SNPsAlzheimer's DiseaseHaplotype MapsImagine …Differences between individualsBasic ConceptsHapMap GlossaryHapMap ProjectRelease NotesPhase 3 Samples1: Surf to the HapMap Browser2: Search for TCF7L23: Examine Region3: Examine Region (cont)4: Generate Text Reports4: Generate Reports (cont)5: Find GWA hits5: Find GWA hits (cont)6: Examine GWA hits in entire genome6: Custom GWA hits in karyogramEpigenomicsProgress in Disease TreatmentSNPs•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 mappedAlzheimer'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 knowledgeHaplotype 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 searchImagine …SNP 1 2 3 4 5… 10,000,000Alzheimers 0 1 0 1 0 0 0Leukemia 1 0 0 0 0 0 1Breast Cancer 0 0 1 1 0 0 1… 1 0 0 0 0 0 0Differences between individuals•Pima Indians•Anti-depressants•Coronary Artery DiseaseBasic ConceptsA Ba bA Ba bHigh LD -> No Recombination(r2 = 1) SNP1 “tags” SNP2A BA BA Ba ba ba bLow LD -> RecombinationMany possibilitiesA bA ba Ba bA BA Ba BA betc…A BA BXORParent 1Parent 2HapMap 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? [email protected] ProjectPhase 1 Phase 2 Phase 3Samples & POP panels269 samples(4 panels)270 samples(4 panels)1,115 samples (11 panels)Genotyping centersHapMap International Consortium Perlegen Broad & SangerUnique QC+ SNPs1.1 M 3.8 M(phase I+II)1.6 M (Affy 6.0 & Illumina 1M) Reference Nature (2005) 437:p1299Nature (2007) 449:p851Draft 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 bphttp://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 CollegePhase 3 Sampleslabelpopulation sample # samples QC+ Draft 1ASW* African ancestry in Southwest USA 90 71CEU*Utah residents with Northern and Western European ancestry from the CEPH collection180 162CHBHan Chinese in Beijing, China 90 82CHDChinese in Metropolitan Denver, Colorado 100 70GIHGujarati Indians in Houston, Texas 100 83JPTJapanese in Tokyo, Japan 91 82LWKLuhya in Webuye, Kenya 100 83MEX* Mexican ancestry in Los Angeles, California 90 71MKK* Maasai in Kinyawa, Kenya 180 171TSIToscans in Italy 100 77YRI * Yoruba in Ibadan, Nigeria 180 1631,301 1,115* Population is made of family trios1: Surf to the HapMap Browser1b. Select “HapMap phase 3”1a. Go to www.hapmap.org2: Search for TCF7L22. Type search term – “TCF7L2”Search for a gene name, a chromosome band, or a phrase like “insulin receptor”3: Examine RegionRegion view puts your ROI in genomic contextChromosome-wide summary data is shown in overviewDefault 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 detailUse the Scroll/Zoom buttons and menu to change position & magnification3: Mouse over a SNP to see allele frequency tableClick to go to SNP details page4: Generate Text Reports4: Select the desired “Download” option and press “Go” or “Configure”Available phase 3 downloads: - Individual genotypes - Population allele & genotype frequencies4: Generate Reports (cont)The Genotype download format can be saved to disk or loaded directly into Haploview v4.15: Find GWA hits5a: Scroll down to turn on GWA studies tracks in overview & region panels5b: Find GWA hits in nearby region. Click on a GWA hit to re-center5: Find GWA hits (cont)5c: Mouse over & click on GWA hit for more info6: Examine GWA hits in entire genome6: From www.hapmap.org, select “Karyogram”6: Custom GWA hits in karyogramDetailed help on the format is under the “Help” link6: Follow these instructions to upload your own GWA dataEpigenomics•Even with identical DNA, offspring can retain features for up to 4 generations•Work with Huntsman on MethelationProgress 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