The genetic structure of the Turkish population reveals high levels of variation and admixture

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 50% 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.

Even in the Paleolithic period, Anatolia (or Asia Minor as it was once called) served as a bridge for migrations between Africa, Asia, and Europe. Long before the establishment of nation states, intermixing between human populations occurred in Anatolia. Indeed, Anatolia has been home to many civilizations including Hattians, Hurrians, Assyrians, Hittites, Greeks, Thracians, Phrygians, Urartians, Armenians, and Turks. Gene flow between Anatolian, Caucasus, and northern Levantine populations occurred during the Late Neolithic and Chalcolithic to the Early Bronze age, including long-distance migration from Central Asia to Anatolia (1). The Turkic peoples, a collection of ethnolinguistically related populations originating from Central Asia, were first documented in western Eurasia in the fourth/fifth century BCE and currently live in Central, Eastern, Northern, and Western Asia as well as in parts of Europe and in North Africa. The expansion of Turkic tribes into Western Asia and Eastern Europe occurred between the sixth and 11th centuries, beginning with the Seljuk Turks followed by the Ottomans (2). The sphere of Ottoman influence started to increase greatly, beginning in the 14th century; following the conquest of Constantinople in 1453, the Ottoman Empire controlled a vast region including all of southeastern Europe south of Vienna, parts of Central Europe, Western Asia, the Caucasus, North Africa, and the Horn of Africa. The modern Republic of Turkey was founded in 1923 after the fall of the Ottoman Empire at the end of World War I and is currently home to more than 80 million people. Turkish-speaking people constitute the major ethnolinguistic group in Turkey. There are also more than 70 million people who live in the five independent Turkic countries in Central Asia, namely Azerbaijan, Turkmenistan, Uzbekistan, Kazakhstan, and Kyrgyzstan. A study investigating the Y haplogroups of Turkish (TR) males revealed that the proportion of recent paternal gene flow from Central Asia was ∼9%, thereby raising the possibility that modern-day Anatolia is an admixture of preexisting Anatolian and Turkic peoples (3).The practice of consanguineous marriage is frequent in Turkey, especially in the eastern provinces (4). This should, in principle, help to facilitate disease gene discovery, as the increased frequency of homozygosity among members of inbred populations has led to the identification of many disease genes (5–8). The genetic admixture and consanguinity have had a significant effect on the genetic diversity of Middle Eastern populations (9, 10). The characterization of the Greater Middle East (GME) Variome, comprising the most comprehensive genomic database for Middle Eastern populations, has shown that knowledge of the genomic architecture of these populations facilitates disease gene identification in family studies and in genome-wide association studies (GWAS) of populations (11). Until now, the GME has been the largest resource representing the genetic variation in Turkey, albeit with only 140 out of a total of 1,111 samples coming from the TR Peninsula. Thus, based on the larger population of Turkey relative to its immediate neighbors, the TR population is underrepresented in current genomic databases. Furthermore, gnomAD, as one of the most comprehensive genetic variation resources, does not contain TR whole-exome sequencing (WES) or whole-genome sequencing (WGS) data (12). Therefore, a comprehensive database of alleles in the TR population should facilitate disease gene identification in consanguineous families and the assessment of the clinical phenotypes of individuals who are homozygous for mutations in specific genes.Finally, most GWAS to date have analyzed DNA from European ancestry–derived populations, and it will be important to extend the GWAS of complex traits to underrepresented populations. One of the key steps in GWAS is to “predict” or “impute” the missing genotypes by using a reference haplotype panel. It is becoming increasingly common for researchers to generate such panels for imputation from population-specific WGS data. Population-specific reference panels increase imputation accuracy, especially when they are combined with existing reference panels such as the 1000 Genomes Project (1000GP) (13–15). In this study, we have described the high-resolution genetic structure of the TR population, generated a TR Variome, and imputed a TR reference panel for future genetics studies.