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Genome wide expression consequences of a disease resistance QTL are strongly
influenced by the genetic background
Finding QTL genes in mice
Few genes of large effect Many genes of small effect
>2000 QTL mapped
Mouse models of Trypanosomiasis
Survival of F6 and parental strains
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1 21 41 61 81 101 121
Days Post Challenge
% S
urvi
val
F6AJC57BL
Survival of F6 and parental strains
Trypanosoma infection response (Tir) loci
C57/BL6 x AJ and C57/BL6 x BALB/C
Iraqi et al Mammalian Genome 2000 11:645-648 Kemp et al. Nature Genetics 1997 16:194-196
Microarray designResistant C57BL/6Susceptible AJ
Networks responding to infection
P53
Daxx in Tir1 QTL
C57BL/6 ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDED129/J ETDDDDDDDDDDDDEDNEESEEEEEEEEEEKEATEDEDEDBALB/c ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDEDA/J ETDDDDD-DDDDDDEDNEESEEEEEEEEEEKEATEDEDED
Fisher et al. NAR 2007 Vol. 35, No. 16 5625-5633
Polymorphism in p53 binding region
C57BL/6 regions in
Tir 1 congenicsTir1
Tir3Tir2
Congenic mice carrying C57BL/6 regions on A/J background
No genes are differentially expressed in both congenics and parentals
Parentals Tir1 congenics
417456
Liver
Parentals Tir1 congenics
5225883
Spleen
Forms of gene regulation and discovery of QTG
Direct regulation:- eg transcription factor (SREBP) Polymorphisms might cause reproducible
phenotype Indirect regulation:- eg negative
feedback of cholesterol levels on cholesterol synthesis pathway Polymorphisms less likely to cause
reproducible phenotype
Participants ILRI, Nairobi Morris Agaba John Gibson Olivier Hanotte Hassan Musa Joel Mwakya Daniel Mwanga Jan Naessens Joseph Nganga Moises Ogugu John Wambugu Lilliam Wambua
University of Manchester
Andy Brass Helen Hulme Paul Fisher Leo Zeef Leanne Wardlesworth
University of Liverpool Anthea Broadhead Derek Daly Steve Kemp Harry Noyes Katie Rennie Luke Thomas Kate Goodheart
Roslin InstituteAlan ArchibaldSusan AndersonLaurence Hall
Genome wide expression consequences of a disease resistance QTL are strongly influenced by the genetic backgroundFinding QTL genes in miceSlide Number 3Trypanosoma infection response (Tir) loci C57/BL6 x AJ and C57/BL6 x BALB/CMicroarray designNetworks responding to infectionDaxx in Tir1 QTLCongenic mice carrying C57BL/6 regions on A/J background No genes are differentially expressed in both congenics and parentalsSlide Number 10Forms of gene regulation and discovery of QTGSlide Number 12Participants