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Anatomy of a founder effect : myotonic dystrophy in Northeastern Quebec

Yotova Vania, Labuda Damian, Zietkiewicz Ewa, Gehl Dominik, Lovell Alan, Lefebvre Jean-François, Bourgeois Stéphane, Lemieux-Blanchard Émilie, Labuda Marcin, Vézina Hélène, Houde Louis, Tremblay Marc, Toupance Bruno, Heyer Evelyne, Hudson Thomas J. et Laberge Claude. (2005). Anatomy of a founder effect : myotonic dystrophy in Northeastern Quebec. Human Genetics, 117, (2-3), p. 177-187.

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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.

Type de document:Article publié dans une revue avec comité d'évaluation
Pages:p. 177-187
Version évaluée par les pairs:Oui
Identifiant unique:10.1007/s00439-005-1298-8
Sujets:Sciences sociales et humaines > Sciences humaines > Histoire
Sciences sociales et humaines > Sciences sociales > Démographie
Sciences de la santé > Sciences médicales > Génétique
Département, module, service et unité de recherche:Départements et modules > Département des sciences humaines
Mots-clés:SNPs, founder effect, myotonic dystrophy, Northeastern Quebec
Déposé le:15 oct. 2022 17:48
Dernière modification:15 oct. 2022 17:48
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