SNP Selection

1. SNP Selection University of Louisville Center for Genetics and Molecular Medicine January 10, 2008 Dana Crawford, PhD Vanderbilt University Center for Human Genetics Research

2. Outline of Tutorial • Concepts of tagSNPs • LD and haplotype definitions • Haplotype blocks and definitions • Tools to identify tagSNPs

3. Ex: E2F2 Average Gene: • 26.5 kb • 130 SNPs • 44 SNPs ≥5% MAF Why Do We Need tagSNPs? Too Many SNPs to Genotype! • Whole Genome: • 15,000,000 SNPs • 6,000,000 SNPs > 5% MAF

4. Genotype at one site can predict genotype at another site Proportion of genotypes are correlated SNP Genotypes Are Correlated (aka linkage disequilibrium) “the nonindependence ofalleles at different sites.” Pritchard and Przeworski 2001

5. Measuring Pair-wise SNP Correlations • SNP genotype correlation described by • linkage disequilibrium (LD) • Pair-wise measures of LD: D´ and r2 • D = pAB - pApB; D´ = D/Dmax Recombination • r2 = D2 • f(A1)f(A2)f(B1)f(B2) Power

6. LD Statistics: Practical Uses • r2 is inversely related to power (“effective sample size”) • 1/r2 • 1,000 cases 1,250 cases • 1,000 controls r2=1.0 1,250 controls r2 = 0.80 • D´ is related to recombination history • D´ = 1 no recombination • D´ < 1 historical recombination

7. Where to Find Population LD Statistics For your gene or region of interest, search • HapMap www.hapmap.org • Perlegen genome.perlegen.com • SeattleSNPs PGA pga.gs.washington.edu • NIEHS SNPs egp.gs.washington.edu

8. Where to Find Population LD Statistics For your gene or region of interest, search • HapMap www.hapmap.org • Perlegen genome.perlegen.com • SeattleSNPs PGA pga.gs.washington.edu • NIEHS SNPs egp.gs.washington.edu

9. Visualizing Pair-wise LD

10. Visualizing Pair-wise LD

11. Visualizing Pair-wise LD

12. Where to Find Population LD Statistics For your gene or region of interest, search • HapMap www.hapmap.org • Perlegen genome.perlegen.com • SeattleSNPs PGA pga.gs.washington.edu • NIEHS SNPs egp.gs.washington.edu Genome Variation Server

13. Visualizing Pair-wise LD

14. Visualizing Pair-wise LD

15. Visualizing Pair-wise LD

16. Visualizing Pair-wise LD

17. Visualizing Pair-wise LD

18. Visualizing Pair-wise LD

19. Visualizing Pair-wise LD

20. Visualizing Pair-wise LD

21. Visualizing Pair-wise LD

22. Multi-SNP Genotype Correlations (aka Haplotypes) “…a unique combination of genetic markers present in a chromosome.” pg 57 in Hartl & Clark, 1997

23. Collect pedigrees Somatic cell hybrids Rodent Human C/C, A/G C/T, A/A Hybrid TT GG CC AG T/T, G/G C/C, A/G Allele-specific PCR SNP 1 SNP 2 CT AG C/T A/G C/T, A/G Constructing Haplotypes

24. Constructing Haplotypes Examples of Haplotype Inference Software: EM Algorithm Haploview http://www.broad.mit.edu/mpg/haploview/index.php Arlequin http://lgb.unige.ch/arlequin/ PHASE v2.1 http://www.stat.washington.edu/stephens/software.html HAPLOTYPER http://www.people.fas.harvard.edu/~junliu/Haplo/docMain.htm

25. Haplotypes in NIEHS SNPs • >625 genes re-sequenced • Cell cycle, DNA repair/replication, apoptosis • 2 DNA panels • 1: Polymorphism Discovery Resource (PDR90) • 2: Europeans, Africans, Hispanics, and Asians • PHASEv2.0 results posted on website • Interactive tool (VH1) to visualize and sort haplotypes http://egp.gs.washington.edu

26. Haplotypes in NIEHS SNPs

27. Haplotypes in NIEHS SNPs

28. Haplotypes in NIEHS SNPs

29. Haplotypes in NIEHS SNPs

30. Haplotypes in NIEHS SNPs

31. Haplotypes in NIEHS SNPs

32. Haplotypes in NIEHS SNPs

33. Haplotypes in NIEHS SNPs

34. Haplotypes in NIEHS SNPs

35. Haplotypes in NIEHS SNPs

36. Haplotypes in NIEHS SNPs

37. Haplotypes in NIEHS SNPs

38. Using LD and Haplotypes to Pick tagSNPs • r2 is inversely related to power (“effective sample size”) • 1/r2 • 1,000 cases 1,250 cases • 1,000 controls r2=1.0 1,250 controls r2 = 0.80 • D´ is related to recombination history • D´ = 1 no recombination • D´ < 1 historical recombination Example: Tagger and LDSelect Example: Haplotype “blocks”

39. Discovery genotype data pair-wise LD pick tagSNPs Using LD and Haplotypes to Pick tagSNPs • r2 is inversely related to power (“effective sample size”) • 1/r2 • 1,000 cases 1,250 cases • 1,000 controls r2=1.0 1,250 controls r2 = 0.80 Example: Tagger and LDSelect

40. LDSelect: Using LD to Pick tagSNPs • LDSelect • Uses SNP discovery data (not haplotypes) • Finds all correlated SNP genotypes to minimize the total number • Maintains genetic diversity of locus Carlson et al. AJHG (2004)

41. TagSNPs Are Population Specific European-descent (BLM) African-descent (BLM)

42. SNP Selection: tagSNP Data BLM

43. Side Note: Categorizing tagSNPs • SNP context • Nonrepetitive > repetitive • Location of SNP • Coding > noncoding • Function • Nonsynonymous > synonymous

44. Categorizing tagSNPs LPO

45. Haplotypes Pick tagSNPs Genotype samples Pick tagSNPs Infer haplotypes Test for association Haplotypes in Genetic Association Studies Two main approaches with haplotypes:

46. Recombination Natural selection Haplotype block definition Population history Population demography Haplotypes in Genetic Association Studies Two main approaches with haplotypes: Haplotypes Pick tagSNPs Genotype samples Pick tagSNPs Infer haplotypes Test for association

47. Represent most chromosomes Few Haplotypes Strong LD Haplotype “Blocks” Daly et al Nat. Genet. (2001) Daly et al 2001

48. Block Definitions Daly et al Nat. Genet. (2001) Daly et al 2001 D´ [Gabriel et al Science (2002)]

49. Four-gamete test: A B B A a b A b a b a B <4 haplotypes, D´=1 block 4 haplotypes, D´<1 boundary Block Definitions

50. Haplotype Blocks and tagSNPs • Identifying blocks and tagSNPs: • Manually • Visual haplotype • Algorithms • HapMap and Haploview