title: 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.
authors.affiliation: Centre de recherche, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, PQ, Canada, H3T 1C5.
authors.forename: Vania
authors.initials: V
authors.lastname: Yotova
authors.forename: Damian
authors.initials: D
authors.lastname: Labuda
authors.forename: Ewa
authors.initials: E
authors.lastname: Zietkiewicz
authors.forename: Dominik
authors.initials: D
authors.lastname: Gehl
authors.forename: Alan
authors.initials: A
authors.lastname: Lovell
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lefebvre
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Emilie
authors.initials: E
authors.lastname: Lemieux-Blanchard
authors.forename: Marcin
authors.initials: M
authors.lastname: Labuda
authors.forename: Hélène
authors.initials: H
authors.lastname: Vézina
authors.forename: Louis
authors.initials: L
authors.lastname: Houde
authors.forename: Marc
authors.initials: M
authors.lastname: Tremblay
authors.forename: Bruno
authors.initials: B
authors.lastname: Toupance
authors.forename: Evelyne
authors.initials: E
authors.lastname: Heyer
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Claude
authors.initials: C
authors.lastname: Laberge
mesh_terms: D000483:Alleles; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011792:Quebec