Genomics: sequence and variation

Genetics: the inherited contribution to phenotypic variation

Example: inherited contribution to risk of type 2 diabetes

Correlating biological variation with variation in DNA sequence

Available tools work well at finding single genes with a big impact on risk of disease

Finding the genes for monogenic diseases

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Human Genetics 1985 - . . .

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But little success for common diseases caused by multiple genes and environment

And most common diseases are caused bya combination of genes and environment

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Most DNA variants change a single DNA letter:single nucleotide polymorphism (“SNP”)

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Question: what is the contributionof rare vs. common variation?

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Understanding polymorphism rate: Humans are small population, that grew large fast

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Association studies with common variants offer the greatest statistical power

Finding variants that influence function

Common variants found in the coding region of 106 human genes (n=114 chromosomes)

Regulatory variants: how many?

Finding new regulatory elements

Can we comprehensively characterize all the common genetic variation across the genome?

It will be critical to test variation across each gene, not just in the coding region

Disease association: direct and indirect

Disease association: direct and indirect

Humans are small population, that grew large fast

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Disease association: Indirect

Disease association: Indirect

Building a genome-wide catalogue of SNPs

An explosion in publicly available SNPs

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How correlated are nearby SNPs?

Extent of SNP correlation: pairs of markers

Fine structure of LD in each region

Fine structure of LD in each region

Patterns of LD across a region reveal block structure

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Summary of blocks: low historical recombinationprovisional definition of a‘block’: a set of contiguous SNPs for which all pair-wise comparisons show D’ɬ.8

Haplotype Map of Human Genome

LD Mapping in Practice:Inflammatory Bowel Disease

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The “red” haplotype is a major risk factor for Crohn’s Disease

“Candidate Gene” studies

Testing previous T2DM associations

Testing previous T2DM associations

Direct Association Study: Type 2 Diabetes

What is PPARg?

PPARg P12A and type 2 diabetesMeta-analysis of all published studies

Implications

Conclusions: potential impact of genetics on medical practice

Overall conclusions