Variation and Functional Impact of Neanderthal Ancestry in Western Asia

Abstract

Neanderthals contributed genetic material to modern humans via multiple admixture events. Initial admixture events presumably occurred in Western Asia shortly after humans migrated out of Africa. Despite being a focal point of admixture, earlier studies indicate lower Neanderthal introgression rates in some Western Asian populations as compared with other Eurasian populations. To better understand the genome-wide and phenotypic impact of Neanderthal introgression in the region, we sequenced whole genomes of nine present-day Europeans, Africans, and the Western Asian Druze at high depth, and analyzed available whole genome data from various other populations, including 16 genomes from present-day Turkey. Our results confirmed previous observations that contemporary Western Asian populations, on an average, have lower levels of Neanderthal-introgressed DNA relative to other Eurasian populations. Modern Western Asians also show comparatively high variability in Neanderthal ancestry, which may be attributed to the complex demographic history of the region. We further replicated the previously described depletion of putatively functional sequences among Neanderthal-introgressed haplotypes. Still, we find dozens of common Neanderthal-introgressed haplotypes in the Turkish sample associated with human phenotypes, including anthropometric and metabolic traits, as well as the immune response. One of these haplotypes is unusually long and harbors variants that affect the expression of members of the CCR gene family and are associated with celiac disease. Overall, our results paint a complex first picture of the genomic impact of Neanderthal introgression in the Western Asian populations.

Analyses of Neanderthal introgression suggest that Levantine and southern Arabian populations have a shared population history

“…Based on f 4 ratios, we find that proportions of introgression are relatively low and very similar among the Levantine and southern Arabian populations (Figure 2; Table S3). These findings are consistent with previous findings that Near Eastern populations have lower levels of introgression than other non-Africans (Lazaridis et al, 2016; Rodriguez-Flores et al, 2016; Taskent et al, 2017). The low levels of introgression in these populations cannot be attributed to gene flow from sub-Saharan Africa as some of these Levantine and southern Arabian populations (such as the Druze and Saudis) were found to have minimal sub-Saharan ancestry (Vyas et al 2017a).…”

“…The Levantine and southern Arabians have significantly more introgression than sub-Saharan Africans as depicted by significantly negative D statistics in Figure 4. Furthermore, the Levant and southern Arabia have significantly less introgression than most other non-Africans as depicted by the significantly positive D statistics in Figure 4; these findings are consistent with previous studies of Near Eastern populations (Lazaridis et al, 2016; Rodriguez-Flores et al, 2016; Taskent et al, 2017). The Levantine and southern Arabian pooled populations also share very similar D statistic values when compared to other non-African pooled populations (compare top and bottom of Figure 4; Table S6).…”

“…An alternative, “dilution” model was put forth by Lazaridis et al (2016) based on analyses of genomic sequence data from archaeological populations from the Levant and nearby regions along with SNP genotypes from contemporary, global populations. Lazaridis et al (2016) and others (e.g., Rodriguez-Flores et al, 2016; Taskent et al, 2017) found that Near Eastern populations have less Neanderthal introgression than other Eurasians. Lazaridis et al (2016) also found that Near Eastern populations have high levels of ancestry deriving from a group known as the “Basal Eurasians” that diverged from all other non-Africans prior to the separation of western Eurasians from eastern non-Africans (i.e., eastern Eurasians, Native Americans, and Oceanians).…”

Impact of Historic Migrations and Evolutionary Processes on Human Immunity

“…This was highlighted by different studies that showed that the introgression of diverse genes related to immune functions, such as the OAS cluster, TLR1, or the histocompatibility complex from Denisovans and Neanderthals shaped the genetic landscape of present-day Eurasian, but not African, communities. Genomic sequences and expression data from lymphoblastoid cell lines from 421 individuals of European and African ancestry confirmed that the TLR1-TLR6-TLR10 genetic loci, presenting signs of local positive selection and repeated introgression from both Neanderthal and Denisovan genomes [24][25][26], showed a significantly higher expression in individuals carrying archaic-like alleles than in individuals carrying the nonintrogressed modern human alleles [2,26,27]. The expression of these genes has shaped human immune responses against different types of pathogens.…”

Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes

“…However, whatever the potential benefits of archaic introgression in the past, alleles of Neanderthal origin have been also associated with several neurological, dermatological, and immunological phenotypes, indicating an influence of ancient admixture on current disease risk in humans (Mozzi et al, 2017;Simonti et al, 2016;Taskent et al, 2017). For example, introgressed alleles associated to the immune system response can increase the risk of inflammation or autoimmunity under the environmental factors changing overtime (Barreiro & Quintana-Murci, 2010;Brinkworth & Barreiro, 2014;Corbett et al, 2018;Sironi & Clerici, 2010; S. C. Stearns, 2012).…”