Exploring the effects of genome structural variation on human health and disease
Genetic variation is known to be an important contributor to nearly all health-related traits. However, the precise genetic variants that affect most diseases and traits are largely unknown, in part because many forms of genetic variation are difficult to ascertain. We will analyze a particular class of understudied genetic variants known as structural variants, which affect large segments of DNA. We will develop methods for detecting these variants in UK Biobank genotyping data, and we will then examine their effects on a broad spectrum of health-related traits by studying UK Biobank genotype and phenotype data for N=500,000 individuals. For variants of particular interest, we will further investigate how these variants have been passed down across generations. We anticipate that this multi-year project will identify many genome structural variants likely to have causal effects on health-related traits (e.g., diabetes, cardiovascular disease, and cancer).
Scope extension: We aim to develop methods to sensitively detect forms of genomic variation that have previously been difficult to ascertain -- including structural variants and mosaic mutations -- and apply these methods to analyze the effects of such variation on a broad spectrum of health-related traits. We also aim to explore the evolutionary history of trait-associated structural variants, examining the interplay between mutation and selection, and to explore the ways in which inherited risk and clonal evolution contribute to mosaicism. We plan to analyze genomic and phenotypic data in the full UK Biobank cohort.