RESUMO
Lack of diversity in human genomics limits our understanding of the genetic underpinnings of complex traits, hinders precision medicine, and contributes to health disparities. To map genetic effects on gene regulation in the underrepresented Indonesian population, we have integrated genotype, gene expression, and CpG methylation data from 115 participants across three island populations that capture the major sources of genomic diversity in the region. In a comparison with European datasets, we identify eQTLs shared between Indonesia and Europe as well as population-specific eQTLs that exhibit differences in allele frequencies and/or overall expression levels between populations. By combining local ancestry and archaic introgression inference with eQTLs and methylQTLs, we identify regulatory loci driven by modern Papuan ancestry as well as introgressed Denisovan and Neanderthal variation. GWAS colocalization connects QTLs detected here to hematological traits, and further comparison with European datasets reflects the poor overall transferability of GWAS statistics across diverse populations. Our findings illustrate how population-specific genetic architecture, local ancestry, and archaic introgression drive variation in gene regulation across genetically distinct and in admixed populations and highlight the need for performing association studies on non-European populations.
Assuntos
Regulação da Expressão Gênica , Genética Populacional , Genoma Humano , Locos de Características Quantitativas , Biologia Computacional/métodos , Metilação de DNA , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Indonésia , Masculino , Modelos Genéticos , Anotação de Sequência Molecular , Herança Multifatorial , Característica Quantitativa Herdável , Seleção Genética , Sequenciamento Completo do GenomaRESUMO
OBJECTIVES: Skin color is a highly visible and variable trait across human populations. It is not yet clear how evolutionary forces interact to generate phenotypic diversity. Here, we sought to unravel through an integrative framework the role played by three factors-demography and migration, sexual selection, and natural selection-in driving skin color diversity in India. METHODS: Skin reflectance data were collected from 10 diverse socio-cultural populations along the latitudinal expanse of India, including both sexes. We first looked at how skin color varies within and between these populations. Second, we compared patterns of sexual dimorphism in skin color. Third, we studied the influence of ultraviolet radiation on skin color throughout India. Finally, we attempted to disentangle the interactions between these factors in the context of available genetic data. RESULTS: We found that the relative importance of these forces varied between populations. Social factors and population structure have played a stronger role than natural selection in shaping skin color diversity across India. Phenotypic overprinting resulted from additional genetic mutations overriding the skin lightening effect of variants such as the SLC24A5 rs1426654-A allele in some populations, in the context of the variable influence of sexual selection. Furthermore, specific genotypes are not associated reliably with specific skin color phenotypes. This result has relevance for DNA forensics and ancient DNA research. CONCLUSIONS: India is a crucible of macro- and micro-evolutionary forces, and the complex interactions of physical and social forces are visible in the patterns of skin color seen today in the country.