Whole-Exome Sequencing Reveals a Rapid Change in the Frequency of Rare Functional Variants in a Founding Population of Humans

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Abstract

Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France. We show that in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. Our results highlight the impact of population demography on genetic fitness and the contribution of rare variants to the human genetic variation landscape, emphasizing the need for deep cataloguing of genetic variants by resequencing worldwide human populations in order to truly assess disease risk.

Author Summary

Recent resequencing of the whole genome or the coding part of the genome (the exome) in thousands of individuals has described a large excess of low frequency variants in humans, probably arising as a consequence of recent rapid growth in human population sizes. Most rare variants are private to specific populations and are enriched for functional mutations, thus potentially having some medical relevance. In this study, we analyze whole-exome sequences from over a hundred individuals from the French-Canadian population, which was founded less than 400 years ago by about 8,500 French settlers who colonized the province between the 17th and 18th centuries. We show that in a remarkably short period of time this population has accumulated substantial differences, including an excess of rare, functional and potentially damaging variants, when compared to the original European population. Our results show the effects of population history on genetic variation that may have an impact on genetic fitness and disease, and have implications in the design of genetic studies, highlighting the importance of extending deep resequencing to worldwide human populations............