Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

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

Denisovan introgression has shaped the immune system of present-day Papuans

“…To begin validating the potential influence these TFBS-disrupting SNPs might have on their target genes, we focused on a set of 3,996 genes found to be differentially expressed (DE) at a FDR ≤ 0.01% between 19 Korowai individuals, a genetically Papuan population living on the Indonesian side of New Guinea Island, and 48 individuals of Austronesian ancestry sampled in Mentawai, a small island located off the western coast of Sumatra, in western Indonesia, from [41]. These two populations are indicative of the extremes of the cline of Papuan and Denisovan ancestry that is observed across the Indonesian archipelago [5, 42].…”

“…We thus asked how many of the genes associated with the GO terms and whose regulation was predicted to be affected by our subset of TFBS-disrupting variants within immune T and B cells were differentially expressed between Mentawai and Korowai in [41]. Overall, we found that 31, 26 and 426 genes predicted to be regulated by Denisovan, Neanderthal and non-archaic TFBS-disrupting variants (31.0%, 22.4% and 26.1% of those associated with all GO terms) were differentially expressed.…”

“…Finally, to understand whether these expression differences might be related to the diverse genetic background of these human populations, we retrieved allele frequencies in western Indonesia for the TFBS-disrupting SNPs from Jacobs et al [5] (we note that this sample does not contain the majority of individuals from Natri et al [41], but it does include nearby groups, and allele frequencies are broadly similar amongst these populations). We focused only on 124 Denisovan and 95 Neanderthal TFBS-disrupting aSNPs associated by GREAT with genes that were DE between Mentawai and Korowai (respectively 28.2% and 24.8% of those considered in the previous step), and asked how many of these were also segregating within western Indonesia.…”

“…Notably, among these Denisovan TFBS-disrupting aSNPs 5 (rs370899715, rs372433785, rs146859513, rs375463218, rs372139279) were predicted by GREAT to regulate OAS2 and OAS3 , both of which are differentially expressed between Korowai and Mentawai (Fig. 6a,b) [41]. In all five cases, archaic alleles segregate at frequencies between ≥ 0.33 and 0.39 in Papuans, while west Indonesians are fixed for the reference, non-archaic alleles.…”

“…Log 2 RNA-seq counts per million (CPM) in whole blood for a) OAS2 and b) OAS3 between Korowai (New Guinea) and Mentawai (western Indonesia), from [41]. Violin plots represent the full distribution of the log 2 CPM.…”