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.
Similar content being viewed by others
References
Abbruzzese C, Costanzi Porrini S, Mariani B, Gould FK, McAbney JP, Monckton DG, Ashizawa T, Giacanelli M (2002) Instability of a premutation allele in homozygous patients with myotonic dystrophy type 1. Ann Neurol 52:435–441
Austerlitz F, Heyer E (1998) Social transmission of reproductive behavior increases frequency of inherited disorders in a young-expanding population. Proc Natl Acad Sci USA 95:15140–15144
Austerlitz F, Kalaydjieva L, Heyer E (2003) Detecting population growth, selection and inherited fertility from haplotypic data in humans. Genetics 165:1579–1586
Bengtsson BO, Thomson G (1981) Measuring the strength of associations between HLA antigens and diseases. Tissue Antigens 18:356–363
Brais B (1998) Oculopharyngeal muscular dystrophy: from phenotype to genotype. McGill University, Montreal
Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, Rommens JM, Uyama E, Nohira O, Blumen S, Korczyn AD, Heutink P, Mathieu J, Duranceau A, Codere F, Fardeau M, Rouleau GA, Korcyn AD (1998) Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 18:164–167
Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T et al (1992) Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68:799–808
Brunner HG, Korneluk RG, Coerwinkel-Driessen M, MacKenzie A, Smeets H, Lambermon HM, van Oost BA, Wieringa B, Ropers HH (1989) Myotonic dystrophy is closely linked to the gene for muscle-type creatine kinase (CKMM). Hum Genet 81:308–310
Brunner HG, Nillesen W, van Oost BA, Jansen G, Wieringa B, Ropers HH, Smeets HJ (1992) Presymptomatic diagnosis of myotonic dystrophy. J Med Genet 29:780–784
Demers SI, Phaneuf D, Tanguay RM (1994) Hereditary tyrosinemia type I: strong association with haplotype 6 in French Canadians permits simple carrier detection and prenatal diagnosis. Am J Hum Genet 55:327–333
Fu YH, Pizzuti A, Fenwick RG Jr, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, de Jong P et al (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255:1256–1258
Gauvreau D, Guerin M, Hamel M (1991) De Charlevoix au Saguenay: mesure et caractéristiques du mouvement migratoire avant 1911. In: Bouchard G, de Braekeleer M et al (eds) Histoire d’un génome. Population et génétique dans l’est du Québec. Presses de l’Université du Québec, Sillery, pp 145–159
Goldman A, Ramsay M, Jenkins T (1995) New founder haplotypes at the myotonic dystrophy locus in southern Africa. Am J Hum Genet 56:1373–1378
Goldman A, Krause A, Ramsay M, Jenkins T (1996) Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies. Am J Hum Genet 59:445–452
Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J (1994) The 1993–94 Genethon human genetic linkage map. Nat Genet 7:246–339
Harley HG, Brook JD, Floyd J, Rundle SA, Crow S, Walsh KV, Thibault MC, Harper PS, Shaw DJ (1991) Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker. Am J Hum Genet 49:68–75
Harley HG, Rundle SA, Reardon W, Myring J, Crow S, Brook JD, Harper PS, Shaw DJ (1992) Unstable DNA sequence in myotonic dystrophy. Lancet 339:1125–1128
Harper PS (1989) Gene mapping and the muscular dystrophies. Prog Clin Biol Res 306:29–49
Hastbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver A, Lander E (1992) Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland [published erratum appears in Nat Genet 1992 Dec 2(4):343]. Nat Genet 2:204–211
Jetté R, Gauvreau D, Guerin M (1991) Aux origines d’une région: le peuplement fondateur de Charlevoix avant 1850. In: Bouchard G, de Braekeleer M et al (eds) Histoire d’un génome. Population et génétique dans l’est du Québec. Presses de l’Université du Québec, Sillery, pp 75–106
Jomphe M, Tremblay M, Vézina H (2001) Analyses généalogiques à partir du fichier RETRO. Projet BALSAC, Chicoutimi, pp Document 1-C-204
Junghans RP, Ebralidze A, Tiwari B (2001) Does (CUG)n repeat in DMPK mRNA ‘paint’ chromosome 19 to suppress distant genes to create the diverse phenotype of myotonic dystrophy? A new hypothesis of long-range cis autosomal inactivation. Neurogenetics 3:59–67
Kaplan NL, Weir BS (1995) Are moment bounds on the recombination fraction between a marker and a disease locus too good to be true? Allelic association mapping revisited for simple genetic diseases in the Finnish population. Am J Hum Genet 57:1486–1498
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at UCSC. Genome Res 12:996–1006
Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247
Labuda M, Labuda D, Korab-Laskowska M, Cole DE, Zietkiewicz E, Weissenbach J, Popowska E, Pronicka E, Root AW, Glorieux FH (1996) Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians. Am J Hum Genet 59:633–643
Labuda D, Zietkiewicz E, Labuda M (1997) The genetic clock and the age of the founder effect in growing populations: a lesson from French Canadians and Ashkenazim [letter]. Am J Hum Genet 61:768–771
Labuda M, Labuda D, Miranda C, Poirier J, Soong BW, Barucha NE, Pandolfo M (2000) Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion. Neurology 54:2322–2324
Lavedan C, Hofmann-Radvanyi H, Boileau C, Bonaiti-Pellie C, Savoy D, Shelbourne P, Duros C, Rabes JP, Dehaupas I, Luce S et al (1994) French myotonic dystrophy families show expansion of a CTG repeat in complete linkage disequilibrium with an intragenic 1 kb insertion. J Med Genet 31:33–36
Lee N, Daly MJ, Delmonte T, Lander ES, Xu F, Hudson TJ, Mitchell GA, Morin CC, Robinson BH, Rioux JD (2001) A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16. Am J Hum Genet 68:397–409
Lewontin RC, Kojima K (1960) The evolutionary dynamics of complex polymorphisms. Evolution 14:458–472
Luria SE, Delbrück M (1943) Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28:491–511
Mahadevan MS, Amemiya C, Jansen G, Sabourin L, Baird S, Neville CE, Wormskamp N, Segers B, Batzer M, Lamerdin J et al (1993) Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene. Hum Mol Genet 2:299–304
Martorell L, Monckton DG, Sanchez A, Lopez De Munain A, Baiget M (2001) Frequency and stability of the myotonic dystrophy type 1 premutation. Neurology 56:328–335
Mathieu J, De Braekeleer M, Prevost C (1990) Genealogical reconstruction of myotonic dystrophy in the Saguenay-Lac-Saint-Jean area (Quebec, Canada). Neurology 40:839–842
Neville CE, Mahadevan MS, Barcelo JM, Korneluk RG (1994) High resolution genetic analysis suggests one ancestral predisposing haplotype for the origin of the myotonic dystrophy mutation. Hum Mol Genet 3:45–51
Nokelainen P, Shelbourne P, Shaw D, Brook JD, Harley HG, Johnson K, Somer H, Savontaus ML, Peltonen L (1993) The DM mutation; diagnostic applications in the Finnish population. Clin Genet 43:190–195
Pouyez C, Lavoie Y (1983) Les Saguenayens. Introduction à l’histoire des populations du Saguenay. Les Presses de l’Université du Québec, Sillery
Richter A, Rioux JD, Bouchard JP, Mercier J, Mathieu J, Ge B, Poirier J, Julien D, Gyapay G, Weissenbach J, Hudson TJ, Melancon SB, Morgan K (1999) Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix–Saguenay, in chromosome region 13q11. Am J Hum Genet 64:768–775
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386
Rozen R, De Braekeleer M, Daigneault J, Ferreira-Rajabi L, Gerdes M, Lamoureux L, Aubin G, Simard F, Fujiwara TM, Morgan K (1992) Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis. Am J Med Genet 42:360–364
Schneider MP, Erdmann J, Delles C, Fleck E, Regitz-Zagrosek V, Schmieder RE (2000) Functional gene testing of the Glu298Asp polymorphism of the endothelial NO synthase. J Hypertens 18:1767–1773
Scriver CR (2001) Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet 2:69–101
Segel R, Silverstein S, Lerer I, Kahana E, Meir R, Sagi M, Zilber N, Korczyn AD, Shapira Y, Argov Z, Abeliovich D (2003) Prevalence of myotonic dystrophy in Israeli Jewish communities: inter-community variation and founder premutations. Am J Med Genet 119A:273–278
Shen MR, Jones IM, Mohrenweiser H (1998) Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res 58:604–608
Thibault MC, Mathieu J, Moorjani S, Lescault A, Prevost C, Gaudet D, Morissette J, Laberge C (1989) Myotonic dystrophy: linkage with apolipoprotein E and estimation of the gene carrier status with genetic markers. Can J Neurol Sci 16:134–140
Thompson EA, Neel JV (1997) Allelic disequilibrium and allele frequency distribution as a function of social and demographic history. Am J Hum Genet 60:197–204
Tremblay M, Vezina H (2000) New estimates of intergenerational time intervals for the calculation of age and origins of mutations. Am J Hum Genet 66:651–658
Tremblay M, Lavoie EM, Houde L, Vézina H (2002) Demogenetic study of three populations within a region with strong founder effect. Eur J Hum Genet 10:183
Valdes AM, Slatkin M, Freimer NB (1993) Allele frequencies at microsatellite loci: the stepwise mutation model revisited. Genetics 133:737–749
Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, Portale AA, Miller WL (1998) Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am J Hum Genet 63:1694–1702
Whiting EJ, Tsilfidis C, Surh L, MacKenzie AE, Korneluk RG (1995) Convergent myotonic dystrophy (DM) haplotypes: potential inconsistencies in human disease gene localization. Eur J Hum Genet 3:195–202
Yamagata H, Miki T, Ogihara T, Nakagawa M, Higuchi I, Osame M, Shelbourne P, Davies J, Johnson K (1992) Expansion of unstable DNA region in Japanese myotonic dystrophy patients. Lancet 339:692
Yamaoka LH, Pericak-Vance MA, Speer MC, Gaskell PC Jr, Stajich J, Haynes C, Hung WY, Laberge C, Thibault MC, Mathieu J et al (1990) Tight linkage of creatine kinase (CKMM) to myotonic dystrophy on chromosome 19. Neurology 40:222–226
Zietkiewicz E, Yotova V, Jarnik M, Korab-Laskowska M, Kidd KK, Modiano D, Scozzari R, Stoneking M, Tishkoff S, Batzer M, Labuda D (1997) Nuclear DNA diversity in worldwide distributed human populations. Gene 205:161–171
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).
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-005-1298-8