Abstract


HUMAN GENETICS: Lessons from Quebec Populations1

Charles R. Scriver

Departments of Human Genetics, Pediatrics, and Biology, McGill University, Montreal, Quebec, Canada H3G 1Y6; e-mail: cscriv@po-box.mcgill.ca






Abstract


The population of Quebec, Canada (7.3 million) contains 6 million French Canadians; they are the descendants of 8500 permanent French settlers who colonized Nouvelle France between 1608 and 1759. Their well-documented settlements, internal migrations, and natural increase over four centuries in relative isolation (geographic, linguistic, etc.) contain important evidence of social transmission of demographic behavior that contributed to effective family size and population structure. This history is reflected in at least 22 Mendelian diseases, occurring at unusually high prevalence in its subpopulations. Immigration of non-French persons during the past 250 years has given the Quebec population further inhomogeneity, which is apparent in allelic diversity at various loci. The histories of Quebec's subpopulations are, to a great extent, the histories of their alleles. Rare pathogenic alleles with high penetrance and associated haplotypes at 10 loci (CFTR, FAH, HBB, HEXA, LDLR, LPL, PAH, PABP2, PDDR, and SACS) are expressed in probands with cystic fibrosis, tyrosinemia, -thalassemia, Tay-Sachs, familial hypercholesterolemia, hyperchylomicronemia, PKU, oculopharyngeal muscular dystrophy, pseudo vitamin D deficiency rickets, and spastic ataxia of Charlevoix-Saguenay, respectively) reveal the interpopulation and intrapopulation genetic diversity of Quebec. Inbreeding does not explain the clustering and prevalence of these genetic diseases; genealogical reconstructions buttressed by molecular evidence point to founder effects and genetic drift in multiple instances. Genealogical estimates of historical meioses and analysis of linkage disequilibrium show that sectors of this young population are suitable for linkage disequilibrium mapping of rare alleles. How the population benefits from what is being learned about its structure and how its uniqueness could facilitate construction of a genomic map of linkage disequilibrium are discussed.

The HHH Syndrome (hyperornithinaemia-hyperammonaemia-hypercitrullinuria, OMIM 238970), an inborn error or urea cycle function, results from mutations in the ORNTI gene (locus 13q14) encoding the inner mitochondrial membrane ornithine transporter. The disease clusters in French Canadians where the F188 deletion mutation accounts for 19 of the 20 mutant alleles. Ancestry of probands maps to various regions in Southern Quebec, but not to the northeast region. Here is further evidence that Quebec province harbors genetically diverse subpopulations of French Canadians. (Camacho JA, Obie C, Biery B, Goodman BK, Hu C-A, et al. 1999. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat. Genet. 22:151-58.)