Selection of Populations for Mapping Genes of Complex Diseases

Abstract

Mapping genes for complex diseases requires population-genetic and genetic-epidemiological studies that identify genetic architectonics developed over a lengthy period of demographic history of human populations with a high aggregation of a specific pathology. Due to a high concentration of ethnically, genetically, and geographically subdivided isolates, Dagestan is one of the most interesting regions for gene mapping. The genetic similarities among all 30 groups of indigenous mountain people of Dagestan suggest that they share a common proto-population that existed 8–10 thousand years ago. The results of our study suggest that in the subsequent demographic history, the ancient “proto-population” differentiated into many endogamous communities, which in following history was related to the development of new original languages. Our long-term studies in isolated populations of indigenous ethnic groups in Dagestan showed that the combination of a severe highland environment, marital isolation, and genetic drift contributes to relative insulation from severe hereditary diseases. Numerous invasions of the North and South Caucasus regions affected the gene pool of indigenous people. Severe highland conditions and difficult access to the mountain region led to less mixing of gene pools between Dagestan highland ethnics. By such geographical and genetic isolations, these indigenous people of the Caucasus developed significant cultural, linguistic, and genetic diversity. The significance of these ethnogenetic studies has important implications for complex disease gene mapping, as genetic architectonics depend on the local populations’ gene pools. The ages of manifestation of mental disorders are exacerbated in traditional Dagestani villages using a survey for epidemiologic studies, and the DIGS and FIGS clinical techniques revealed valuable information about family and kindred (tukhum) history in traditional Dagestani villages. We selected four ethnically and demographically diverse genetic isolates with an aggregation of SCZ for mapping genes of the disease. Results obtained in the study of DNA polymorphisms in selected genetic isolates indicated significant differences between them in the frequency of DNA alleles, as well as in the level of heterozygosity, and in the presence of rare unique alleles. We found unique alleles in the minimal sizes of microsatellite alleles, which most likely can be explained by genetic drift. The founder effect, in conjunction with the features of marriage structure (endogamy, inbreeding, early marriage), and the specificity of complex disease manifestation age, contributes to the accumulation of mutant genes of complex diseases in isolates.