Distinct genetic diversity and substantial heterogeneity
The 11 included Iranian ethnic groups featured distinct and substantial genetic heterogeneity (Fig 1A). Seven groups (Iranian Arabs, Azeris, Gilaks, Kurds, Mazanderanis, Lurs and Persians) strongly overlapped in their overall autosomal diversity in an MDS analysis (Fig 1B), suggesting the existence of a Central Iranian Cluster (CIC), notably also including Iranian Arabs and Azeris. The other four groups (Iranian Baluchis, Persian Gulf (PG) Islanders, Sistanis and Turkmen) presented as strongly admixed populations with contributions by different ancestral populations but always with an orientation towards the CIC, being strikingly different from the CIC and from each other, except for Baluchis and Sistanis who partially overlapped (Fig 1A). On a global scale (Fig 2 including “Old World” populations only; see S2 Fig for all 1000G populations), CIC Iranians closely clustered with Europeans, while Iranian Turkmen showed similar yet distinct degrees of admixture compared to other South Asians. The degree was less pronounced for Baluchis, Sistanis and PG Islanders, with the latter showing a pointed orientation towards Sub-Saharan Africans and a co-localization with numerous Latin American samples. Notably, Iranian Arabs now showed some detachment from the CIC towards Sub-Saharan populations. A local comparison corroborated the distinct genetic diversity of CIC Iranians relative to other geographically close populations [2, 6, 44] (Fig 3 and S3 Fig). Strikingly, the relative genetic location of the Iranian ethnic groups mirrored their geographic location at the nexus between South and Central Asia and West Asia, Northern Africa and the Caucasus. Iranian Baluchis and Sistanis clustered with or nearby Pakistani and other South Asian populations, whereas Iranian Turkmen located next or atop Central Asian populations, respectively. Iranian Arabs appeared distinct from other Arab populations in West Asia and Northern Africa. Furthermore, Zoroastrian samples [6] located as essential CIC members. These results were closely mirrored by the pairwise fixation index (FST) values (Table 2 and S5 Table). CIC groups showed little differentiation (FST~0.0008–0.0033), whereas non-CIC groups consistently yielded much larger values, most extreme for PG Islanders vs Iranian Turkmen (FST = 0.0110). Still, genetic substructure was much smaller among Iranian groups than in relation to any of the 1000G populations, supporting the view that the CIC groups form a distinct genetic entity, despite internal heterogeneity. European (FST~0.0105–0.0294), South Asians (FST~0.0141–0.0338), but also some Latin American populations (Puerto Ricans: FST~0.0153–0.0228; Colombians: FST~0.0170–0.0261) were closest to Iranians, whereas Sub-Saharan Africans and admixed Afro-Americans (FST~0.0764–0.1424) as well as East Asians (FST ~ 0.0645–0.1055) showed large degrees of differentiation with Iranians. If not corrected for, the observed degree of population substructure could severely confound population-based genetic association studies in Iran. In the extreme scenario of cases being sampled exclusively from one ethnic group and controls from another, CIC groups would yield moderate, although still problematic, genomic inflation factor (GIF) values (1.17–1.61), whereas non-CIC groups may yield values up to 3.0 (Table 2).
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