The Genetic and Evolutionary Basis of Gene Expression Variation in East Africans

Abstract

Background: Mapping of quantitative trait loci (QTL) associated with molecular phenotypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases. How the genetic architecture of molecular traits varies across human populations, however, has been less explored. To better understand the genetics of gene regulation in East Africans, we perform expression and splicing QTL mapping in whole blood from a cohort of 162 diverse Africans from Ethiopia and Tanzania. We assess replication of these QTLs in cohorts of predominantly European ancestry and identify candidate genes under selection in human populations. Results: We find the gene regulatory architecture of African and non-African populations is broadly shared, though there is a considerable amount of variation at individual loci across populations. Comparing our analyses to an equivalently sized cohort of European Americans, we find that QTL mapping in Africans improves the detection of expression QTLs and fine mapping of causal variation. Integrating our QTL scans with signatures of selection, we find several genes related to immunity and metabolism that are highly differentiated between Africans and non-Africans, as well as a gene associated with pigmentation, TMEM216, with evidence of population-specific selection in Nilo-Saharan speaking pastoralists. Conclusion: Extending QTL-mapping studies beyond groups of European ancestry, particularly to diverse indigenous populations, is vital for a complete understanding of the genetic architecture of human traits and can reveal novel functional variation underlying human traits and disease.

Profiling genetically driven alternative splicing across the Indonesian Archipelago

“…In spite of our limited sample size, these findings suggest a distinctive and distinguishable (relative to previously characterized European data) Indonesian sQTL signal, as we would expect sharing between GTEx and BLUEPRINT to also be negatively impacted by the relatively low sample size in BLUEPRINT and their distinct processing pipelines. By profiling the differences and similarities across these groups, we can more accurately characterize the gene regulatory mechanisms underlying diversity in genetic traits, highlighting the value of trans-ethnic, trans-environment QTL mapping to maximize discovery of gene regulatory variation across humans [30,32].…”

“…A study of the response to infection in monocytes from individuals of European and African descent living in Belgium showed that genetic ancestry consistently contributed to differences in splicing, and highlighted the role of archaic introgression from Neanderthals [21] in particular. Recently, a separate study examining both expression and splicing in whole blood in East African populations has shown that overall, the genetic architecture of splicing is shared between individuals of African and European ancestry, but nonetheless identified a substantial number of sQTLs in individuals from Tanzania and Ethiopia that have not been reported in European cohorts [32].…”

Multi‐Omics Studies in Historically Excluded Populations: The Road to Equity

“…Only 112,316 of the 354,931 (31.64%) eSNPs in African Americans were also identified in European Americans. The latest eQTL research using 162 East African whole blood samples by Kelly et al 80 identified 99,685 SNPs associated with 1,330 eGenes. Ninety-eight of 1,330 eGenes were not found in the GTEx eQTL database.…”