Evidence of polygenic adaptation to high altitude from Tibetan and Sherpa genomes

Abstract

Although Tibetans and Sherpa present several physiological adjustments evolved to cope with selective pressures imposed by the high-altitude environment, especially hypobaric hypoxia, few selective sweeps at a limited number of hypoxia related genes were confirmed by multiple genomic studies. Nevertheless, variants at these loci were found to be associated only with downregulation of the erythropoietic cascade, which represents an indirect aspect of the considered adaptive phenotype. Accordingly, the genetic basis of Tibetan/Sherpa adaptive traits remains to be fully elucidated, in part due to limitations of selection scans implemented so far and mostly relying on the hard sweep model.In order to overcome this issue, we used whole-genome sequence data and several selection statistics as input for gene network analyses aimed at testing for the occurrence of polygenic adaptation in these high-altitude Himalayan populations. Being able to detect also subtle genomic signatures ascribable to weak positive selection at multiple genes of the same functional subnetwork, this approach allowed us to infer adaptive evolution at loci individually showing small effect sizes, but belonging to highly interconnected biological pathways overall involved in angiogenetic processes.Therefore, these findings pinpointed a series of selective events neglected so far, which likely contributed to the augmented tissue blood perfusion observed in Tibetans and Sherpa, thus uncovering the genetic determinants of a key biological mechanism that underlies their adaptation to high altitude.

The thermodynamics of protein aggregation reactions may underpin the enhanced metabolic efficiency associated with heterosis, some balancing selection, and the evolution of ploidy levels

“…Appendix A.2. Polygenic adaptation and the benefits of sexual reproduction Several authors have argued that adaptation, especially in humans, may be highly polygenic, resulting from allele frequency shifts across many gene loci (Gnecchi-Ruscone et al 2018;Bergey et al 2018;Boyle et al 2017;Berg and Coop 2014;Hancock et al 2010;Pritchard and Rienzo 2010;. However, there is some debate over the likelihood of such adaptation and proper interpretation of the data (Höllinger et al 2018;Berg et al 2018).…”

Cross-Species Insights Into Genomic Adaptations to Hypoxia

“…Subsequent studies identified associations between the adaptive PPARA candidate gene and metabolic parameters suggesting reduced fatty acid oxidation (Ge et al, 2012), in addition to greater oxygen utilization and protection from oxidative stress in skeletal muscle (Horscroft et al, 2017;O'Brien et al, 2019). In addition to Tibetan populations, various studies across Sherpa and Central Asian populations provide further support of key adaptive signatures in these populations (Foll et al, 2014;Jeong et al, 2014;Arciero et al, 2018;Gnecchi-Ruscone et al, 2018).…”

Selection signatures for high‐altitude adaptation in ruminants

“…Another major selective sweep was detected for the FGF7 gene in a different sheep population adapted to the same region (Gorkhali et al 2016). Despite the identification of several genes showing evidence of strong selective sweeps, highaltitude adaptation is considered to be a complex trait, with underlying polygenic architecture (Yang et al 2017;Gnecchi-Ruscone et al 2018).…”

“…There are a number of areas for which further data collection and analysis are warranted. The choice of method applied to identify genes underlying adaptation determines the type of selection signal that can be detected (selective sweep of a single loci vs. allele frequency shifts of many loci), which has led to a focus on selective sweeps, although polygenic adaptation was reported to be a major mechanism underlying the genetic architecture of high‐altitude adaptation (Yang et al ; Gnecchi‐Ruscone et al ). To dissect the polygenic component, data from GWAS, e.g.…”