Abstract
Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates.
Highlights
Population isolates are subpopulations that originated from a small number of founders and subsequently remained relatively isolated for long periods of time due to geographical, cultural and social barriers
Population isolates provide a valuable window into the roles of rare genetic variation in human phenotypes, as a result of their unusual evolutionary histories, that often lead to relatively high frequencies of variants that are exceptionally rare elsewhere
As expected we find the imprint of Shetland population history in the Shetland genome, with strong evidence for founder effects and genetic drift, but we discover a relaxation of selective constraint across the genome
Summary
Population isolates are subpopulations that originated from a small number of founders and subsequently remained relatively isolated for long periods of time due to geographical, cultural and social barriers. Such populations have been recognised to be of significant interest for some time [1], due to their unusual genetic characteristics. Isolates are subject to lower variation in environmental factors, tend to have better genealogical records, more uniform phenotyping and higher participation rates in studies [2] Taken together, these genetic and other factors increase the power of gene mapping and association studies for both Mendelian and complex diseases and traits [5]. The breadth and depth of high-coverage WGS provides unprecedented opportunities for interrogation of the effects of rare and ultra-rare variants genome wide, and may prove instrumental for addressing the “missing heritability” problem [25,26]
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