Dottorato in GENETICA E BIOLOGIA MOLECOLARE

Titolo della tesi: A comprehensive picture of the genomic history of Iran

Iran, a country with a population of around 85 million people, has a diverse composition of ethnicities, tribes and religions. This complicated social structure provides genetic researchers with a uniquely heterogeneous gene pool and a wealth of genetic variants. The preservation of different ethnic groups within the country has been particularly supported by geographical boundaries and a long-standing cultural tradition favouring intra-family marriages, which has contributed to the formation of an exceptionally diverse population. Present-day Iran is characterised by significant ethnic and linguistic diversity, encompassing over ten distinct ethnic groups and three language families: Indo-European, Afro-Asiatic and Turkic, which are believed to have been introduced into the region in the 3rd millennium BCE, 7th century AD and 9th century AD, respectively. Ancient genome studies revealed that Iran has played a central role in the history of Eurasia being one of the three major centres of agriculture invention and cattle domestication in the Fertile Crescent. While an “Iranian Neolithic component” is currently recognized in most of Eurasia as a consequence of past migrations, the genetic diversity of contemporary Iranians, especially at the whole genome sequencing (WGS) level, has been poorly studied. To paint a more comprehensive picture of the genomic diversity and history of the Iranian populations, we conducted a novel WGS study (depth > 30×) of 87 males spanning 11 different populations and 3 language families (Indo-European, Afro-Asiatic and Turkic). After merging our WGS data with the relevant available modern and ancient genomes, and considering Y chromosome and mitogenome diversity, we have found that all present-day Iranians, regardless of ethnicity, have two major genomic components: a predominantly pre-Neolithic Iranian autochthonous ancestry and a significant (although variable) ancestry from the Near East/Anatolia introduced into Iran since the Late Neolithic. The genomic impact of Bronze Age western Steppe pastoralists is also clearly detectable since 4,000 years ago and is evident in all the present-day ethnicities, although its association with the introduction of the Indo-European languages in Iran remains disputed. Despite sharing these three major genomic ancestries, different Iranian ethnic groups also showed striking differences due to varying gene flow from sub-Saharan Africa (in Arabs and Southern Iranians), Central/Eastern Asia (mainly in Iranian Turkic-speakers Turkmen, Qashqai and Azeri as well as in North-Eastern Persian), and South Asia (in Indo-European speakers of southern Iran). Uniparental marker diversity supported autosomal inferences, but also revealed that gene flow from Africa into Iranian Arabs (but not into southern Persian) was sex-biased, possibly due to past female slave trade. Our results not only shed light on the differential history of Iranian ethnicities, but also may have biomedical implications. Our study produced the first large scale and ethnicity-aware collection of Iranian complete genomes, which will be made publicly available to the scientific community contributing to fill a gap in the scarce Middle East representation in variome world-wide collections. This would allow the creation of a population-specific reference genome that could increase imputation accuracy in SNP-based genome-wide association studies as well as gene identification in family studies.