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HapMap PROJECT

HapMap PROJECT. Basics. HapMap. The International HapMap Project is analyzing DNA from populations with African, Asian, and European ancestry. Multiple Populations. The DNA samples for the HapMap have come from a total of 270 people.

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HapMap PROJECT

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  1. HapMap PROJECT Basics

  2. HapMap • The International HapMap Project is analyzing DNA from populations with African, Asian, and European ancestry

  3. Multiple Populations • The DNA samples for the HapMap have come from a total of 270 people. • The Yoruba people of Ibadan, Nigeria, provided 30 sets of samples from two parents and an adult child (each such set is called a trio). • In Japan, 45 unrelated individuals from the Tokyo area provided samples. • In China, 45 unrelated individuals from Beijing provided samples. • Thirty U.S. trios provided samples, which were collected in 1980 from U.S. residents with northern and western European ancestry by the Centre d'Etude du Polymorphisme Humain (CEPH).

  4. Methods • The blood samples are being converted into cell lines, DNA extracted. • The samples and cell lines are not linked to any individual in the populations studied. However, the samples and cell lines are identified as coming from one of the four populations participating in the study, which raises ethical issues associated with conducting genetic research in named populations.

  5. SNP Nomenclature • http://snp500cancer.nci.nih.gov/terms_snp_region.cfm

  6. Hardy Weinberg Test • http://innateimmunity.net/IIPGA2/Bioinformatics/exacthweform

  7. IIPGA

  8. Exact HWE

  9. Fishers Exact Test

  10. Fishers Exact Test

  11. Homework http://www.hsph.harvard.edu/bioinfocore/Documents/Talk%20slides/Bioinfo_training_August_10_05_tutorial_Niu_T.pdf

  12. SNPcutter http://bioinfo.bsd.uchicago.edu/SNP_cutter.htm

  13. SNP and Cancer • A SNP is defined as a genomic locus where two or more alternative bases occur with appreciable frequency (>1%). • Occurs every several hundred bases. • Whole genome SNP analysis is possible.

  14. Applications • Direct Association Analysis: • Test association between putative functional variants and disease risk. • Evaluation of nonsynonymous SNPs or regulatory polymorphisms = functional SNPs. • Problem: there are not that many functional SNPs. • Uncharacterized de novo mutations???

  15. Examples • 2 MMP9 nonsynonymous SNPs associated with risk of lung cancer with metastasis (Hu et al. 2005b) • Coding polymorphisms within UGT1A7 predict response of colorectal patients to capecitabine (Carlini et al. 2005). • Functional MTHFR mutations linked to several different cancers.

  16. Direct Association • Candidate gene or genomic region. • Linkage analysis • Expression array analysis • Knowledge of development and physiology • Comparative genomics

  17. Tools • PANTHER database- evolutionary analysis of coding SNPs. • SNPEffect-estimate likelihood that a particular SNP is causing a functional effect. • SNPSeek->90 000 coding SNPs in the exons of known genes • SNP500Cancer – identification, validation, and characterization of polymorphisms.

  18. PANTHER http://www.pantherdb.org/tools/csnpScoreForm.jsp

  19. PANTHER http://www.pantherdb.org/tools/csnpScoreForm.jsp

  20. PANTHER

  21. ABCA1

  22. PolyPhen • http://genetics.bwh.harvard.edu/pph/

  23. PolyPhen • http://genetics.bwh.harvard.edu/pph/

  24. SNPEffect http://snpeffect.vib.be/search.php

  25. SNPSeek

  26. Search for BRCA1

  27. Search for BRCA1

  28. Search for BRCA1

  29. Search for BRCA1

  30. SNP500 Cancer Database

  31. SNP500 vs HDP

  32. Test if SNP500 and HDP differ

  33. Do subpopulations differ?

  34. Compare Caucasion vs African

  35. Compare Caucasian vs Hispanic

  36. Test whether in HWE

  37. HWE

  38. HWE

  39. TDT

  40. TDT

  41. HapMap • Polymorphisms identified by HapMap are likely to be neural in phenotypic effect but can inform on nearby alleles that might play a role in disease.

  42. Haplotype • SNP alleles tend to be correlated together in a predictable way-known as haplotype. • The linear, LD ordered arrangement of alleles on a chromosome • The correlation between SNPs is mediated by linkage disequilibrium (LD). • LD exists when alleles at distinctive loci occur together more frequently than expected given the known allele frequencies and recombination fraction between the loci.

  43. Disease allele and haplotypes • In the presence of LD, polymorphisms that are in physical proximity to a causal polymorphism will show a difference between cases and controls.

  44. HapMap • Three phases:I, II, III • I: completed in October 2005-genotyping of 1M SNPs at average spacing of 5kb. An additional SNP finding in 48 samples from original populations across 10 specific 500kb ENCODE regions (represent a genome wide rage of evolutionary conservation and gene density). Later this was extended to 269 samples.

  45. HapMap • Phase II: 269 samples, 2.9 M SNPs were genotyped, a total of 3.9 M. • Phase III: other populations will be added.

  46. Results of Phase I and Phase II • Intensity of SNP data across ENCODE regions 1SNP/279 bp. • Intensity of phase II Hapmap 1SNP/kb

  47. Robust measures of LD • D’ and r2 are the two major measures of LD. • D’, if two SNPs have not been separated by recombination during the history of the sample D’ is 1. • R2 is the correlation between two SNPs; when two SNPs always observed together r2 is 1. Generally is a better measure.

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