Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec

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.

Identification de la mutation responsable de la mucolipidose de type II dans la région du Saguenay-Lac-St-Jean /

“…It is the underlying basis to the high prevalence of SLSJ genetic diseases. It is noteworthy that more than one mutation can cause each disease in SLSJ [33,36,37]. Hence, if a disease is the result of multiple mutations, more than one ancestor is involved.…”

Obesity and type 2 diabetes in Northern Canada's remote First Nations communities: the dietary dilemma

“…39 The frequency of certain rare mutations associated with hereditary disorders may be higher in isolated communities owing to lower genetic diversity, as observed with the Founder effect in Northeastern Québec communities. 42 Nevertheless, the genetic influence of complex diseases in Northern First Nations is probably attributable to a set of small effect size variants, which collectively confer a global genetic predisposition to disease development.…”

Effets fondateurs et variabilité génétique au Québec

“…L'existence de données généalogiques de qualité exceptionnelle offre un contexte favorable pour étudier la relation entre l'histoire démographique du Québec et sa diversité génétique. Jusqu'à maintenant, les travaux se sont beaucoup appuyés sur l'étude des maladies monogéniques et se sont concentrés sur la région du Saguenay-Lac-St-Jean (appelée Saguenay dans la suite du texte) [1][2][3]. Pour obtenir une image plus globale de la diversité génétique, nous avons entrepris un programme de recherche portant sur l'ensemble des populations régionales du Québec en débutant avec l'étude de la Gaspésie, une région maritime qui se caractérise par la diversité des fondateurs d'origine européenne venus s'y installer.…”

“…Au cours des générations qui suivent la migration, la dérive génétique peut aussi modifier les fréquences alléliques et l'ampleur de son effet sera fonction de l'effectif et de la dynamique démographique de la nouvelle population. Quand on parle de l'effet fondateur au Québec, on pense d'abord aux maladies mendéliennes qui y sont particulièrement fréquentes par rapport aux autres populations [1][2][3]. Ainsi, une douzaine de maladies héréditaires ont été observées dans la région du Saguenay et leur identification est à l'origine du paradigme saguenéen de l'effet fondateur québécois.…”