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 … SNP12345…10,000,000 Alzheimers Leukemia Breast Cancer …

Differences between individuals Pima Indians Anti-depressants Coronary Artery Disease

Basic Concepts ABabABab ABabABab High LD -> No Recombination (r 2 = 1) SNP1 “tags” SNP2 A B a b Low LD -> Recombination Many possibilities A b a B a b A B a B A b etc… A B X OR Parent 1 Parent 2

HapMap Glossary LD (linkage disequilibrium): For a pair of SNP alleles, it’s a measure of d eviation from random association (i.e., no recombination). Measured by D’, r 2, 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. r 2 = 1 indicates two SNPs are redundant, so each one perfectly “tags” the other.

HapMap Project Phase 1Phase 2Phase 3 Samples & POP panels 269 samples (4 panels) 270 samples (4 panels) 1,115 samples (11 panels) Genotyping centers HapMap International Consortium PerlegenBroad & Sanger Unique QC+ SNPs 1.1 M3.8 M (phase I+II) 1.6 M (Affy 6.0 & Illumina 1M) ReferenceNature (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 –Added back chrX SNPs dropped in previous releases –Corrected allele flips from rel#23a Phase 3: Draft release #1 (NCBI build 36) –HapMap3 Broad Institute, Sanger Center and Baylor College

Phase 3 Samples * Population is made of family trios

1: Surf to the HapMap Browser 1b. Select “HapMap phase 3” 1a. Go to

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 hits 5a: 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 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