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

Ferran Casals, Alan Hodgkinson, Julie Hussin, Youssef Idaghdhour, Vanessa Bruat, Thibault de Maillard, Jean Cristophe Grenier, Elias Gbeha, Fadi F. Hamdan, Simon Girard, Jean François Spinella, Mathieu Larivière, Virginie Saillour, Jasmine Healy, Isabel Fernández, Daniel Sinnett, Jacques L. Michaud, Guy A. Rouleau, Elie Haddad, Françoise Le DeistPhilip Awadalla

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1003815
JournalPLoS Genetics
Volume9
Issue number9
DOIs
StatePublished - Sep 1 2013

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Exome
human population
Population
demographic statistics
Medical Genetics
Demography
explosions
founder effect
genetic disorders
genetic isolation
homozygosity
demographic history
Cataloging
demography
population bottleneck
human diseases
Genetic Fitness
etiology
population genetics
Inborn Genetic Diseases

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Whole-Exome Sequencing Reveals a Rapid Change in the Frequency of Rare Functional Variants in a Founding Population of Humans. / Casals, Ferran; Hodgkinson, Alan; Hussin, Julie; Idaghdhour, Youssef; Bruat, Vanessa; de Maillard, Thibault; Grenier, Jean Cristophe; Gbeha, Elias; Hamdan, Fadi F.; Girard, Simon; Spinella, Jean François; Larivière, Mathieu; Saillour, Virginie; Healy, Jasmine; Fernández, Isabel; Sinnett, Daniel; Michaud, Jacques L.; Rouleau, Guy A.; Haddad, Elie; Le Deist, Françoise; Awadalla, Philip.

In: PLoS Genetics, Vol. 9, No. 9, e1003815, 01.09.2013.

Research output: Contribution to journalArticle

Casals, F, Hodgkinson, A, Hussin, J, Idaghdhour, Y, Bruat, V, de Maillard, T, Grenier, JC, Gbeha, E, Hamdan, FF, Girard, S, Spinella, JF, Larivière, M, Saillour, V, Healy, J, Fernández, I, Sinnett, D, Michaud, JL, Rouleau, GA, Haddad, E, Le Deist, F & Awadalla, P 2013, 'Whole-Exome Sequencing Reveals a Rapid Change in the Frequency of Rare Functional Variants in a Founding Population of Humans', PLoS Genetics, vol. 9, no. 9, e1003815. https://doi.org/10.1371/journal.pgen.1003815
Casals, Ferran ; Hodgkinson, Alan ; Hussin, Julie ; Idaghdhour, Youssef ; Bruat, Vanessa ; de Maillard, Thibault ; Grenier, Jean Cristophe ; Gbeha, Elias ; Hamdan, Fadi F. ; Girard, Simon ; Spinella, Jean François ; Larivière, Mathieu ; Saillour, Virginie ; Healy, Jasmine ; Fernández, Isabel ; Sinnett, Daniel ; Michaud, Jacques L. ; Rouleau, Guy A. ; Haddad, Elie ; Le Deist, Françoise ; Awadalla, Philip. / Whole-Exome Sequencing Reveals a Rapid Change in the Frequency of Rare Functional Variants in a Founding Population of Humans. In: PLoS Genetics. 2013 ; Vol. 9, No. 9.
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