SNPs

• DNA differs between humans by 0.1%, (1 in 1300 bases)

• This means that you can map DNA variation to around 10,000,000 sites in the genome

• Almost all variation is ancient and 90% of SNP variation are constant across all populations

• These Single Nucleotide Polymorphisms (SNPs) can be correlated to human disease

• 1998 – 4,000 SNPs, 1994 – 7,800,000 nearly all mapped

Alzheimer's Disease

• Apolipoprotein E (ApoE) carries cholesterol and fat. It comes in three variants with two SNPs APoE2 (T-T), APoE3 (T-C), ApoE4 (C-C).

• In 1993, ApoE4 was correlated with 1/3 of the cases of Alzheimer’s disease

• If you have the E4 variant, you have a 60-70% lifetime risk of Alzheimer’s Disease

• Current research is focused on drug development that takes advantage of this knowledge

Haplotype Maps

• Although there are around 10,000,000 SNPs, they group into a small number of groups of SNPs that are correlated with each other.

• So, there are around around 300,000 unique arrangements of the SNPS

• This is not that big of a number!• CS people can imagine an exhaustive search

Imagine …

SNP 1 2 3 4 5… 10,000,000

Alzheimers 0 1 0 1 0  0 0

Leukemia 1 0 0 0 0  0 1

Breast Cancer 0 0 1 1 0 0 1

… 1 0 0 0 0 0 0

Differences between individuals

• Pima Indians• Anti-depressants• Coronary Artery Disease

Basic Concepts

A Ba b

A Ba b

High LD -> No Recombination(r2 = 1) SNP1 “tags” SNP2

A B

A B

A B

a b

a b

a b

Low LD -> RecombinationMany possibilities

A b

A ba Ba b

A BA B

a B

A b

etc…

A B

A B

X

OR

Parent 1 Parent 2

HapMap Glossary• LD (linkage disequilibrium): For a pair of SNP

alleles, it’s a measure of deviation from random association (i.e., no recombination). Measured by D’, r2, LOD

• Phased haplotypes: Estimated distribution of SNP alleles. Alleles transmitted from Mom are in same chromosome haplotype, while Dad’s form the paternal haplotype.

• Tag SNPs: Minimum SNP set to identify a haplotype. r2= 1 indicates two SNPs are redundant, so each one perfectly “tags” the other.

• Questions? help@hapmap.org

HapMap Project

Phase 1 Phase 2 Phase 3

Samples & POP panels

269 samples(4 panels)

270 samples(4 panels)

1,115 samples (11 panels)

Genotyping centers

HapMap International Consortium

Perlegen Broad & Sanger

Unique QC+ SNPs

1.1 M 3.8 M(phase I+II)

1.6 M (Affy 6.0 & Illumina 1M)

Reference Nature (2005) 437:p1299

Nature (2007) 449:p851

Draft Rel. 1 (May 2008)

Release Notes• Phase 1+2: Latest Release #24, October 2008

(NCBI build 36):

3.9 M unique QC+ SNPs -- > 1 SNP/700 bp

http://ftp.hapmap.org/00README.releasenotes_rel24

– Added back chrX SNPs dropped in previous releases– Corrected allele flips from rel#23a

• Phase 3: Draft release #1 (NCBI build 36)

http://ftp.hapmap.org/genotypes/2008-07_phaseIII/00README.txt

– HapMap3 sites @ Broad Institute, Sanger Center and Baylor College

Phase 3 Sampleslabel population sample # samples QC+ Draft 1ASW* African ancestry in Southwest USA 90 71

CEU*Utah residents with Northern and Western

European ancestry from the CEPH collection180 162

CHB Han Chinese in Beijing, China 90 82CHD Chinese in Metropolitan Denver, Colorado 100 70GIH Gujarati Indians in Houston, Texas 100 83JPT Japanese in Tokyo, Japan 91 82LWK Luhya in Webuye, Kenya 100 83MEX* Mexican ancestry in Los Angeles, California 90 71MKK* Maasai in Kinyawa, Kenya 180 171TSI Toscans in Italy 100 77

YRI* Yoruba in Ibadan, Nigeria 180 1631,301 1,115

* Population is made of family trios

1: Surf to the HapMap Browser

1b. Select “HapMap phase

3”

1a. Go to www.hapmap.o

rg

2: Search for TCF7L2

2. Type search term – “TCF7L2”

Search for a gene name, a

chromosome band, or a phrase like

“insulin receptor”

3: Examine Region

Region view puts your ROI in

genomic context

Chromosome-wide summary data is

shown in overview

Default tracks show HapMap genotyped SNPs, refGenes with exon/intron splicing

patterns, etc.

3: This exonic region has many typed SNPs.

Click on ruler to re-center image.

3: Examine Region (cont)

As you zoom in further, the

display changes to include more

detail

Use the Scroll/Zoom

buttons and menu to change position &

magnification

3: Mouse over a SNP to see allele frequency

table

Click to go to SNP details page

4: Generate Text Reports

4: Select the desired “Download” option and

press “Go” or “Configure”

Available phase 3 downloads:

- Individual genotypes - Population allele & genotype frequencies

4: Generate Reports (cont)

The Genotype download format can be saved to disk or loaded directly into

Haploview v4.1

5: Find GWA hits5a: Scroll down to turn on GWA studies tracks in overview & region

panels

5b: Find GWA hits in nearby region. Click on a GWA hit to re-center

5: Find GWA hits (cont)

5c: Mouse over & click on GWA hit for more

info

6: Examine GWA hits in entire genome

6: From www.hapmap.org, select “Karyogram”

6: Custom GWA hits in karyogram

Detailed help on the format is

under the “Help” link

6: Follow these instructions to upload your own GWA data

Epigenomics

• Even with identical DNA, offspring can retain features for up to 4 generations

• Work with Huntsman on Methelation

Progress in Disease Treatment

• Personalized medicine is becoming more prevalent for several kinds of cancer treatment

• 10-Feb-2009 – Breast Bioclassifier developed at the Huntsman Cancer Institute– 1/8 women will be diagnosed with breast cancer– Microarray analysis can separate large group who

need no treatment– Savings in cost and lifestyle– With $100 human genomes, doctors can determine

which drugs will be effective for your genotype