Abstract
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.
Highlights
Modern human genomics does not equitably represent the full breadth of humanity
We examined gene expression and DNA methylation in 116 individuals across Indonesia, the world’s fourth most populous country
To provide a benchmark dataset of regional molecular phenotypes, here we report genomewide measurements of DNA methylation and gene expression for 116 individuals drawn from three population groups that capture the major genomic and geographical axes of diversity across Indonesia
Summary
While genome sequences for people of European descent number a million or more, most of the world is deeply understudied [1]. This is true of Indonesia [2], a country geographically as large as continental Europe and the world’s fourth largest by population. The first three Indonesian genome sequences were only reported in 2016 [5] with the first representative survey of diversity across the archipelago only appearing in 2019 [6]. This extreme lack of representation extends to molecular phenotypes. There are no analyses of diversity in gene regulatory mechanisms in either Indonesia or, more broadly, Island Southeast Asia
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