Browsing by Subject "Admixture"

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    Characterization of the fine-scale genetic structure of the Turkish population
    (2022-01) Kars, Meltem Ece
    The construction of population-based genetic resources plays a pivotal role in the study of human biology and disease. In this study, the fine-scale genetic structure of the Turkish (TR) population was characterized using the whole-exome (WES, n =2,589)andwhole-genome(WGS, n =773)sequencesof3,362unrelatedin-dividuals from Turkey. Significant levels of admixture from Balkan, Caucasus, Middle East, and Europe were detected in the TR subregions, consistent with the history of Anatolia. Results of the population structure analyses showed that the TR and European populations have a closer genetic relationship than previously appreciated. Inbreeding coefficient calculations and runs of homozygosity analysis reflected the unique effects of the high rate of consanguineous marriage on the TR genome. A TR Variome comprising over 40 million variants was constructed using the data generated in this study. Derived allele frequency (DAF) calculations revealed that 28% of TR-WES and 49% of TR-WGS variants in the very rare frequency bins (DAF < 0.005) were not listed in the Genome Aggregation Database. The lists of clinically-relevant variants and human gene knockouts in the TR Variome were also listed in this study, presenting the potential of the TR Variome being an invaluable resource for future disease gene identification studies. Additionally, a reference panel for genotype imputation was generated using TR-WGS data. Since this panel significantly increased imputation accuracy in both TR and neighboring populations, it will probably facilitate genome-wide association studies in these populations. In the second part of the study, the sequencing data of a total of 3,599 unrelated TR individuals were assessed for previously reported pathogenic (RP) variants and predicted pathogenic (PP) variants in Online Inheritance in Men (OMIM) genes associated with a pheno-type. Analyses revealed that no less than 70% of TR people have at least 1 RP variant, and all individuals possess at least one RP and/or PP variant in their genome. Moreover, 25% of individuals carried at least one RP variant in the newborn screening genes. Each individual in the study also had at least a 1 in 17 chance of carrying an RP variant in one of the 73 American College of Medical Genetics recommended actionable genes. MEFV, ABCA4, CYP21A2, PAH,and CFTR displayed the highest cumulative carrier frequencies (CF), consistent with the high prevalence of the phenotypes they are responsible for. By estimating the CF and genetic prevalence in 3,251 OMIM genes using RP and PP variants, this study presents the most comprehensive data so far demonstrating the landscape of genetic disease in the TR population.
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    ItemOpen Access
    The genetic structure of the Turkish population reveals high levels of variation and admixture
    (National Academy of Sciences, 2020-12-18) Kars, Meltem Ece; Başak, A. N.; Onat, Onur Emre; Bilguvar, K.; Choi, J.; Itan, Y.; Çağlar, C.; Palvadeau, R.; Casanova, J.-L.; Cooper, D. N.; Stenson, P. D.; Yavuz, A.; Buluş, H.; Günel, M.; Friedman, J. M.; Özçelik, Tayfun
    The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 30% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.