Extensive genome-wide autozygosity in the population isolates of Daghestan

Abstract

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.

Weighted likelihood inference of genomic autozygosity patterns in dense genotype data

“…Consistent with previous studies [12,18,22], ROA of different lengths have different continental patterns among the 26 populations included in Phase 3 of The 1000 Genomes Project both with regards to their total lengths (Figure 8) in individual genomes as well as in their non-uniform distributions across the genome (Figure 9) that are correlated with spatially variable genomic properties such as recombination rate (Additional File 1: Figure S16) and signals of natural selection (Additional File 1: Figure S17), reflecting the distinct forces generating ROA of different lengths. Total lengths and numbers of ROA in the shortest (G = 1-3) and to some extent intermediate (G = 4) classes increase with distance from Africa, rising in a stepwise fashion in successive continental groups (Figures 8), in agreement with the observed reduction in haplotype diversity with increasing distance from Africa [162,[183][184][185].…”

“…Population-genetic studies in worldwide human populations over the past decade have found ROA ranging in size from tens of kb to multiple Mb to be ubiquitous and frequent even in ostensibly outbred populations and to have a non-uniform distribution across the genome [7,10,13,18] that is correlated with spatially variable genomic properties [2][3][4]18] creating autozygosity hotspots and coldspots [18]. ROA of different sizes have different continental patterns both with regards to their total lengths in individual genomes [12,18,22,24,[26][27][28] and in their distribution across the genome [18] reflecting the distinct forces generating ROA of different lengths. Studies of ROA in the genomes of ancient hominins [29][30][31] and early Europeans [32] have provided unique insights into the mating patterns and effective population sizes of our early forbearers.…”

Siberian genetic diversity reveals complex origins of the Samoyedic‐speaking populations

“…After removing close relatives, the total number of samples in our Axiom data set was 311. For several analyses we added samples from Central Asia (CAS), as well as from Iran, Germany and India as representatives of the Near East (NEA), Europe (EUR), and South Asia (SAS), respectively; all of which were previously genotyped on the same platform and published elsewhere (Karafet et al, ) (Figure ).…”

Overcoming the dichotomy: new insights into the genomic diversity of open and isolated European populations

“…Using autosomal variation, we can detect signatures of isolation which are not revealed by unilinear markers, such as the increase in the number and size of stretches of consecutive homozygous genotypes, shared chromosomal segments identical by descent (IBD) and Linkage Disequilibrium (LD) 11,12,13,14,2,3 . Investigations published so far have provided accurate genetic characterizations of a number of human genetic isolates, with a prevalent focus on one or few populations and their potential use in gene-disease association studies 15,16,17,18,19 . Relations between genomic differences and demographic or historical factors and their implications for the gene mapping of Mendelian or complex traits were also studied 1,2,3 , while LD patterns were compared in isolates distributed worldwide 14 .…”

“…Relations between genomic differences and demographic or historical factors and their implications for the gene mapping of Mendelian or complex traits were also studied 1,2,3 , while LD patterns were compared in isolates distributed worldwide 14 . More recently, other studies have simultaneously investigated multiple isolates, mostly focusing on populations with shared historical and demographic features 17,18,20 . However, to the best of our knowledge, no study has systematically explored the structure of genomic diversity in isolated populations comparing them with a comprehensive set of open populations.…”