SNP Selection

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

• Concepts of tagSNPs
• LD and haplotype definitions
• Haplotype blocks and definitions
• Tools to identify tagSNPs

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Why Do We Need tagSNPs?
Too Many SNPs to Genotype!

• Whole Genome
• 15,000,000 SNPs
• 6,000,000 SNPs gt 5 MAF

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SNP Genotypes Are Correlated (aka linkage
disequilibrium)
the nonindependence of alleles at different
sites. Pritchard and Przeworski 2001
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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

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LD Statistics Practical Uses

• r2 is inversely related to power (effective
  sample size)
• 1/r2
• 1,000 cases 1,250 cases
• 1,000 controls r21.0 1,250 controls r2 0.80
• D is related to recombination history
• D 1 no recombination
• D lt 1 historical recombination

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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

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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

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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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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
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Visualizing Pair-wise LD
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Multi-SNP Genotype Correlations (aka Haplotypes)
a unique combination of genetic markers present
in a chromosome. pg 57 in Hartl Clark, 1997
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Constructing Haplotypes
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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.e
du/stephens/software.html HAPLOTYPER http//www.p
eople.fas.harvard.edu/junliu/Haplo/docMain.htm
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Haplotypes in NIEHS SNPs

• gt625 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
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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Haplotypes in NIEHS SNPs
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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 r21.0 1,250 controls r2 0.80
• D is related to recombination history
• D 1 no recombination
• D lt 1 historical recombination

Example Tagger and LDSelect
Example Haplotype blocks
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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 r21.0 1,250 controls r2 0.80

Example Tagger and LDSelect
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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)
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TagSNPs Are Population Specific
European-descent (BLM)
African-descent (BLM)
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SNP Selection tagSNP Data
BLM
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Side Note Categorizing tagSNPs

• SNP context
• Nonrepetitive gt repetitive
• Location of SNP
• Coding gt noncoding
• Function
• Nonsynonymous gt synonymous

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Categorizing tagSNPs
LPO
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Haplotypes in Genetic Association Studies
Two main approaches with haplotypes
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Haplotypes in Genetic Association Studies
Two main approaches with haplotypes
Haplotypes Pick tagSNPs Genotype
samples
Pick tagSNPs Infer haplotypes Test for
association
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Haplotype Blocks
Daly et al 2001
Daly et al Nat. Genet. (2001)
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Block Definitions
Daly et al 2001
Daly et al Nat. Genet. (2001)
D Gabriel et al Science (2002)
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Block Definitions
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Haplotype Blocks and tagSNPs

• Identifying blocks and tagSNPs
• Manually
• Visual haplotype
• Algorithms
• HapMap and Haploview

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Haplotype Blocks and tagSNPs
LTA 16 SNPs (MAF gt10) 6 common haplotypes
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Haplotype Blocks and tagSNPs

• Identifying blocks and tagSNPs
• Manually
• Visual Haplotype
• Algorithms
• HapMap and HaploView

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HapMap Data and Haploview
www.hapmap.org
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HapMap Data and Haploview
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http//www.broad.mit.edu/mpg/haploview/
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Import HapMap Data into Haploview
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Note HapMap is not complete variation data
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Variation data, LD, and tagSNPs for ANAPC10 in
European-Americans
HapMap 5 tagSNPs
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tagSNPs and Genome Variation Server
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Note Tagger is essentially the same as LDSelect
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Haplotypes, TagSNPs, and Caveats

• Haplotypes are inferred
• Block-like structure assumed for some software
• Different block definitions
• Block boundaries sensitive to marker density
• Genotype savings may not be great (recombination)

tagSNPs based on LD more popular than htSNPs
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SNP Selection Summary

• Resources available for pair-wise LD and
  haplotypes
• Software for tagSNP selection available
• Be aware the limitations of the approach you
  choose
• Be aware that some SNP datasets may not
  represent
• all common variation of gene or gene region
• Be aware that a fraction of tagSNPs do not
  convert
• into a successful genotyping assay