Characterising Diversity in Gene Regulation Across the Indonesian Archipelago

Irene Gallego Romero⁰
(0) University of Melbourne

Find me on Wed Nov 25th, 1:30-2:50pm AEDT in Remo, table 58

Abstract
Title: Genetic Drivers Of Gene Expression And DNA Methylation Across The Indonesian Archipelago

Lack of diversity in human genomics limits our understanding of the genetic underpinnings of complex traits, hinders precision medicine, and contributes to health disparities. Island Southeast Asia – a region that includes Indonesia, the Philippines, Papua New Guinea and other smaller island states – accounts for nearly 7% of the world’s population and remains dramatically underrepresented in modern human genetics studies. Genetically, the region is home to a wealth of genetic diversity not present anywhere else in the world, including signals of Denisovan introgression that account for up to 5% of the genome of present-day Papuans and Indigenous Australians.

I will discuss ongoing research, in partnership with local researchers, to address two fundamental questions about the peopling and settling of the region: characterising the legacy of DNA from archaic Denisovans in present-day Papuans, and contextualising Indonesia – the world’s 4th largest country by population – in the global human genetics landscape. By examining the function of archaic hominin alleles within 72 genomes from individuals of Papuan genetic ancestry we find that introgressed SNPs are often located within cis-regulatory elements, suggesting that they are actively involved in a wide range of cellular regulatory processes. Our analyses identify 39,269 high-confidence Denisovan variants that have the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, and point towards a consistent signal across Denisovan variants of strong involvement in immune-related processes.

In parallel, we have generated whole genome sequencing, CpG methylation, and gene expression data in over 100 Indonesian individuals. We identify substantial differences in both methylation and expression, some of which are directly associated with varying ancestry proportions. Genes identified in these analyses are enriched in pathways involved in immunity, hinting at possible adaptation to the local environment. We identify nearly 1,900 expression QTLs and over 48,000 methylation QTLs, many of which are not shared between Indonesian and European populations, and contribute to hematological traits. Altogether, our research highlights the importance of diverse sampling and inclusion in human genetics if it is to deliver benefits to all.