Program Abstracts - Or Zuk

Analysis of rare variants in humans: from population genetics to association studies

Or Zuk - HUJI

Recent exome and whole genome sequencing enables, for the first time, a systematic analysis of rare variants and their association with common human traits. However, the methodology for association analysis of rare variants is not well established, mainly due to the need to aggregate multiple variants when testing for association.

We study rare variants from a population genetics perspective, and determine the effect of selection and demographics on the pathogenicity of single alleles.

We propose a simple two-class model for exonic rare variants, in which missense alleles are either benign, or have an effect on both fitness and phenotype. We fit the model parameters and use them to design association tests for rare variants with improved power.

We demonstrate the benefits of our model and our proposed tests by analyzing an early-onset myocardial exome sequencing dataset, and analyze the contribution of LDLR and APOA5 to disease risk.

Finally, we use recent large-scale exome sequencing data to estimate gene-specific and population-specific parameters in these models, offering new insights into selection forces acting on human genes, in addition to improved tests for association.

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