Abstract
The aim of this study is to identify genetic variants that harbour signatures of recent positive selection and may facilitate physiological adaptations to hypobaric hypoxia. To achieve this, we conducted whole genome sequencing and lung function tests in 19 Argentinean highlanders (>3500 m) comparing them to 16 Native American lowlanders. We developed a new statistical procedure using a combination of population branch statistics (PBS) and number of segregating sites by length (nSL) to detect beneficial alleles that arose since the settlement of the Andes and are currently present in 15–50% of the population. We identified two missense variants as significant targets of selection. One of these variants, located within the GPR126 gene, has been previously associated with the forced expiratory volume/forced vital capacity ratio. The other novel missense variant mapped to the EPAS1 gene encoding the hypoxia inducible factor 2α. EPAS1 is known to be the major selection candidate gene in Tibetans. The derived allele of GPR126 is associated with lung function in our sample of highlanders (p < 0.05). These variants may contribute to the physiological adaptations to hypobaric hypoxia, possibly by altering lung function. The new statistical approach might be a useful tool to detect selected variants in population studies.
Highlights
High altitude represents an extreme environment characterised by low concentrations of atmospheric oxygen, arid climate, high solar radiation and other environmental stressors
Using simulations to inform our targeted approach, we chose to combine several aspects of the population genetic data and genome annotation information. To search for these signals, we focused on derived allele frequency (DAF) ≥ 15% and ≤50% to identify alleles at the beginning of selection which are overlooked in the traditional positive selection tests
By combining different selection statistics, along with genome annotation information, we were able to identify intermediate frequency variants that may contribute to high altitude adaptation in two very prominent candidate genes, GPR126 and EPAS1
Summary
High altitude represents an extreme environment characterised by low concentrations of atmospheric oxygen (hypoxia), arid climate, high solar radiation and other environmental stressors. Populations have resided at high elevations in Ethiopia, the Himalayas and the Andes for several millennia[1]. Given that there has been shorter duration for selection to act, rather than being close to fixation, it is likely that proportionally more advantageous gene variants exist at intermediate frequencies To this end, we complement the scans for hard sweep variants with scans for signatures of incomplete selective processes. We complement the scans for hard sweep variants with scans for signatures of incomplete selective processes These tests are applied on high coverage whole genome sequence data for healthy Andean highlanders from Northwest Argentina together with sequence data from Native American lowlanders and pinpoint to variants advantageous in the adaptation to high altitude
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