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PLoS Genet. 2019 Nov 25;15(11):e1008480. doi: 10.1371/journal.pgen.1008480. [Epub ahead of print]

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

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MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Crewe Road, Edinburgh, United Kingdom.
Centre for Genomic and Experimental Medicine, MRC IGMM, University of Edinburgh, Crewe Road, Edinburgh, United Kingdom.
The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
Centre for Clinical Brain Sciences, Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
Mater Research Institute, University of Queensland, Woolloongabba, Australia.
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh, George Square, Edinburgh, United Kingdom.
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, United Kingdom.


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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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