Scriver C R
Departments of Human Genetics, Pediatrics, and Biology, McGill University, Montreal, Quebec, Canada.
Annu Rev Genomics Hum Genet. 2001;2:69-101. doi: 10.1146/annurev.genom.2.1.69.
The population of Quebec, Canada (7.3 million) contains approximately 6 million French Canadians; they are the descendants of approximately 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, beta-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.
加拿大魁北克省有730万人口，其中约600万是法裔加拿大人；他们是大约8500名法国永久定居者的后裔，这些定居者在1608年至1759年间开拓了新法兰西。他们有详细记录的定居、内部迁移以及四个世纪以来在相对隔离状态下（地理、语言等方面）的自然增长，包含了人口行为社会传播的重要证据，这些证据对有效家庭规模和人口结构产生了影响。这段历史反映在至少22种孟德尔疾病中，这些疾病在其亚群体中的发病率异常高。在过去250年里，非法国人的移民使魁北克人口更加多样化，这在各个基因座的等位基因多样性中很明显。魁北克亚群体的历史在很大程度上就是其等位基因的历史。10个基因座（CFTR、FAH、HBB、HEXA、LDLR、LPL、PAH、PABP2、PDDR和SACS）上具有高外显率的罕见致病等位基因及相关单倍型，分别在患有囊性纤维化、酪氨酸血症、β地中海贫血、泰-萨克斯病、家族性高胆固醇血症、高乳糜微粒血症、苯丙酮尿症、眼咽型肌营养不良、假性维生素D缺乏佝偻病和沙勒沃伊-萨格奈痉挛性共济失调的先证者中表现出来，揭示了魁北克群体间和群体内的遗传多样性。近亲繁殖并不能解释这些遗传疾病的聚集和患病率；由分子证据支持的系谱重建在多个实例中指向奠基者效应和遗传漂变。对历史减数分裂的系谱估计和连锁不平衡分析表明，这个年轻群体的部分人群适合进行罕见等位基因的连锁不平衡定位。文中讨论了该群体如何从对其结构的了解中受益，以及其独特性如何有助于构建连锁不平衡基因组图谱。
