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Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec

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Abstract

Founder effects are largely responsible for changes in frequency profiles of genetic variants in local populations or isolates. They are often recognized by elevated incidence of certain hereditary disorders as observed in regions of Charlevoix and Saguenay-Lac-Saint-Jean (SLSJ) in Northeastern Quebec. Dominantly transmitted myotonic dystrophy (DM1) is highly prevalent in SLSJ where its carrier rate reaches 1/550, compared with 1/5,000 to 1/50,000 elsewhere. To shed light on the origin of DM1 in this region, we have screened 50 nuclear DM1 families from SLSJ and studied the genetic variation in a 2.05 Mb (2.9 cM) segment spanning the site of the expansion mutation. The markers analyzed included 22 biallelic SNPs and two microsatellites. Among 50 independent DM1 chromosomes, we distinguished ten DM1-associated haplotypes and grouped them into three haplotype families, A, B and C, based on the relevant extent of allele sharing between them. To test whether the data were consistent with a single entry of the mutation into SLSJ, we evaluated the age of the founder effect from the proportion of recombinant haplotypes. Taking the prevalent haplotype A1_21 (58%) as ancestral to all the disease-associated haplotypes in this study, the estimated age of the founder effect was 19 generations, long predating the colonization of Nouvelle-France. In contrast, considering A1_21 as ancestral to the haplotype family A only, yielded the estimated founder age of nine generations, consistent with the settlement of Charlevoix at the turn of 17th century and subsequent colonization of SLSJ. We conclude that it was the carrier of haplotype A (present day carrier rate of 1/730) that was a “driver” of the founder effect, while minor haplotypes B and C, with corresponding carrier rates of 1/3,000 and 1/10,000, respectively, contribute DM1 to the incidence level known in other populations. Other studies confirm that this might be a general scenario in which a major “driver” mutation/haplotype issued from a founder effect is found accompanied by distinct minor mutations/haplotypes occurring at background population frequencies.

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Acknowledgements

We are thankful to Jack Puymirat for estimating DM1 prevalence in Quebec, to André Lescault for samples and earlier RFLP data, Julie Fortin and Pierre Lepage for sequencing of dHPLC variants, and Dominika Kozubska for secretarial assistance. S.B. had a studentship from the Fondation de l’Hôpital Sainte-Justine, while B.T. a postdoctoral fellowship of the Association Française contre les Myopathies. This study was supported by the Réseau de Médecine Génétique Appliquée of the Fonds de la Recherche en Santé du Québec (FRSQ).

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Authors and Affiliations

  1. Centre de recherche, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, PQ, Canada, H3T 1C5

    Vania Yotova, Damian Labuda, Ewa Zietkiewicz, Dominik Gehl, Alan Lovell, Jean-François Lefebvre, Stéphane Bourgeois, Émilie Lemieux-Blanchard & Marcin Labuda

  2. Département de Pédiatrie, Université de Montréal, Montréal, PQ, Canada

    Damian Labuda

  3. Interdisciplinary Research Group in Demography and Genetic Epidemiology, Université du Québec à Chicoutimi, Chicoutimi, PQ, Canada

    Hélène Vézina, Louis Houde & Marc Tremblay

  4. Unité d’Eco-Anthropologie, UMR CNRS/Université Paris, Paris, France

    Bruno Toupance & Evelyne Heyer

  5. McGill University and Genome Quebec Innovation Centre, Montreal, PQ, Canada

    Thomas J. Hudson

  6. Centre Hospitalier Université Laval, Québec, PQ, Canada

    Claude Laberge

  7. Institute of Human Genetic, Polish Academy of Sciences, Poznan, Poland

    Ewa Zietkiewicz

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  1. Vania Yotova
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  2. Damian Labuda
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  16. Claude Laberge
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Correspondence to Damian Labuda.

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Yotova, V., Labuda, D., Zietkiewicz, E. et al. Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec. Hum Genet 117, 177–187 (2005). https://doi.org/10.1007/s00439-005-1298-8

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