Isolated populations are valuable resources for mapping disease genes, as inbreeding increases genome-wide homozygosity and enhances the ability to map disease alleles on a genetically uniform background within a relatively homogenous environment. The populations of Daghestan are thought to have resided in the Caucasus Mountains for hundreds of generations and are characterized by a high prevalence of certain complex diseases. To explore the extent to which their unique population history led to increased levels of inbreeding, we genotyped 4550 000 autosomal single-nucleotide polymorphisms (SNPs) in a set of 14 population isolates speaking Nakh-Daghestanian (ND) languages. The ND-speaking populations showed greatly elevated coefficients of inbreeding, very high numbers and long lengths of Runs of Homozygosity, and elevated linkage disequilibrium compared with surrounding groups from the Caucasus, the Near East, Europe, Central and South Asia. These results are consistent with the hypothesis that most ND-speaking groups descend from a common ancestral population that fragmented into a series of genetic isolates in the Daghestanian highlands. They have subsequently maintained a long-term small effective population size as a result of constant inbreeding and very low levels of gene flow. Given these findings, Daghestanian population isolates are likely to be useful for mapping genes associated with complex diseases.
AbstractWe conducted a 10-cM genome-wide linkage scan in two extended pedigrees, ascertained from two diverse Dagestan genetic isolates with high aggregation of major depressive disorder (MDD) and suicides. Using genome wide multipoint parametric linkage analyses with short tandem repeat markers, we found two previously undetected genomic regions with significant linkage in isolate #6007 with LODs=3.1–3.4 at 2p13.2–p11.2 (and some signal in same region for #6008) and in 14q31.12–q32.13. We also obtained suggestive evidence for linkage with MDD at 9q33.3–q34.2 (#6008), 13q31.1–q31.2(#6007), 11p15(#6008), 17q25.3(#6007) and 19q13.31–q13.33 (#6008). Five regions (1p36.1–p35.2, 2p13.2–p11.2, 17q25.3, 18q22 and 22q12.3) demonstrated at least nominal linkage in both isolates’ pedigrees, while all other linkage regions demonstrated population-specific genetic heterogeneity.
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