Coban-Akdemir Zeynep, Song Xiaofei, Ceballos Francisco C, Pehlivan Davut, Karaca Ender, Bayram Yavuz, Mitani Tadahiro, Gambin Tomasz, Bozkurt-Yozgatli Tugce, Jhangiani Shalini N, Muzny Donna M, Lewis Richard A, Liu Pengfei, Boerwinkle Eric, Hamosh Ada, Gibbs Richard A, Sutton V Reid, Sobreira Nara, Carvalho Claudia M B, Shaw Chad A, Posey Jennifer E, Valle David, Lupski James R
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Genet Med Open. 2024 Feb 14;2:101830. doi: 10.1016/j.gimo.2024.101830. eCollection 2024.
The variome of the Turkish (TK) population, a population with a considerable history of admixture and consanguinity, has not been deeply investigated for insights on the genomic architecture of disease.
We generated and analyzed a database of variants derived from exome sequencing data of 773 TK unrelated, clinically affected individuals with various suspected Mendelian disease traits and 643 unaffected relatives.
Using uniform manifold approximation and projection, we showed that the TK genomes are more similar to those of Europeans and consist of 2 main subpopulations: clusters 1 and 2 ( = 235 and 1181, respectively), which differ in admixture proportion and variome (https://turkishvariomedb.shinyapps.io/tvdb/). Furthermore, the higher inbreeding coefficient values observed in the TK affected compared with unaffected individuals correlated with a larger median span of long-sized (>2.64 Mb) runs of homozygosity (ROH) regions ( value = 2.09e-18). We show that long-sized ROHs are more likely to be formed on recently configured haplotypes enriched for rare homozygous deleterious variants in the TK affected compared with TK unaffected individuals ( value = 3.35e-11). Analysis of genotype-phenotype correlations reveals that genes with rare homozygous deleterious variants in long-sized ROHs provide the most comprehensive set of molecular diagnoses for the observed disease traits with a systematic quantitative analysis of Human Phenotype Ontology terms.
Our findings support the notion that novel rare variants on newly configured haplotypes arising within the recent past generations of a family or clan contribute significantly to recessive disease traits in the TK population.
土耳其（TK）人群有着大量的混血和近亲结婚历史，但其疾病基因组结构尚未得到深入研究以获取相关见解。
我们生成并分析了一个变异数据库，该数据库来自773名患有各种疑似孟德尔疾病特征的未关联临床患者以及643名未受影响亲属的外显子组测序数据。
使用均匀流形近似和投影法，我们发现TK基因组与欧洲人基因组更为相似，且由两个主要亚群组成：第1组和第2组（分别为235人和1181人），这两组在混合比例和变异组方面存在差异（https://turkishvariomedb.shinyapps.io/tvdb/）。此外，与未受影响个体相比，在受影响的TK个体中观察到的较高近亲繁殖系数值与较长大小（>2.64 Mb）的纯合子区域（ROH）的中位数跨度较大相关（P值 = 2.09e - 18）。我们表明，与未受影响的TK个体相比，受影响的TK个体中较长大小的ROH更有可能在富含罕见纯合有害变异的最近形成的单倍型上形成（P值 = 3.35e - 11）。对基因型 - 表型相关性的分析表明，在较长大小的ROH中具有罕见纯合有害变异的基因，通过对人类表型本体术语的系统定量分析，为观察到的疾病特征提供了最全面的分子诊断。
我们的研究结果支持这样一种观点，即家族或氏族近代产生的新配置单倍型上的新型罕见变异对TK人群中的隐性疾病特征有显著贡献。
