Abstract
Recent human adaptations have shaped population differentiation in genomic regions containing putative functional variants, mostly located in predicted regulatory elements. However, their actual functionalities and the underlying mechanism of recent adaptation remain poorly understood. In the current study, regions of genes and repeats were investigated for functionality depending on the degree of population differentiation, FST or ΔDAF (a difference in derived allele frequency). The high FST in the 5´ or 3´ untranslated regions (UTRs), in particular, confirmed that population differences arose mainly from differences in regulation. Expression quantitative trait loci (eQTL) analyses using lymphoblastoid cell lines indicated that the majority of the highly population-specific regions represented cis- and/or trans-eQTL. However, groups having the highest ΔDAFs did not necessarily have higher proportions of eQTL variants; in these groups, the patterns were complex, indicating recent intricate adaptations. The results indicated that East Asian (EAS) and European populations (EUR) experienced mutual selection pressures. The mean derived allele frequency of the high ΔDAF groups suggested that EAS and EUR underwent strong adaptation; however, the African population in Africa (AFR) experienced slight, yet broad, adaptation. The DAF distributions of variants in the gene regions showed clear selective pressure in each population, which implies the existence of more recent regulatory adaptations in cells other than lymphoblastoid cell lines. In-depth analysis of population-differentiated regions indicated that the coding gene, RNF135, represented a trans-regulation hotspot via cis-regulation by the population-specific variants in the region of selective sweep. Together, the results provide strong evidence of actual intricate adaptation of human populations via regulatory manipulation.
Highlights
Recent large-scale human genome studies have revealed that all human beings share an almost identical genome [1,2,3,4]; minor differences among human populations exist as a result of genetic drift and adaptation
The results indicated that East Asian (EAS) and European populations (EUR) experienced mutual selection pressures
More recent efforts to identify classic selective sweeps were successful in ascertaining a considerable number of genes under hard selective sweeps [13, 14], using differences in derived allele frequencies (ΔDAF) [15] and two methods that were robust against background selection [16, 17]
Summary
Recent large-scale human genome studies have revealed that all human beings share an almost identical genome [1,2,3,4]; minor differences among human populations exist as a result of genetic drift and adaptation. Using the genotyping data from the HapMap consortium [5], genome-wide FST estimates and a composite method involving FST have been used to identify genes under selection pressure [6,7,8]. Recent studies indicated that classic selective sweeps were rare in the human genome [10, 11]; analysis of the 1000 Genomes Project Data identified many genes under positive selection using the composite method [7, 12]. More recent efforts to identify classic selective sweeps were successful in ascertaining a considerable number of genes under hard selective sweeps [13, 14], using differences in derived allele frequencies (ΔDAF) [15] and two methods that were robust against background selection [16, 17]
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