부산대학교 도서관

Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes. Author summary: Understanding how gene expression varies across individuals and environments is fundamental for the success of molecular medicine. However, the vast majority of studies of gene expression, particularly in healthy individuals, have primarily involved populations of European descent. It is unclear whether these findings are generalizable to the rest of humanity. We examined gene expression and DNA methylation in 116 individuals across Indonesia, the world's fourth most populous country. Our three populations–Mentawai off the western coast of Sumatra, Sumba in central Indonesia, and a group of hunter-gatherers, the Korowai, living in the province of West Papua in New Guinea–span the main axes of genetic and geographic diversity in the region. Up to 10% of genes show differences in expression and methylation patterns between islands, with many involved in immune function. Variation between villages within each location can likely be attributed to small-scale environmental differences. These findings emphasise the need to consider a broad range of genetic and environmental backgrounds when examining how molecular patterns and processes are shared across human populations. [ABSTRACT FROM AUTHOR]