666.03 - Linkage Disequilibrium Biostatistics 666 Last...

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Linkage Disequilibrium Biostatistics 666
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Last Lecture z Basic properties of a locus Allele Frequencies Genotype Frequencies z Hardy-Weinberg Equilibrium Relationship between allele and genotype frequencies that holds for most genetic markers z Exact Tests for Hardy-Weinberg Equilibrium
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Today … z We’ll consider properties of pairs of alleles z Haplotype frequencies z Linkage equilibrium z Linkage disequilibrium
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Let’s consider the history of two neighboring alleles…
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Alleles that exist today arose through ancient mutation events… A A C After Mutation Before Mutation Mutation
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One allele arose first, and then the other… AG CG CC After Mutation Before Mutation Mutation
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Recombination generates new arrangements for ancestral alleles AG CG CC AC After Recombination Before Recombination Recombinant Haplotype
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Linkage Disequilibrium Ancestor Present-day z Chromosomes are mosaics z Extent and conservation of mosaic pieces depends on Recombination rate Mutation rate Population size Natural selection z Combinations of alleles at very close markers reflect ancestral haplotypes
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Why is linkage disequilibrium important for gene mapping?
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Association Studies and Linkage Disequilibrium z If all polymorphisms were independent at the population level, association studies would have to examine every one of them… z Linkage disequilibrium makes tightly linked variants strongly correlated producing cost savings for association studies
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Tagging SNPs z In a typical short chromosome segment, there are only a few distinct haplotypes z Carefully selected SNPs can determine status of other SNPs Haplo1 TT T Haplo2 T Haplo3 T Haplo4 T Haplo5 T 10% 30% 20% 20% 20%
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Linkage Disequilibrium Enables Genetic Association Studies z In contrast to linkage studies, association studies can identify variants with relatively small individual contributions to disease risk z However, they require detailed measurement of genetic variation and there are >10,000,000 catalogued genetic variants z Until recently, studies limited to candidate genes or regions A hit-and-miss approach… z Because assay costs are decreasing and a modest number of variants can represent all others, genome-wide association studies are now possible.
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666.03 - Linkage Disequilibrium Biostatistics 666 Last...

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