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An inter-disciplinary approach for identifying evolutionary active regions in the human genome

Final Report Summary - MALADAPTED (An inter-disciplinary approach for identifying evolutionary active regions in the human genome)

Humans have been successful in the evolution because of their ability to adapt to their environment. For most of our evolutionary history the fitness of our ancestors was determined by their survival in environments of sub-Saharan Africa and only recently, since the dispersal out of Africa, within the past 100,000 years, have we been challenged to cope with the wider range of natural environments and climate of our planet. The economic and cultural shifts from a non-sedentary lifestyle to a food producing and settled way of life in the last 10,000 years have further exposed us to a range of new diets and diseases related to increased population densities. The MALADAPTED project created genome-wide genotype and sequence data from more than 20 human populations world-wide to cover geographic regions and environments not covered by previous projects in order answer the question - How adapted to their environment are humans today? Using a multidisciplinary approach that combines genetic and non-genetic evidence on human demographic history the project has revealed which parts of our genome have experienced the highest degree of change recently, thus showing us the way to identify those aspects of our biology that have been, or still are, most maladapted to our modern environments. Using scans of high haplotype homozygosity and allele frequency differentiation in genome-wide genotype data generated for 672 individuals the project identified candidate regions of positive selection in populations of Siberia, Andes, Madagascar, and Southeast Asia. Thereafter, using evidence from high coverage whole genome sequences individual variants that are likely to be causative targets of selection were uncovered and functionally characterized. Among the Northeast Siberian group which is genetically closely related to North American Inuit populations the project identified candidates of positive selection among genes associated with thermoregulation and metabolism of fatty acids. One particular variant in CPT1A gene had been previously characterized in Inuits in association with high infant mortality and hypoglycaemia. The findings of the MALADAPTED project suggest that these functionally deleterious properties of the gene must have been surpassed by the beneficial effect of the mutation within the past environments to allow for selection to bring the allele frequency close to fixation in the Arctic populations. In Andean populations who live in high altitude the project found evidence of positive selection in genes associated with the development of heart and cardiac hypertrophy. An Andean population living in conditions of high arsenic levels in their drinking water was confirmed to carry a signature of positive selection in arsenic methyltransferase AS3MT gene. In Malagasy population the project detected high haplotype homozygosity in genes related to adaptive immunity and oxidation of phytanic acid which is an important component in dairy products, ruminant animal fats, and certain fish. Analyses of high coverage whole genome sequences undertaken as the second significant stage in the project revealed significant deficiency of low frequency variants in Africans relative to non-African populations in pigmentation and viral immunity genes consistent with the effect of stronger purifying selection in low latitudes. Analyses of balancing selection detected a significant enrichment of antigen processing and presentation genes as targets of selection with the HLA-C-associated gene BTNL2 appearing as the most selected gene in eight of 12 geographic regions considered. The positive selection scans and variant-based analyses revealed many novel signals in previously under-studied populations.