Implementation of a coalescence-based method to infer metabolic adaptations to cold climate in a Siberian human population

The Yakut represent a remarkable example of a population that had successfully adapted to one of the most remote and climatically extreme environments inhabited by modern humans: the harshly cold region of Siberia. Adaptation to such conditions required much more than cultural adaptations, it also necessitated the evolution of biological adaptations with a genetic basis. This thesis just explores the patterns of genomic variation that might have led to relevant metabolic adjustments, which enabled Yakut ancestors to thrive in such an extreme cold environment. By relying on the analysis of whole genome sequence (WGS) data for 25 Yakut individuals from the Human Genome Diversity Panel (HGDP), the effective population size of the population was first inferred through a coalescence-based method, which exploits a Hidden Markov Model (HMM) framework to infer the demographic history of a certain human group. Then the Relate algorithm was used to reconstruct the genealogies of genetic variants across the entire genome, by estimating their ancestral relationships and coalescence times to infer the complete genealogies of each mutation. Such an approach was used to infer the action of natural selection on the Yakut gene pool and the candidate adaptive genes identified, on which the present thesis has been focused, were shortlisted as the loci i) showing the most significant p-values from the performed selection test and ii) having being pinpointed by multiple selection analyses previously performed in other thesis projects. Genes such as PLPP3, ERBB4, and PRKG1 emerged from this crosscheck of significant results. The involvement of all of these loci in various signaling pathways regulating insulin signaling, lipid metabolism and cardiovascular processes have been explored as the primary biological framework through which the genetic and phenotypic architecture of Yakut cold adaptation evolved. Although these metabolic adaptations have likely contributed for millennia to determine the evolutionary success of the Yakuts in inhabiting one of the world’s most extreme environment, such peculiar lipid and cardiovascular traits may comport an increased susceptibility of this population to complex metabolic disorders under contemporary socio-cultural settings. In fact, the abandonment of traditional diet, the concomitant increasing nutritive impoverishment of the westernized diet and the shifts in lifestyle associated to climate change are becoming the new and more challenging “environmental” pressures.