A Genome-wide Scan for Exploring Filipinos’ Adaptive History and Its Implications in Health and Disease

The present evolutionary genomics study represents an exploratory scan of genome-wide data generated for a few Filipino populations with the aim of inferring their adaptive history and its potential impacts on their health patterns. Genome-wide data were analysed in silico to identify the genetic determinants of biological adaptations evolved by the ancestors of present-day Filipino population groups due to the action of natural selection in response to ancient selective pressures. For this purpose, a Filipino dataset was assembled using both novel and publicly available genome-wide data, which were combined with those generated for several human populations with different ancestries to perform comparative analyses. After the implementation of stringent quality control procedures, population structure analyses were conducted to contextualise Filipinos’ genetic variability within the Asian genomic landscape, revealing high genetic homogeneity for three out of the four Filipino groups considered. According to the available sample size, geographic origins, and demographic history of these homogeneous populations, genome-wide data for twenty-three Filipino individuals were analysed as a single unit to search for genomic signatures attributable to the action of natural positive selection. In detail, the LASSI method was adopted, and the top 1% putative adaptive genomic regions identified by such an approach were mapped and annotated, pinpointing 529 protein-coding genes whose variation patterns have been significantly shaped by natural selection throughout Filipino evolutionary history. These candidate adaptive genes were subjected to STRING enrichment analysis, which led to the identification of a functional network comprising 135 genes with established significant interactions among them. The most prominent cluster of functionally-related loci (including 41 genes) was found to be involved in the regulation of lipid and retinol metabolism. Interestingly, adjustments in retinoid signalling seem to have mediated the metabolic adaptations of Filipino populations, plausibly in response to various environmental and cultural factors. Retinoid signalling is involved in various physiological functions, so that its dysregulation underlies many pathophysiological processes. Therefore, we can hypothesize that some adaptive traits previously shaped by natural selection in these human groups have then turned into maladaptive ones due to recent climate change, dietary shifts, and/or exposure to new pathogens. The ubiquity of signalling disruptors today may thus contribute to disease epidemiology in modern Filipinos. Several questions exploring themes outlined in this thesis are raised and could be addressed by future research to test such “mismatch” hypotheses.