Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions

Abstract

AbstractHuman 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.Author SummaryPopulation isolates provide a valuable window on 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. Such populations show increased levels of background relatedness among individuals and are often subject to stronger genetic drift, leading to a higher frequency of deleterious variants. Here, for the first time, we present whole genome sequencing data from the Shetland population in Northern Scotland, encompassing 500 individuals, and compare these genomes to the mainland Scottish population. 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 also discover a relaxation of selective constraint across the genome. These influences have combined to endow the Shetland genome with thousands of ultra-rare genetic variants, not observed previously in other populations. Surprisingly these variants are significantly enriched in functional regions including protein coding regions of genes and regulatory elements. Among regulatory regions, promoters are particularly enriched for ultra-rare variants, suggesting the potential for rapid divergence of gene expression in isolates.