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SNPs

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

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SNPs

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  1. 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

  2. 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

  3. 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

  4. Imagine …

  5. Differences between individuals • Pima Indians • Anti-depressants • Coronary Artery Disease

  6. Basic Concepts Parent 2 Parent 1 A B a b A B a b X a b A B A b A B a b OR A B a B A B A b a b A B a B A b A B a b A B etc… High LD -> No Recombination (r2 = 1) SNP1 “tags” SNP2 Low LD -> Recombination Many possibilities

  7. 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

  8. HapMap Project

  9. 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

  10. Phase 3 Samples * Population is made of family trios

  11. 1: Surf to the HapMap Browser 1a. Go to www.hapmap.org 1b. Select “HapMap phase 3”

  12. 2: Search for TCF7L2 Search for a gene name, a chromosome band, or a phrase like “insulin receptor” 2. Type search term – “TCF7L2”

  13. 3: Examine Region Chromosome-wide summary data is shown in overview Region view puts your ROI in genomic context 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.

  14. 3: Examine Region (cont) Use the Scroll/Zoom buttons and menu to change position & magnification 3: Mouse over a SNP to see allele frequency table As you zoom in further, the display changes to include more detail Click to go to SNP details page

  15. 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

  16. 4: Generate Reports (cont) The Genotype download format can be saved to disk or loaded directly into Haploview v4.1

  17. 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

  18. 5: Find GWA hits (cont) 5c: Mouse over & click on GWA hit for more info

  19. 6: Examine GWA hits in entire genome 6: From www.hapmap.org, select “Karyogram”

  20. 6: Custom GWA hits in karyogram 6: Follow these instructions to upload your own GWA data Detailed help on the format is under the “Help” link

  21. Epigenomics • Even with identical DNA, offspring can retain features for up to 4 generations • Work with Huntsman on Methelation

  22. 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

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