SNP Selection - PowerPoint PPT Presentation

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SNP Selection

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Title: PowerPoint Presentation Author: Mark J Rieder Last modified by: Eric Torskey Created Date: 11/15/2004 6:31:25 AM Document presentation format – PowerPoint PPT presentation

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Title: 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
Why Do We Need tagSNPs?
Too Many SNPs to Genotype!
  • Whole Genome
  • 15,000,000 SNPs
  • 6,000,000 SNPs gt 5 MAF

4
SNP Genotypes Are Correlated (aka linkage
disequilibrium)
the nonindependence of alleles 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 r21.0 1,250 controls r2 0.80
  • D is related to recombination history
  • D 1 no recombination
  • D lt 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
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.e
du/stephens/software.html HAPLOTYPER http//www.p
eople.fas.harvard.edu/junliu/Haplo/docMain.htm
25
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
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 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
39
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
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 gt repetitive
  • Location of SNP
  • Coding gt noncoding
  • Function
  • Nonsynonymous gt synonymous

44
Categorizing tagSNPs
LPO
45
Haplotypes in Genetic Association Studies
Two main approaches with haplotypes
46
Haplotypes in Genetic Association Studies
Two main approaches with haplotypes
Haplotypes Pick tagSNPs Genotype
samples
Pick tagSNPs Infer haplotypes Test for
association
47
Haplotype Blocks
Daly et al 2001
Daly et al Nat. Genet. (2001)
48
Block Definitions
Daly et al 2001
Daly et al Nat. Genet. (2001)
D Gabriel et al Science (2002)
49
Block Definitions
50
Haplotype Blocks and tagSNPs
  • Identifying blocks and tagSNPs
  • Manually
  • Visual haplotype
  • Algorithms
  • HapMap and Haploview

51
Haplotype Blocks and tagSNPs
LTA 16 SNPs (MAF gt10) 6 common haplotypes
52
Haplotype Blocks and tagSNPs
  • Identifying blocks and tagSNPs
  • Manually
  • Visual Haplotype
  • Algorithms
  • HapMap and HaploView

53
HapMap Data and Haploview
www.hapmap.org
54
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HapMap Data and Haploview
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http//www.broad.mit.edu/mpg/haploview/
60
Import HapMap Data into Haploview
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Note HapMap is not complete variation data
69
Variation data, LD, and tagSNPs for ANAPC10 in
European-Americans
HapMap 5 tagSNPs
70
tagSNPs and Genome Variation Server
71
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72
Note Tagger is essentially the same as LDSelect
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74
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
75
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
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