLELIC EFFECTS AND REVEAL A SIGNIFICANT INTERACTION BETWEEN GENES MAPPING TO TWO MAJOR LOCI AFFECTING HYPEROXIC ACUTE LUNG INJURY SURVIVAL TIME

Daniel Prows1 ,2 1 1, Megan Reynolds1 1Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, 2University of Cincinnati, Cincinnati, USA

Acute lung injury (ALI) represents a continuum of pulmonary severity that can culminate in acute respiratory distress syndrome (ARDS), a life-threatening disease with high mortality. Genetic strategies to identify important susceptibility

established a mouse model of hyperoxic acute lung injury (HALI) susceptibility, using survival time for genetic analysis

resistant. QTL analyses of separate F2on Chromosomes 1 (Shali1) and 4 (Shali2). As expected, X1-alleles for Shali1 were associated with added resistance and B-alleles with increased sensitivity. Interestingly, Shali2 alleles had the opposite effect on survival time;; B-alleles for Shali2 led to increased survival times and X1-alleles imparted added sensitivity. These opposing effects suggested that single congenics for either QTL would bring together (synchronize) sensitive or resistance alleles for both QTLs. Indeed, the reciprocal allelic effects were validated in vivo and the dramatic increased (Shali2) and decreased (Shali1) survival times, compared to the predicted effects from QTL analysis, supported a strong interaction between effector genes within

the apparent bidirectional epistatic interactions between these major-effect loci.

P-50

CELL-BASED SIMULATION OF DYNAMIC EXPRESSION PATTERNS IN THE PRESOMITIC MESODERM AND GROWING PANCREATIC DUCT

Hendrik Tiedemann1 ,2, Elida Schneltzer1 ,2, Stefan Zeiser3, Bastian Hoesel1, Daniel Gradinger1 ,2 1 ,4, Gerhard Przemeck1 ,2, Martin Hrabé de Angelis1 ,4 1Institute of Experimental Genetics, Helmholtz Zentrum München – German Research Center for Environmental Health, Munich/Neuherberg, Germany, 2German Center for Diabetes Research, Munich/Neuherberg, Germany, 3Kinesis Pharma BV, NK Breda, The Netherlands, 4Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany

Dynamic gene expression patterns, proliferation and differentiation are key features of early embryo development and organogenesis. The periodic separation of somites from the growing presomitic mesoderm (PSM), or the differentiation and separation of endocrine precursor cells from the growing pancreatic duct are both processes for which Delta/Notch (D/N) signaling is essential.

For somitogenesis, the basic mechanisms are often discussed in terms of the clock-and-wave-front model. Candidate genes are the cyclically expressed Hes genes functioning as the clock and posteriorly expressed Fgf, Tbx6, and Wnt genes establishing the gradient(s). Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we propose a cell- and gene-based computer model for mammalian somitogenesis, simulating a gene regulatory network combining clock (Hes1/7) and gradient (Tbx6, Fgf8, Wnt3a) with D/N signaling resulting in dynamic gene expression patterns, as observed in vivo

Furthermore, we adapted our cell-based computer model that simulates the collective behavior of many cells to the growing pancreatic duct, where a gene regulatory network, driven by the D/N pathway, leads to the formation of Neurog3 positive endocrine precursor cells.


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P-51

INFRAFRONTIER – THE EUROPEAN INFRASTRUCTURE FOR THE PHENOTYPING, ARCHIVING AND DISTRIBUTION OF MODEL MAMMALIAN GENOMES

Michael Raess, Martin Hrabé de Angelis, The Infrafrontier Consortium Helmholtz Zentrum Muenchen, Neuherberg, Germany

Medically related life sciences use mouse models to understand the functional basis of human disease. However, the existing capacities for the systemic phenotyping, archiving and distribution of mouse models in Europe do not match the increasing demand by the community. Moreover, sustainable funding solutions are not always in place. These issues are being addressed by Infrafrontier, which is part of the Roadmap of the European Strategy Forum on Research Infrastructures (ESFRI) since the year 2006:

1) Capacity building(bottom-up) and for large-scale top-down programs such as the International Mouse Phenotyping Consortium (IMPC);; 2) Securing sustainable funding for the mouse productions centres, mouse repositories and primary phenotyping centres that contribute to the Infrafrontier Research Infrastructure, both through national funding and the funding instruments for research infrastructures within Horizon 2020;; 3) Providing a single point-of entryResearch Infrastructure;; underpinned by common quality standards and operation procedures, pan-European capacity and risk management, and user training.

The Infrafrontier consortium consists of 29 partners, representing the leading mouse clinics, and the major archiving and distribution nodes organized in the European Mouse Mutant Archive (EMMA), as well as the related ministries and major funding bodies from 12 European countries and Canada. The Infrafrontier Research Infrastructure will shape the

function in human health and disease.

P-52

FIND YOUR MOUSE VIA THE INTERNATIONAL MOUSE STRAIN RESOURCE (IMSR) (WWW.FINDMICE.ORG)

Beverly Richards-Smith Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor ME, USA

The IMSR is a searchable online database of mouse strains, stocks and mutant ES cell lines, including mutants from several large-scale ENU/targeted mutagenesis projects, available from repositories around the world. The purpose of

How can users search IMSR? Any part of a strain name or of a gene/allele symbol/name may be entered in the Search box. One or more values can be selected for State (live, embryo, germplasm or ES cell), Strain Type (e.g., congenic, noninbred, recombinant inbred), Repository/map region, and Mutation Type (e.g., deletion, spontaneous, transgenic).

What information can be accessed via IMSR? For each strain or cell line listed, IMSR provides the Strain Name, Synonyms and Type;; Mutation Types for associated alleles;; the Repository maintaining the strain and in what State(s). IMSR also contains links to strain descriptions on the holding Repositories’ Web sites and to gene, allele and transgene details in the Mouse Genome Informatics (MGI) database (www.informatics.jax.org). A click opens an order form on the Repository site or an email form to send a query to the Repository.

April 2012 saw IMSR 3.0 released, with an entirely rewritten Web application incorporating multiple new features including greatly improved performance, optimized searching and direct links to Repository order forms. Results are

and exported in tab-delimited or Excel format.

Supported by NIH grant LM009693.


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P-53

SEROTONIN SIGNALING IN NEURAL CREST-DERIVED PROGENITORS IN THE LOWER URINARY TRACT

Elaine Ritter2 ,3, Dennis Buehler1 ,2, Sara Ireland1 ,2, Michelle Southard-Smith1 ,2 1Department of Medicine, Vanderbilt University, Nashville, TN, USA, 2Division of Genetic Medicine, Vanderbilt University, Nashville, TN, USA, 3Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA


P-54

FUNCTIONAL ANALYSIS OF THE OPIOID RECEPTOR, DELTA ON ALCOHOL METABOLISM

Christine Rubinshteyn1, David Aylor2, Wendy Foulds-Mathes2, Darla Miller2, Daniel Pomp2, Fernando Pardo-Manuel de Villena2, David Threadgill1 1North Carolina State University, Raleigh, NC, USA, 2University of North Carolina at Chapel Hill, Chapel Hill, NC, USA



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P-55

COMPREHENSIVE MOLECULAR CHARACTERIZATION OF MUTANT MOUSE STRAINS GENERATED FROM THE EUCOMM / KOMP ES CELL RESOURCE

Ed Ryder, Diane Gleeson, Debarati Sethi, Sapna Vyas, Evelina Miklejewska, Priya Dalvi, Bishoy Habib, Ross Cook,


cells is currently the biggest single resource of targeted mutations available for the mouse. The Wellcome Trust Sanger Institute Mouse Genetics Project (Sanger MGP) generates the strains from these clones, and characterizes the phenotypic

To date over 700 lines have been produced by the Sanger MGP. To ensure the quality of this resource, new colonies are subject

absence of additional insertions and for the presence of the 3’ LoxP site. Approximately 86% of lines passed the targeting and cassette structure tests;; while 96% had the expected 3’ LoxP site. The characteristics of the QC-failed lines are discussed and should act as a guide for researchers generating their own lines on what potential issues may exist and how to detect them. Many of the issues observed in the mouse lines may be derived from mixed clone populations which were not detected using the mainly PCR-based primary screen on the ES cells. Therefore, it is vital to check all heterozygous chimera progeny for each colony with all tests to detect these events and prevent them from propagating through the colony.

P-56

AN ALBINO C57BL/6N STRAIN FOR EUCOMM/KOMP MOUSE GENERATION IN A PURE GENETIC BACKGROUND

Ed Ryder


are characterized in a comprehensive primary screen. All mice are now produced on a pure C57BL6/N background, in line with the emerging International Mouse Phenotyping Consortium (IMPC) and associated programmes including the NIH-funded KOMP2 project.

Normally, to preserve the purity of the genetic background, all chimeras are mated to black C57BL/6N mice. Therefore colour selection cannot be used to detect germ-line transmission (GLT), and consequently all G1 mice have to be genotyped. Here, we introduce a C57BL/6N albino strain which restores the ability to score GLT by coat colour of the chimera progeny, greatly decreasing costs and effort, and improving animal welfare. The new strain originated from a mutation of the tyrosinase locus in an ES clone used to generate one of the mutant strains in the MGP. This mutation consists of a 14.3Kb deletion spanning 940bp 5’ of the start of exon 1 to 3.75kb 3’ of exon 2.

Genome sequencing of the two albino founder mice of the colony is now underway to determine whether any large deleterious mutations are present which could limit its use in future downstream applications.


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P-57

DERIVATION OF GENETICALLY STABLE ES CELL SUBLINES FROM CHROMOSOMALLY INSTABLE ES CELLS

Elizabeth Hughes, Virginia Zawistowski, Keith Childs, Thomas Saunders University of Michigan, Ann Arbor, MI, USA

Mouse embryonic Stem (ES) cells are used to manipulate the mouse genome and produce mouse models of human disease and to understand gene function. The C57BL/6 Bruce4 ES cell line was determined to be genetically instable in a series of gene-targeting projects. ES cell clones were characterized by chromosome counting to establish if they were euploid. Twenty chromosome spreads were counted for each clone. If twelve or more spreads contained

transmission by ES cell-mouse chimeras. We found that only 35% of targeted Bruce4 ES cell clones were euploid. Several Bruce4 sublines were developed and characterized by chromosome counting and germline transmission from chimeras. The Bruce4.G9 subline contained 90% euploid chromosome spreads and formed germline ES cell-mouse chimeras. Electroporation of Bruce4 and Bruce4.G9 cells in parallel showed that whereas only 26% of gene-targeted Bruce4 clones were euploid, 100% of Bruce4.G9 clones were euploid. When ES cell clones were tested for germline transmission only 40% of Bruce4 clones were germline whereas 80% of Bruce4.G9 clones were germline. Gene targeting

was established from parental ES cells characterized by genetic instability and weak germline potential.

P-58

TRANSCRIPTOMES OF MOUSE OLFACTORY EPITHELIUM REVEAL SEXUAL DIFFERENCES IN ODORANT DETECTION

Meng-Shin Shiao1, Andrew Ying-Fei Chang2, Yung-Hao Ching3, Ben-Yang Liao2 1, Stella Maris Chen1, Wen-Hsiung Li1 ,4 1Academia Sinica, Taipei, Taiwan, 2National Health Research Institutes, Miaoli County, Taiwan, 3Tzu Chi University, Hualien, Taiwan, 4The University of Chicago, Chicago, USA



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P-59

GENE INTERACTION NETWORKS REVEALED IN Mom14-Mom18: NEW MODIFIER LOCI OF ApcMIN-MEDIATED INTESTINAL POLYPOSIS DISCOVERED IN THE BXH14 RI STRAIN

Linda Siracusa Thomas Jefferson University, Philadelphia, PA, USA

More than 1,000,000 individuals are currently diagnosed with cancers of the small intestine and colon worldwide. Mice carrying a mutation in the adenomatous polyposis coli (ApcMin) gene are useful models because they are predisposed to

in ApcMinApcMinenhance polyposis in either a cell autonomous or non-cell autonomous fashion. BXH recombinant inbred (RI) strains (derived from B6 and C3H progenitors) were tested by crossing females with B6 ApcMin males and analyzing polyp phenotypes in the F1 offspring. Of all strains tested, the BXH14 RI strain had the lowest number of polyps. Additional

Mom14-18, that suppress polyposis in a dominant fashion. The greatest

interaction network analysis using Ingenuity Pathway Analysis (IPA) revealed multiple networks with proven gene-gene

P-60

MULTIPLE QTLs ASSOCIATED WITH AGE-RELATED HEARING LOSS IN DBA/2J MICE

Sari Suzuki1 ,2, Yasuhiro Oshiba1 ,3, Shumpei Yasuda1, Yuki Miyasaka1 ,3, Michinari Yokohama2, Hiromichi Yonekawa4, Yoshiaki Kikkawa1 1Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-Ku, Tokyo, Japan, 2Graduate School of Bioindustry, Tokyo University of Agriculture, Abashiri-Shi, Hokkaido, Japan, 3Graduate School of Medical and Dental Science, Niigata University, Niigata-Shi, Niigata, Japan, 4Basic Technology Research Center, Tokyo Metropolitan Institute of Medical Science, Setagaya-Ku, Tokyo, Japan

age-related hearing loss (ahl) locus on Chromosome 10, which has been shown to be a splice variant of the cadherin 23 (otocadherin) gene (Cdh23

QTL mapped to a region approximately 13 Mb distal of Cdh23the Cdh23ahl variant. On the other hand, the ahl8 mice;; a SNP in the mouse fascin homolog 2, actin-bundling protein, retinal (Strongylocentrotus purpuratus) gene (Fscn2)

Fscn2ahl8 variant with the hearing abilities of mice

be allelic with ahl2 as major contributors to the hearing loss in NOD/Shi mice.


– 88 –

P-61

AUDIOGENIC SEIZURES IN DEER MICE ARE CONTROLLED BY TWO LOCI

Gabor Szalai Peromyscus Genetic Stock Center, University of South Carolina, Columbia, SC, USA

Epilepsy is a debilitating disease that can arise from either acquired brain lesions or from an inherited susceptibility to cortical hyperexcitability. At least 40-50% of epilepsies have a presumed genetic basis. Rodents prone to audiogenic seizures (AGS) display generalized seizures (loss of conscious-ness accompanied by rigid muscle stiffness and rhythmic muscle spasms) after intense sound stimulation. In 1935 a spontaneous AGS mutation appeared among laboratory stocks of Peromyscus maniculatus artemisiae at the University of Michigan and at the Peromyscus Genetic Stock Center it has been maintained as a separate stock denoted as ‘epl’.

In order to assure the outbred status of the ‘epl’ stock we recently carried out the following cross: (epl/epl x BW)F1 x epl/epl. Phenotyping of these animals revealed that only 23 out of the total number of 89 offspring seized. However, animals that did not display clonus and tonus showed altered behavior as compared to wild-type deer mice, such as wild-run only, waltzing. Thus instead of the expected 50% only 25% seized, but the other 25% showed some other, non-normal behavior. This suggests a presence of a second, modifying locus that plays a role in modulating the severity of seizures. The presence of this locus was further demonstrated when we tested the offspring of epl/epl x epl/epl crosses. Twelve

P-62

THE ROLE OF ESTROGEN RECEPTOR 1 (ALPHA) SIGNALING IN B CELLS IN THE (NZBxNZW)F1 MODEL OF LUPUS

Dana Tabor University of Nebraska Medical Center, Omaha, NE, USA

The pathogenesis of lupus, a chronic autoimmune disease affecting ~1.5 million Americans, is not completely understood. It is known that B cell hyperactivity and loss of tolerance lead to the production of autoantibodies, but what causes these changes is unknown. Evidence suggests that estrogens play an important role in lupus. Estrogens are thought to promote lupus by enhancing loss of tolerance, enhancing survival of autoreactive B cells, and promoting pathogenic autoantibody production. However, the underlying cellular and molecular mechanisms are largely unknown. Estrogens act through estrogen receptors (ESRs) which are expressed by immune cells, including B cells. Knocking out ESR1 in the (NZBxNZW)F1 model of lupus reduces B cell activation and lowers levels of autoantibodies (without perturbing general B cell development) resulting in reduced nephritis and prolonged survival. However, in this complete knockout model it cannot be determined whether these effects are due to B cell intrinsic effects of ESR1. To investigate the role

accelerated development of albuminuria and mortality from lupus nephritis. We are currently investigating the causes

autoantibody production, cytokine production, and B cell activation.


– 89 –

P-63

ANCESTRY OF EXTANT JAPANESE FANCY MICE CONTRIBUTED TO THE MOSAIC GENOMES OF CLASSICAL INBRED STRAINS

Toyoyuki Takada1, Toshinobu Ebata1, Thomas Keane2, Kim Wong2, David Adams2, Takanori Narita1, Tadasu Shin-I1, Hironori Fujisawa3, Hideki Noguchi1, Atsushi Toyoda1, Kuniya Abe1, Yuichi Obata4, Yoshiyuki Sakaki5, Kazuo Moriwaki4, Asao Fujiyama1, Yuji Kohara1, Toshihiko Shiroishi1 1National Institute of Genetics, Mishima, Shizuoka, Japan, 2The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK, 3The Institute of Statistical Mathematics, Tachikawa, Tokyo, Japan, 4RIKEN BRC, Tsukuba, Ibaraki, Japan, 5RIKEN GSC, Yokohama, Kanagawa, Japan

Commonly used classical inbred mouse strains have mosaic genomes from different origins. Their genomes are derived predominantly from west European subspecies Mus musculus domesticus, and the remainder is derived mostly from

M. m. molossinusoccurred during the establishment of classical inbred strains. In this study, we resequenced genomes of two inbred strains,

dataset of 17 inbred strains. The result unequivocally shows that genome introgression from M. m. molossinus into M. m. domesticus

of M. m. molossinus M. m. molossinus. These results M. m. molossinus genome in classical

P-64

THE EFFECT OF Prdm9 INTERALLELIC INTERACTIONS ON HYBRID STERILITY

Petr Flachs1, Ondrej Mihola1, Karel Stein1, Eliska Skaloudová1, Yasuhisa Matsui2 1, Zdenek Trachtulec1 1Institute of Molecular Genetics ASCR, Prague, Czech Republic, 2Tohoku University, Sendai, Japan

The Dobzhansky-Muller model of hybrid incompatibilities explains speciation by incorrect epistatic interactions;; they

3 methyltransferase necessary for successful meiosis that determines the sites of meiotic cross-overs. The Prdm9 gene participates in meiotic arrest of spermatogenesis in the offspring of PWD females and C57BL/6 (B6) males (Mus m. musculus x M. m. domesticus)F1. These hybrid males carry no sperm, while the males resulting from the reciprocal cross, (B6 x PWD)F1, display reduced sperm count in comparison with the parental strains. Removal as well as overexpression of the Prdm9B6B6 heterozygosity at proximal Chromosome 17, the location of Prdm9, suggesting that its interallelic incompatibility could participate in these phenotypes. To test this hypothesis, we transferred a Prdm9 knock-out to PWD background and

Prdm9PWD allele using B6. The Prdm9PWD deletion did not rescue

F1 hybrids upon removal of Prdm9PWD, but not to the level seen when using Prdm9B6 deletion. Therefore, Prdm9PWD and Prdm9PWD-Prdm9B6 interallelic interactions play a minor role in our model of hybrid sterility compared to the effect of Prdm9B6.


– 90 –

P-65

SEX AND DOSE-RELATED GENETIC DIFFERENCES IN THE HIPPOCAMPUS OF INBRED STRAINS OF MICE

Cynthia Vied, Michelle Arbeitman, Richard Nowakowski Florida State University, Tallahassee, FL, USA

In the brain, differences between the sexes are generally viewed as consequences of gonadal hormone secretions. Recent evidence suggests that other factors, particularly gene products from the sex chromosomes, may be involved in determining sex differences. We have used next generation sequencing to determine the differences in gene expression levels between male and female mouse brains in two inbred strains. We sequenced mRNA from male

obtained from each hippocampus for 3 males and 3 females of each strain. We found that 5 Y Chromosome genes are expressed in males from both strains and Sry was not among them. We also found 20 genes on the X Chromosome

Xist is more highly expressed in females in both strains. In B6, 12 of the 20 differentially expressed genes are more highly expressed in

The expression of Y Chromosome genes and the differential expression of X Chromosome genes could mediate brain differences independent of gonadal secretions. We plan to verify these differences with quantitative PCR and examine differential gene expression between other inbred strains and correlate the role these differences have on behavior and disease processes between the sexes.

P-66

GENE EXPRESSION PROFILING OF THE LENS IN Foxe3-DEFICIENT rct MICE

Kenta Wada1 ,4, Gou Takahashi2, Chihiro Harada1, Saki Okubo1, Yoko Okumoto1, Yo Obara1 ,4, Cao Feng3Saitou4, Tomohiro Kono3, Yoshiaki Kikkawa4 1Department of Bioproduction, Tokyo University of Agriculture, Abashiri, Hokkaido, Japan, 2Graduate School of Bioindustry, Tokyo University of Agriculture, Abashiri, Hokkaido, Japan, 3Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo, Japan, 4Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan

Foxe3 plays crucial roles in normal lens development, and mutations in this gene lead to ocular defects in both humans cis element of Foxe3 as a causative mutation in the rct mice that exhibit

congenital cataract and microphthalmos. Moreover, the rct Foxe3 transcripts. rct

downstream of Foxe3 by performing qRT-PCR. In addition, differential gene expression analysis was performed to determine novel genes related to the signaling cascade of Foxe3 by using GeneChips. Expression of Dnase2b, a gene known to be as one of downstream of Foxe3,Expression of Pdgfra in situ hybridization analysis on lens epithelium. This

rctand reduction of number of lens epithelial cells. Microarray analysis indicated that 48 genes were differentially expressed and 34 genes were not expressed in the rct mice. Next, we selected 8 genes associated with eye development on the basis of functional annotation via Gene Ontology, and validated their expression pattern by performing qRT-PCR. Of the 8 genes tested, 7 genes rct mice. These genes may be novel genes downstream of Foxe3 and be crucial for lens development.


– 91 –

P-67

A 5-bp INSERTION IN Mip GENE CAUSES RECESSIVE CONGENITAL CATARACT IN A KYOTO FANCY RAT STOCK, kfrs44

Kei Watanabe1 ,2, Kenta Wada3 ,2, Saki Okubo3, Kensuke Takekuma3 1, Tadao Serikawa4, Takashi Kuramoto4, Yoshiaki Kikkawa2 1Graduate school of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan, 2Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan, 3Department of Bioproduction, Tokyo University of Agriculture, Hokkaido, Japan, 4Institute of Laboratory Animals Graduate school of Medicine, Kyoto University, Kyoto, Japan

We discovered a new cataract mutation, kfrs4, in the Kyoto Fancy Rat Stock (KFRS). Within 1 month of birth, all the kfrs4/kfrs4 homozygotes developed cataracts, with severe opacity in the nuclei of the lens. In contrast, no opacity was observed in the kfrs4/+ rats. We continued the observation in some rats until they were 1-year old;; however, cataractogenesis did not occur in kfrs4/ kfrs4 rats, sections of the eyes of these mice were prepared. Although the lens of kfrs4/kfrs4 vacuolation of the lens, the lenses of kfrs4/+ heterozygotes appeared normal and similar to that of the wild-type rats. To identify the kfrs4 mutation, we used positional cloning. The mutation was mapped to an approximately 19-Mb interval on Chromosome 7, which contains the major intrinsic protein of the lens gene (Mip), which is responsible for a dominant form of cataract in humans and mice. Sequence analysis of the mutant-derived Mipinsertion is predicted to inactivate the MIP protein, as the frameshift mutation results in a truncated protein lacking 136 amino acids in the C-terminal region. The kfrs4 mutant showed reduced expression of Mip mRNA and the MIP protein

kfrs4-mutant rats. These results demonstrate that kfrs4 Mip gene.

P-68

IN SILICO PREDICTIONS OF THE GENOMIC STRUCTURE FOR EXTANT CC LINES

Catherine Welsh1, Darla Miller1, Kenneth Manly1 1, Leonard McMillan1, David Threadgill2, Fernando Pardo-Manuel de Villena1 1University of North Carolina, Chapel Hill, NC, USA, 2North Carolina State University, Raleigh, NC, USA



– 92 –

P-69

EMBRYONIC LETHALITY, STUNTING AND ORGAN WEIGHT PHENOTYPES IN A SCREEN OF KOMP & IKMC MUTANT MOUSE LINES

David West1 ,2, Andreana Cipollone2, Karrie Beeman2, Kent Lloyd2 1Children’ Hospital of Oakland Research Institute, Oakland, CA, USA, 2Mouse Biology Program, University of California, Davis, CA, USA

To determine the incidence of embryonic lethality, growth retardation (“stunting”), and abnormal organ weights in response to gene targeting, we produced more than 40 live progeny for 117 unique KOMP (Knockout Mouse Project, www.komp.org) and IKMC (International Knockout Mouse Consortium, www.knockoutmouse.org) mutant mouse lines. All targeting was completed in C57BL/6N stem cells and mutants were maintained in this background. Eighteen percent (24 lines) of genes were subviable/embryonic lethal as HOM mutants as determined by diagnostic genotyping of 10-day-old offspring of HETxHET matings. For 93 mutant lines with HOM viable offspring, we necropsied a minimum of 6M and 6F HOM mice and assessed body weights, and organ weights (brain, heart, kidney, liver, lung reproductive adipose tissue, spleen, submandibular gland, testis and thymus) at 50 ± 2.5 days of age. HOM mutants were compared with ~120

the lines. Two mutant lines, Krt16 and Tmem248, had normal viability but the HOM mice were severely stunted and less

enlarged spleens (Au023871] enlarged hearts (Il6ra), decreased thymus weight (Nudt19) and decreased reproductive adipose depot weights (Arap1, Jazf1). The overall percentage of mutant lines with organ weight phenotypes was 5.3%.

assessments of embryonic lethality, stunting and organ weights revealed phenotypes in 25% of the mutant lines we evaluated. Supported by NIH grants U42OD011175 ,U54HG006364 and U01HG004080.

P-70

USING A LARGE N2F1 MOUSE QTL ANALYSIS, HAPMAPPING, SEQUENCE ANALYSIS AND EXPRESSION PROFILING TO IDENTIFY CANDIDATE GENES FOR BODY FAT CONTENT ON Chr 17

David West1 1, Debbie Swinarski1, Ted Choi2 1Children’s Hospital Oakland Research Institute, Oakland, CA, USA, 2Predictive Biology, Carlsbad, CA, USA

A large N2F1 intercross between 129P2/OlaHSD and C57BL/6N in which targeted mutations were segregating was evaluated by QTL analysis to identify genomic regions linked to body weight, body fat content by DEXA and glucose

on body fat with a linkage peak near 22Mbp. This linkage coincided with linkage data from QTL mapping using related strains. Haplotype-based mapping with inbred strain comparisons for body fat from the Mouse Phenome Database (www.

with the same phenotype. Hapmapping narrowed the linkage regions to several megabases which were further narrowed by excluding regions of genomic identify between 129P2 and B6N. An RNAseq analysis comparing differential gene

this Chr17 region. Supported by NIH grant RO1DK085124.


– 93 –

P-71

Abstract Withdrawn

P-72

USING NOVEL RNAseq BASED RESOURCES TO INFORM GENCODE AND POST-GENCODE GENOME ANNOTATION

Laurens Wilming Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK

Over the course of the last few years, new data sources have become available that are extremely useful for manual genome annotation, for example uncovering novel splice variants and allowing us to more accurately establish gene boundaries. They also help inform decisions made during annotation, such as ATG choice or whether a locus/transcript is coding, pseudogenic or non-coding. Previously, the HAVANA manual annotation group mainly relied on homologies to mRNA, EST and protein sequences to build transcript models. Despite the fact that the number of sequences in these nucleotide and protein databases is ever increasing, some loci, especially ncRNAs and genes with restricted expression

(from GENCODE and other collaborators) to investigate gene, transcript and coding region boundaries and to study ncRNAs. Additionally, we use protein mass spectrometry data to aid the annotation of protein-coding transcripts and

al. 2011) we can now better asses the complexity of genes: alternative polyadenylation, splicing, translation start sites, open reading frames and more. In conjunction with more traditional RNAseq data, both short (e.g. 17 mouse strains, bodymap) and long reads, it allows us to generate a much more comprehensive annotation set. This is vital if we want to provide a solid foundation for loss-of-function or disease association studies and it will increase the power of exome sequencing and other transcriptomics studies.


– 94 –

P-73

A CELLULAR GENOMICS APPROACH TO DEFINING TOXICITY PATHWAYS

Amber Frick1, Rusty Thomas2, Kristy Richards1, Blossom Damania1, Yuri Fedoriw1, Bethany Parks2, Emmanuel Chan1, Tim Wiltshire1 1University of North Carolina, Chapel Hill, NC, USA, 2Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA

genetic determinants of drug toxicity are poorly understood. We have developed an approach to identify genes and genetic pathways that underlie the variable toxicity responses of normal immune function cells (i.e., B-cells, T-cells, granulocytes, and monocytes) to anti-lymphoma chemotherapeutic agents: the novel investigational PI3K/mTOR and MEK inhibitors versus standard, traditional anthracycline drugs. We have taken a model organism approach to evaluate pharmacotherapeutic response in a panel of inbred mice, using a cellular genetics screening approach where phenotypic variation (i.e., toxicity) is associated with the genome. Furthermore, environmental factors (e.g.response can be controlled. Genome-wide association mapping in this inbred population utilizes existing dense maps of SNP genotype information to localize quantitative trait loci and candidate genes. Phenotypes (e.g., viability, mitochondrial

interstrain variation for measured phenotypic endpoints. Using this approach, we are evaluating genetic determinants of cellular response to drugs, identifying cellular toxicity pathways for future validation in human studies. Our ultimate goal is to use these genetic biomarkers to detect adverse clinical outcomes, or individuals susceptible to increased risk of

drug cost.

P-74

GENETIC DISSECTION OF DOWN SYNDROME IN MICE

1, Masae Morishima1 ,2, Chunhong Liu1, Kai Meng1, Li Zhang1, Annie Pao1, Michael Parmacek1 ,3, Ping Ye1 ,4, William Mobley1 ,5, Y. Eugene Yu1 1Roswell Park Cancer Institute, Buffalo, NY, USA, 2Tokyo Women’s Medical University, Tokyo, Japan, 3University of Pennsylvania, Philadelphia, PA, USA, 4Washington State University, Pullman, WA, USA, 5University of California, San Diego, La Jolla, CA, USA

Trisomy 21, the most common live-born aneuploidy in humans, causes Down syndrome (DS). This genetic disorder is associated with several major phenotypes, including heart defects, hematopoietic abnormalities and intellectual disabilities. The mouse is a premier model organism for DS because the genomic regions on human chromosome 21 are syntenically conserved with three regions in the mouse genome, located on mouse Chromosomes 10, 16 and 17. To expedite genetic analysis of DS, we have generated a number of mouse mutants with different genetic rearrangements in the human chromosome 21 syntenic regions, using recombinase-mediated chromosome engineering. Using these mutants, we have developed a complete genetic model for DS, which is trisomic for all three human chromosome 21 orthologous regions. Generation and characterization of the smaller chromosomal duplications and deletions have facilitated the establishment of the critical genomic regions associated with the mutant phenotypes. These efforts should

point to the mechanistic details of the altered developmental processes.


– 95 –

P-75

THE FIRST INBRED PIG LINE WORKS AS A NEW LARGE MAMMAL MODEL FOR HUMAN

Rong Zeng1, Yangzhi Zeng1 ,2 1 ,2, Weirong Pan1 1University of Missouri, Columbia,MO, USA, 2Yunnan Agriculture University, Kunming,Yunnan, China



– 96 –

Author Index

– 97 –

Author Index


– 98 –

P-36, P-6Blanchet, Charlène O-47Blank, Robert SO-12/P-32

SO-4/P-7Blease, Andrew O-35Bloch, Konstantin P-27Bolcun-Filas, Ewelina O-21Bondy, Melissa O-43Boswell, Deborah M P-8

O-29, P-55Bowl, Mike O-35Braun, Robert P-40

SO-8/P-21Breton, Sylvie O-31Broman, Karl O-43, SO-

11/P-34Brown, Diane E O-31Brownstein, David O-26Brown, Steve O-35, P-23,

P-25, P-5Buchberg, Arthur P-59Buchner, David O-36Buehler, Dennis O-24, SO-

16/P-53

EP-17

Bult, Carol P-10, P-9Bumpstead, Suzannah P-17Burgio, Gaetan O-48Burkart, Donna P-19

P-56Byers, Candice O-5Bystrykh, Leonid P-11Caddle, Brianna O-18

P-37, SO-14/P-12, O-6

Calaway, Mark O-11, SO-13/P-45

Camper, Sally O-44Carlisle, Francesca SO-9/P-35Carlson, George O-40, P-13Carniel, Elisabeth O-47Carninci, Piero O-4Carpanini, Sarah O-26Carter, Gregory P-14Casellas, Rafael O-45Cavanna, Davide SO-15/P-24,

SO-7/P-15Chan, Emmanuel P-73Chang, Andrew Ying-Fei SO-20/P-58Cheeseman, Michael T P-43

SO-9/P-35Chen, Stella Maris SO-20/P-58

Chesler, Elissa O-10, O-11, P-40

Chevallier, Lucie O-47Childs, Keith P-57Ching, Yung-Hao P-16, SO-

20/P-58Choi, Ted P-70Church, Deanna M O-2Churchill, Gary A O-10, O-3,

O-32, O-46, O-6, P-14

Cipollone, Andreana P-69Clark, Travis O-24Consortium, Fantom5 O-4Cook, Ross P-55Cordier, Gaelle P-18

O-24, SO-5/P-41

Cotman, Susan O-31Cox, Roger O-35, P-23Crawford, Nigel O-37Croniger, Colleen O-36

P-61Cross, Sally O-41Cuppen, Edwin P-48Curtain, Michelle O-18Dalton, Stephen 0-20Dalvi, Priya P-55Damania, Blossom P-73Danecek, Petr O-1, P-17Daub, Carsten O-4David, Victor O-8Davidson, Nicholas O-22Davisson-Fahey, Muriel O-7de la Casa-Esperon, Elena

P-18

de Massy, Bernard SO-18/P-20P-25

Demeure, Christian O-47P-40

Dene, Howard P-19P-37, SO-14/P-12

DiFabio, Christina O-43Dolan, Mary P-6Donahue, Leah Rae O-18, O-28,

O-5, O-7, P-40, P-8

Drabkin, Harold P-6DuBois, Wendy O-45Dunn, Denise P-33Durbin, Durbin P-17

Abe, Kuniya P-63Abreha, Measho O-17Acevedo, Abraham O-35Ackerman, Kate P-1Adam, Elizabeth C P-43Adams, David O-1, O-12,

O-29, P-55, P-56, P-63, P-17

Adams, Elizabeth SO-1/P-2Airey, Mark P-52Aitman, Timothy P-48Aligianis, Irene O-26Amash, Ala P-27Amber, Frick O-30Amlin-Van Schaick, O-43, SO-

11/P-34Anagnostopoulos, Anna P-19Anderson, Sarah O-40Arbeitman, Michelle P-65Athamni, Hanifa P-27, P-3Ayadi, Abdelkader P-46Aylor, David O-11, SO-

13/P-45, SO-3/P-54

Babiuk, Randal O-15, P-19Bagley, Dale P-10Baines, Andrea SO-1/P-2Baker, Christopher E P-30, P-47Banks, Gareth O-35Barsh, Greg O-8Basheer, Wassim O-17, SO-

2/P-38Baudat, Frédéric SO-18/P-20Bautista, Ruben O-12

P-50Bedigian, Rick P-40Beeman, Karrie P-69Beier, David O-14, O-19,

P-13Bello, Susan M P-19Bell, Timothy O-11, O-6,

SO-13/P-45P-26

Benavides, Fernando P-4Benton, Cristina O-30Bergstrom, David O-5, O-7Bethany, Parks O-30Bhattacharyya, Tanmoy O-9Billings, Timothy P-47Birling, Marie-Christine P-46Biswas, Sunita O-31Blake, Andrew P-5

Author Index

– 99 –

Durrant, Caroline O-42, P-27, P-28, P-3, SO-19/P-42

Dzur-Gejdosova, Maria O-9Ebata, Toshinobu P-63Eicher, Eva Verne

Chapman Lecture

Emmanuel, Chan O-30Engel, Nora P-18

O-15, P-10, P-36, P-52, P-9, P-19O-29O-5

Fang, Qing O-44Fay, Petra P-23Fedoriw, Yuri P-73Feng, Cao P-66

SO-12/P-32Flachs, Petr P-64, SO-

18/P-20Fleming, Michelle O-44Flicek, Paul P-25, P-5

O-1, P-17O-38

Foote, Simon O-48O-9, P-64, SO-18/P-20

Forrest, Alistair O-4Foulds-Mathes, Wendy SO-3/P-54Frankish, Adam P-72

O-46Frey, Martin P-43Frick, Amber P-73Fu, Chen-Ping O-11, P-37,

SO-8/P-21Fuchs, Helmut O-31Fufa, Temesgen O-25Fujisawa, Hironori P-63Fujiyama, Asao P-63Fukumura, Ryutaro O-23

P-44, P-62Gailus-Durner, Valérie O-31

O-14, P-13Galli, Antonella O-29

SO-6/P-22Gatti, Daniel O-32, O-46,

O-3Gerdin, Anna Karin O-29

P-49Gillingwater, Thomas O-26Ginsburg, David O-13, O-16,

SO-1/P-2

Gladshev, Vadim O-33Gleeson, Diane P-55, P-56GMC consortium O-31Goessling, Wolfram O-14Goggin, Patricia M P-43Goldsworthy, Michelle O-35, P-23Gondo, Yoichi O-23Gonye, Gregory P-59Goodwin, Leslie P-40Gordon, Sarah O-26Gorjanc, Gregor P-26Gould, Karen P-44, P-62Gradinger, Daniel P-50, SO-

15/P-24, SO-7/P-15O-31

Gregorova, Sona O-9Greth, Andreas O-48

P-4Guidus, Polyxeni O-18Gunn, Teresa O-40Gutkind, Silvio O-37Habib, Bishoy P-55Hagn, Michael P-25Haliw, Larissa O-31Hance, Zahra SO-9/P-35Handel, Mary Ann P-40Handley, Mark O-26Harada, Chihiro P-66Hardy, Matthew P-55Harris, Brett O-17

P-72Ha, Seungshin O-19

P-67Hayashizaki, Yoshihide O-4Haynes, Andrew O-35Haynes, Sara O-16

O-22Heffner, Caleb O-18, P-40Herault, Yann P-25, P-46Hill, David P-6Hoesel, Bastian P-50Hong, Lewis O-8Hortle, Elinor O-48Horvat, Simon P-26Hough, Alison P-23Houghton, Richard O-29, P-56Houri-Haddad, Yael SO-19/P-42Hrabé de Angelis, Martin O-31, P-25,

P-50, P-51, SO-15/P-24, SO-7/P-15

Hubner, Norbert P-48Hughes, Elizabeth P-57

P-43Hunter, Kent O-38

SO-17/P-75Hu, Ying O-38Ibarra-Soria, Ximena O-12Infrafrontier Consortium, The

P-51

Ingham, Neil SO-9/P-35P-59

Iraqi, Fuad O-42, P-27, P-28, P-29, P-3, SO-19/P-42, P-39

Ireland, Sara SO-16/P-53Ishitsuka, Yuichi O-23Itoh, Masayoshi O-4Ivanova, Pavlina P-30

O-26, O-35, O-41P-46O-47P-74O-30O-41O-44O-19O-39O-44O-15

Kaelin, Chris O-8Kane, Coleen O-28Kaneda, Hideki O-23

O-4Kawaji, Hideya O-4Keane, Thomas M P-17, O-1,

P-56, P-63, SO-9/P-35

Kearney, Alison O-41Keighren, Margaret O-41Keum, Sehoon P-33Kikkawa, Yoshiaki P-31, P-60,

P-66, P-67Kim, Sungjin O-43Kissling, Grace O-46Klingenspor, Martin O-31Knopf, Corinna O-9Knowlton, Michelle P-19Kohara, Yuji P-63Kollias, George P-25Kominami, Ryo P-31


– 100 –

Kono, Tomohiro P-66SO-12/P-32

Krupke, Debbie P-10Kuramoto, Takashi P-67Kurtz, Theodore P-48Lackie, Peter M P-43Laplante, Mathieu P-26Lassmann, Timo O-4Lee, Han Kyu P-33Lee, Min-Hyung O-43, SO-

11/P-34Lelliott, Chris O-29Lelliott, Pat O-48Lenarcic, Alan B SO-14/P-12Lendahl, Urban P-25Lenk, Guy M O-39Leshchiner, Ignaty O-14Levitin, Maria O-12Levy, Shawn O-24Lewis, Morag SO-9/P-35Liao, Ben-Yang SO-20/P-58

SO-4/P-7Lin, Eric Yi O-10Litscher, Suzanne SO-12/P-32Liu, Chunhong P-74Liu, Yanhong O-43Li, Wen-Hsiung SO-20/P-58Lloyd, Kent P-69Lo, Chiao-Ling O-27Lo, Donald P-33Logan, Darren O-12Look, Maxime O-38Lossie, Amy O-27

P-43SO-20/P-58

Lutz, Cathleen M P-8, P-40, O-7

Macalinao, Dan O-41Maddox, Dennis O-18Magnuson, Terry SO-8/P-21Mahajne, Mustafa P-29Makino, Shigeru O-23Mallon, Anne-Marie O-35Mallon, Ann-Marie P-5Manly, Kenneth F SO-10/P-68,

P-39Marchuk, Douglas P-33Matesic, Lydia E SO-2/P-38,

O-17Matsui, Yasuhisa P-64, SO-

18/P-20Matsuoka, Kunie P-31McAndrews, Monica P-36

McGowan, Kelly O-8McIntyre, Rebecca E P-17McKie, Lisa O-26, O-41McMillan, Leonard O-6, O-11,

P-37, P-39, SO-10/P-68, SO-13/P-45, SO-8/P-21

McMorran, Brendan O-48Meehan, Terrence P-5Meishery, Delisha P-13Meisler, Miriam O-39Meng, Kai P-74Menotti-Raymond, Marilyn

O-8

Mentrup, Heather SO-2/P-38Michalowski, Aleksandra SO-6/P-22Mihola, Ondrej P-64, SO-

18/P-20Miklejewska, Evelina P-55Miller, Darla R O-11, SO-

10/P-68, SO-3/P-54, P-39

Miller, Richard O-34, O-125Miyasaka, Yuki P-31, P-60Mobley, William P-74Mock, Beverly O-45, SO-

6/P-22Molinolo, Alfredo O-37Montagutelli, Xavier O-47Montoliu, Lluis P-25Morahan, Grant P-39Morgan, Daniel O-46

O-28Morishima, Masae P-74Moriwaki, Kazuo P-63Morton, Nicholas P-26Mostt, Richarrd P-27Mott, Richard O-42, P-28,

P-29, P-3, P-39, SO-19/P-42

Mouse Genetics Project, Sanger

P-55, P-56

Mouse Genomes Consortium

O-1

P-72Mullen, Raymond O-25Munger, Steven O-3Murata, Takuya O-23Murray, Stephen O-15, O-18,

O-5, O-7, P-40, O-28

Musser, Melissa SO-5/P-41

Mustpaha, Mirna O-44O-22, O-36

Narita, Takanori P-63Nashef, Aysar SO-19/P-42

P-70Nellåker, Christoffer P-17Nelson, Vicki O-22Neuhauser, Steve P-10Nicol, Thomas O-35Ni, Li P-6Nnadi, Stephanie P-59Noble, Stuart P-23Noda, Tetsuo O-23Noguchi, Hideki P-63Nolan, Pat O-35Norris, Dominic P P-43Nowakowski, Richard P-65Obara, Yo P-66Obata, Yuichi P-63O’Brien, Deborah O-11, SO-

13/P-45O-39

Odet, Fanny O-11, SO-13/P-45

Oelsligle, Kelli P-44Ohshiba, Yasuhiro P-31Okubo, Saki P-66, P-67Okumoto, Yoko P-66Olszewski, Pawel O-31Onda, Hiroaki P-19Oscar, Suzuki O-30Oshiba, Yasuhiro P-60Otterpohl, Karla P-44Pachulec, Emilia O-47Paigen, Ken P-30, P-47

O-47Pan, Weirong SO-17/P-75Pan, Wenqi O-11, SO-

13/P-45Pao, Annie P-74Pardo-Manuel de Villena, Fernando

O-10, O-11, O-6, P-37, P-39, SO-10/P-68, SO-13/P-45, SO-14/P-12, SO-3/P-54, SO-8/P-21

Parker, Andy O-35Parkinson, Helen P-5Parks, Bethany P-73Parmacek, Michael P-74Parvanov, Emil D P-47

Author Index

– 101 –

SO-9/P-35Patel, Saloni H P-43Patel, Shashank O-37Patricia, McQuaid O-30Pavan, William O-25Pavlovic, Guillaume P-46Payne, Susan P-61Pearson, Selina SO-9/P-35Perez, Carlos P-4

P-13Petkov, Petko P-30, P-47Phillips, Shannon SO-12/P-32

SO-18/P-20Pomp, Daniel SO-3/P-54Ponting, Chris P P-17Potter, Paul O-35, P-23Prasad, Nripesh O-24Pravenec, Michal P-48Prevorsek, Zala P-26Price, Herman O-46Price, Robert O-17Prows, Daniel P-49Pruitt, Margaret O-45Przemeck, Gerhard KH SO-15/P-24,

SO-7/P-15, P-50

Puk, Oliver O-31Raess, Michael P-51Raghupathy, Narayanan O-3Ramirez-Solis, Ramiro O-29, P-25,

P-55, P-56Recio, Leslie O-46

P-10Reed, Deb P-10Reifova, Radka O-9Reilly, Karlyne O-43, SO-

11/P-34Reinholdt, Laura O-5, O-7,

P-40Reynolds, Megan P-49Richards, Kristy P-73

P-10Richards-Smith, Beverly P-19, P-52Rinaldi, Vera O-21Ringwald, Martin O-15Ritter, Elaine SO-16/P-53Roberts-Thomson, Meredith

O-48

Robles-Espinoza, Carla Daniela

O-12

Roche, Sarah O-26Rockwood, Stephen F P-8, O-7Roper, Randall SO-4/P-7

Rose, Lorraine O-41O-31

Rubinshteyn, Christine SO-3/P-54Rülicke, Thomas P-25Rusty, Thomas O-30Ryder, Edward O-29, P-55,

P-56P-66

Sakaki, Yoshiyuki P-63Salaymeh, Yaser SO-19/P-42

P-56Sánchez-Andrade, Gabriela

O-12

Sasner, Michael O-15, O-7, P-8

Saunders, Gary P-72Saunders, Thomas P-57Savignac, Nicole O-32

SO-18/P-20, O-21, P-16

Schiöth, Helgi O-31Schmidt-Kuentzel, Anne O-8Schneltzer, Elida P-50Schweitzer, Kelsey O-40

SO-14/P-12Sedlacek, Radislav P-25Serikawa, Tadao P-67Sethi, Debarati P-55, P-56Shanthakumar, Prasshy O-35Shepard, Kim O-46

O-27Shiao, Meng-Shin SO-20/P-58Shin-I, Tadasu P-63Shiroishi, Toshihiko P-63Shockley, Keith O-46Shusterman, Ariel SO-19/P-42Siegmund, Stephanie O-18Siemieniak, David O-13, O-16Simecek, Petr O-9Simon, Michelle O-35Simpson, Mark O-45Siracusa, Linda P-59Sitnikov, Dmitry P-6Skaloudová, Eliska P-64Skarnes, William P-5Skelton, Stephanie O-24Smith, Clare O-48Smith, Cynthia L P-19

P-49Snapper, Clifford O-45Soininen, Raija P-25Sorg, Tania P-46

Southard-Smith, E Michelle

SO-5/P-41, O-24, SO-16/P-53

Speak, Anneliese O-29Starbuck, Becky O-35

O-31Steel, Karen SO-9/P-35Stein, Karel P-64Stenson, Erin P-16Stevans, Alicia SO-13/P-45Steward, Charles P-72Stottmann, Rolf O-19Sullivan, Patrick O-6Sunyaev, Shamil O-14Suzuki, Harukazu O-4Suzuki, Sari P-31, P-60Svenson, Karen O-3, O-32,

P-14, P-40Swinarski, Debbie P-70Szalai, Gabor P-61

O-6Tabor, Dana P-62Taft, Robert P-40Takada, Toyoyuki P-63Takahashi, Gou P-66Takekuma, Kensuke P-67Tasarfati, Ilan P-27Team, the Repository P-8Tesar, Paul O-22Thakker, Raj O-35Thames, Elizabeth SO-2/P-38The MPI2 consortium P-5Thomas, Rusty P-73Thomson, Derek O-26Threadgill, David W P-39, SO-

10/P-68, SO-3/P-54

Tiedemann, Hendrik P-50Tocchini-Valentini, Glauco

P-25

Toki, Hideaki O-23Tomberg, Kärt O-13, O-16Tomczuk, Monika P-19Tomlinson, Ian P-29Toyoda, Atsushi P-63Trachtulec, Zdenek P-64, SO-

18/P-20Tran, Dena O-45, SO-

6/P-22Tsarfati, Galia P-27Valdar, William SO-14/P-12van ‘t Hof, Rob O-41Vardi, Pnina P-27


– 102 –

Vered, Karin O-42Veres, Monika P-61Vied, Cynthia P-65Vyas, Sapna P-55, P-56Wada, Kenta P-66, P-67Wakana, Shigeharu O-23Walker, Michael P-47Walsh, Christopher O-19

O-6, P-39, SO-10/P-68

Wang, Wei O-10P-56

Washburn, Linda P-19Watanabe, Kei P-67Watkins-Chow, Dawn O-25Watson, Rayneisha P-59Wattenhofer-Donze, Marie

P-46

Weiss, Ervin SO-19/P-42Wells, Sara O-35Welsh, Catherine E P-37, P-39,

SO-10/P-68West, David P-69, P-70Westrick, Randal O-13, O-16Wetendorf, Margeaux SO-2/P-38

O-29, SO-9/P-35

White, Michelle O-21Wiles, Michael P-40Wilming, Laurens P-72Wiltshire, Tim P-73, O-30Wisby, Laura O-35, P-23Witt, Kristine O-46Wong, Kim O-1, P-63Wright, Ann O-26Wynn, Elizabeth O-12Xu, Xiao O-8Yalcin, Binnaz O-1Yang, Hyuna O-6Yasuda, Shumpei P-60Yazbek, Soha O-36Ye, Ping P-74Yokohama, Michinari P-60Yonekawa, Hiromichi P-60

SO-13/P-45Yu, Y Eugene P-74Zawistowski, Virginia P-57Zeiser, Stefan P-50Zeng, Rong SO-17/P-75Zeng, Yangzhi SO-17/P-75Zhang, Ke SO-6/P-22

Zhang, Li P-74Zhang, Nian P-1Zhang, Shuling O-45, SO-

6/P-22Zhu, Guojing O-16


– 103 –

Attendee List


– 104 –

First Name Last Name Organization CountryKate Ackerman University of Rochester UNITED STATESElizabeth Adams University of Michigan UNITED STATES

Angel The University of Texas at Austin UNITED STATESPhilip Avner European Molecular Biology Laboratory ITALYDavid Aylor University of North Carolina UNITED STATESGreg Barsh HudsonAlpha Institute and Stanford University UNITED STATESDavid Beier Brigham & Women’s Hospital, Harvard Medical School UNITED STATESFernando Benavides M.D. Anderson Cancer Center UNITED STATESDavid Bergstrom UNITED STATESAndrew Blake MRC Harwell UNITED KINGDOM

Blake UNITED STATESBlazek Indiana University-Purdue University Indianapolis UNITED STATES

Deborah M. Boswell UNITED STATESSteve Brown Medical Research Council UNITED KINGDOMElizabeth Bryda University of Missouri UNITED STATESDavid Buchner University of Michigan UNITED STATESCarol Bult UNITED STATESGaetan Burgio Macquarie University AUSTRALIALeonid Bystrykh University of Groningen NETHERLANDS

Calaway University of North Carolina UNITED STATESSally Camper University of Michigan UNITED STATESGeorge Carlson McLaughlin Research Institute UNITED STATESPiero Carninci Omics Science Center, RIKEN Yokohama InstituteSarah Carpanini MRC Human Genetics Unit UNITED KINGDOMGreg Carter UNITED STATESDavide Cavanna German Center For Diabetes Research, Helmholtz Zentrum

MünchenGERMANY

Yung-Hao Ching Tzu Chi University TAIWANDeanna Church NIH/NLM/NCBI UNITED STATESGary Churchill UNITED STATESVincenzo Coppola Ohio State University Comprehensive Cancer Center UNITED STATESNigel Crawford National Human Genome Research Institute - National

Institute of HealthUNITED STATES

Sally Cross MRC Human Genetics Unit UNITED KINGDOMStephen Dalton University of Georgia UNITED STATESPetr Danecek Wellcome Trust Sanger Institute UNITED KINGDOMElena De La Casa-Esperon Albacete Science And Technology Park. University of Castilla-

La ManchaSPAIN

Howard Dene UNITED STATESLeah Rae Donahue UNITED STATESEva Eicher UNITED STATESRosemary Elliott Roswell Park Cancer Institute UNITED STATES

Eppig UNITED STATESRozzy Finn Sanford Health UNITED STATES

Forejt Institute of Molecular Genetics, Academy of Sciences of The Czech Republic

CZECH REPUBLIC

Chen-Ping Fu UNC-Chapel Hill UNITED STATESGallego Brigham and Women’s Hospital, Harvard Medical School UNITED STATES

Attendee List

– 105 –

First Name Last Name Organization CountryGary National Cancer Institute UNITED STATES

Daniel Gatti UNITED STATESVadim Gladyshev Brigham & Women’s Hospital, Harvard Medical School UNITED STATES

Michelle Goldsworthy MRC Harwell UNITED STATESYoichi Gondo RIKEN BioResource CenterDaniel Gradinger Helmholtz Zentrum München – German Research Center for

Environmental HealthGERMANY

Teresa Gunn McLaughlin Research Institute UNITED STATESSeungshin Ha Brigham And Women’s Hospital, Harvard Medical School UNITED STATES

Michael Hagn Helmholtz Zentrum München GERMANYSimon Horvat University of Ljubljana, Biotechnical Faculty, Department of

Animal ScienceSLOVENIA

Martin Hrabe de Angelis Helmholtz Zentrum München GERMANYKent Hunter National Cancer Institute UNITED STATESFuad Iraqi Tel-Aviv University ISRAELPavlina Ivanova UNITED STATESIan MRC Human Genetics Unit UNITED KINGDOMThomas Keane Wellcome Trust Sanger Institute UNITED KINGDOMYoshiaki Kikkawa Tokyo Metropolitan Institute of Medical Science

Kristianto University of Wisconsin UNITED STATESHeena Lad Medical Research Council UNITED KINGDOMHan Kyu Lee Duke University Medical Center UNITED STATESMin-Hyung Lee Frederick National Laboratory For Cancer Research, National

Cancer InstituteUNITED STATES

Morag Lewis Wellcome Trust Sanger Institute UNITED KINGDOMDasha Li Kappe UNITED STATESChiao-Ling Lo Purdue University UNITED STATESDarren Logan Wellcome Trust Sanger Institute UNITED KINGDOMAmy Lossie Purdue University UNITED STATESDoug Marchuk Duke University UNITED STATESLydia Matesic University of South Carolina UNITED STATESMonica McAndrews UNITED STATESLeonard McMillan University of North Carolina, Computer Science UNITED STATES

Terrencw Meehan EMBL-EBI UNITED KINGDOMMiriam Meisler University of Michigan UNITED STATESErdogan Memili Mississippi State University UNITED STATESHeather Mentrup University of South Carolina UNITED STATESDarla Miller University of North Carolina at Chapel Hill UNITED STATESRichard Miller University of Michigan UNITED STATESHiromi Miura Tokai UniversityBeverly Mock National Cancer Institute UNITED STATESXavier Montagutelli Institut Pasteur FRANCESteven Munger UNITED STATESTakuya Murata RIKEN BioResource CentorStephen Murray UNITED STATES


– 106 –

First Name Last Name Organization CountryMelissa Musser Vanderbilt University UNITED STATES

Nadeau UNITED STATESAysar Nashef Haddassa Medical Center ISRAELDominic Norris MRC UNITED KINGDOMMasato Ohtsuka Tokai UniversityKarla Otterpohl University of Nebraska Medical Center UNITED STATESKenneth Paigen UNITED STATESWenqi Pan University of North Carolina at Chapel Hill UNITED STATESFernando Pardo-Manuel De

VillenaUniversity of North Carolina UNITED STATES

William Pavan National Institutes of Health UNITED STATESGuillaume Pavlovic Mouse Clinical Institute FRANCELuanne Peters UNITED STATESPetko Petkov UNITED STATESNicholas Plummer National Institute of Environmental Health Sciences UNITED STATES

Paul Potter Mammalian Genetics Unit, MRC Harwell UNITED KINGDOMMichal Pravenec Institute of Physiology, Academy of Sciences of The Czech

RepublicCZECH REPUBLIC

Daniel Prows Cincinnati Children’s Hospital Medical Center UNITED STATESGerhard Przemeck Helmholtz Zentrum München – German Research Center for

Environmental HealthGERMANY

Thomas Randall National Institute of Environmental Health Sciences UNITED STATES

Karlyne Reilly National Cancer Institute UNITED STATESLaura Reinholdt UNITED STATESBeverly Richards-Smith UNITED STATES

Elaine Ritter Vanderbilt University UNITED STATESRandall Roper Indiana University-Indianapolis UNITED STATESLucy Rowe UNITED STATESChristine Rubinshteyn North Carolina State University UNITED STATESEdward Ryder Wellcome Trust Sanger Institute UNITED KINGDOMThom Saunders University of Michigan UNITED STATES

Schimenti Cornell University UNITED STATESKlaus Schughart Helmholtz Centre for Infection Research GERMANYPaul Shaw Takeda Singapore Pte Ltd SINGAPOREMeng-Shin Shiao Academia Sinica TAIWANLinda Siracusa UNITED STATESMartin Smith Ego Matty Inc UNITED STATESMichelle Southard-Smith Vanderbilt University, Genetic Medicine UNITED STATESKaren Steel Wellcome Trust Sanger Institute UNITED KINGDOMSari Suzuki Tokyo University of AgricultureKaren Svenson UNITED STATESGabor Szalai University of South Carolina UNITED STATES

Szatkiewicz University of North Carolina at Chapel Hill UNITED STATESDana Tabor University of Nebraska Medical Center UNITED STATESToyoyuki Takada National Institute of GeneticsGennadiy Tenin University of Manchester UNITED KINGDOM

Attendee List

– 107 –

First Name Last Name Organization CountryDavid Threadgill North Carolina State University UNITED STATESLouise Tinsley Mammalian Genome UNITED KINGDOMKärt Tomberg University of Michigan UNITED STATESZdenek Trachtulec Institute of Molecular Genetics Prague CZECH REPUBLIC

Van Schaick International Mammalian Genome Society UNITED STATESCynthia Vied Florida State University UNITED STATESKenta Wada Tokyo University of Agriculture

Walker Geneseek, Inc UNITED STATESKei Watanabe University of TsukubaCatherine Welsh University of North Carolina at Chapel Hill UNITED STATESDavid West Children’s Hospital Oakland Research Institute UNITED STATESRandal Westrick University of Michigan UNITED STATES

White Wellcome Trust Sanger Institute UNITED KINGDOMLaurens Wilming Wellcome Trust Sanger Institute UNITED KINGDOMTim Wiltshire University of North Carolina UNITED STATESY. Eugene Yu Roswell Park Cancer Institute UNITED STATESRong Zeng University of Missouri UNITED STATES


– 108 –

NOTES


– 109 –

NOTES


– 110 –

NOTES

Documents

Welcometothe26thInternationalMammalianGenomeConferenc ...imgs.org/Archive/abstracts/2012abstracts/IMGC_2012...FinalProgram&BookofAbstracts –7– IMGCP ROGRAM Saturday,October20,2012