biostudies-literature00450Yasumizu YMEXTKAKENHIAdvanced Clinical Epidemiology Investigator’s Research ProjectAMEDTailor-Made Medical Treatment programJapan Agency for Medical Research and DevelopmentMinistry of Education, Culture, Sports, Science, and TechnologyOsaka University Center of Medical Data ScienceOsaka University Medical Doctor Scientist Training ProgramBioinformatics Initiative of Osaka University Graduate School of MedicineJSPSJapan Society for the Promotion of Science1306-1316https://www.ebi.ac.uk/biostudies/studies/S-EPMC7182208biostudies-literatureUnknown37(5)Elucidation of natural selection signatures and relationships with phenotype spectra is important to understand adaptive evolution of modern humans. Here, we conducted a genome-wide scan of selection signatures of the Japanese population by estimating locus-specific time to the most recent common ancestor using the ascertained sequentially Markovian coalescent (ASMC), from the biobank-based large-scale genome-wide association study data of 170,882 subjects. We identified 29 genetic loci with selection signatures satisfying the genome-wide significance. The signatures were most evident at the alcohol dehydrogenase (ADH) gene cluster locus at 4q23 (PASMC = 2.2 × 10-36), followed by relatively strong selection at the FAM96A (15q22), MYOF (10q23), 13q21, GRIA2 (4q32), and ASAP2 (2p25) loci (PASMC < 1.0 × 10-10). The additional analysis interrogating extended haplotypes (integrated haplotype score) showed robust concordance of the detected signatures, contributing to fine-mapping of the genes, and provided allelic directional insights into selection pressure (e.g., positive selection for ADH1B-Arg48His and HLA-DPB1*04:01). The phenome-wide selection enrichment analysis with the trait-associated variants identified a variety of the modern human phenotypes involved in the adaptation of Japanese. We observed population-specific evidence of enrichment with the alcohol-related phenotypes, anthropometric and biochemical clinical measurements, and immune-related diseases, differently from the findings in Europeans using the UK Biobank resource. Our study demonstrated population-specific features of the selection signatures in Japanese, highlighting a value of the natural selection study using the nation-wide biobank-scale genome and phenotype data.Molecular biology and evolutionGenome-Wide Natural Selection Signatures Are Linked to Genetic Risk of Modern Phenotypes in the Japanese Population.PMC7182208JP19ek0109413JP19ek0410041JP19gm601000119H01021JP19km040521115H05911Kamatani YPalamara PFMurakami YOkada YSakaue SKonuma TSuzuki KYasumizu YMatsuda KKubo M45falseGenome-Wide Natural Selection Signatures Are Linked to Genetic Risk of Modern Phenotypes in the Japanese Population.Elucidation of natural selection signatures and relationships with phenotype spectra is important to understand adaptive evolution of modern humans. Here, we conducted a genome-wide scan of selection signatures of the Japanese population by estimating locus-specific time to the most recent common ancestor using the ascertained sequentially Markovian coalescent (ASMC), from the biobank-based large-scale genome-wide association study data of 170,882 subjects. We identified 29 genetic loci with selection signatures satisfying the genome-wide significance. The signatures were most evident at the alcohol dehydrogenase (ADH) gene cluster locus at 4q23 (PASMC = 2.2 × 10-36), followed by relatively strong selection at the FAM96A (15q22), MYOF (10q23), 13q21, GRIA2 (4q32), and ASAP2 (2p25) loci (PASMC < 1.0 × 10-10). The additional analysis interrogating extended haplotypes (integrated haplotype score) showed robust concordance of the detected signatures, contributing to fine-mapping of the genes, and provided allelic directional insights into selection pressure (e.g., positive selection for ADH1B-Arg48His and HLA-DPB1*04:01). The phenome-wide selection enrichment analysis with the trait-associated variants identified a variety of the modern human phenotypes involved in the adaptation of Japanese. We observed population-specific evidence of enrichment with the alcohol-related phenotypes, anthropometric and biochemical clinical measurements, and immune-related diseases, differently from the findings in Europeans using the UK Biobank resource. Our study demonstrated population-specific features of the selection signatures in Japanese, highlighting a value of the natural selection study using the nation-wide biobank-scale genome and phenotype data.2020-01-01T00:00:00Z2020 May2024-11-09T06:27:17.874Z2020-05-22T19:35:35ZS-EPMC71822083195779310.1093/molbev/msaa005