The conservation of human functional variants and their effects across livestock species

Authors: ZHAO, RONGRONG - University Of Edinburgh; TALENTI, ANDREA - University Of Edinburgh; FANG, LINGZHAO - University Of Edinburgh; LIU, SHULI - Westlake University; Liu, Ge - George; CHUE HONG, NEIL - University Of Edinburgh; TENESA, ALBERT - University Of Edinburgh; HASSAN, MUSA - University Of Edinburgh; PRENDERGAST, JAMES - University Of Edinburgh

Submitted to: Communications Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/7/2022
Publication Date: 9/21/2022
Citation: Zhao, R., Talenti, A., Fang, L., Liu, S., Liu, G., Chue Hong, N.P., Tenesa, A., Hassan, M., Prendergast, J.G. 2022. The conservation of human functional variants and their effects across livestock species. Communications Biology. 5:1003. https://doi.org/10.1038/s42003-022-03961-1.
DOI: https://doi.org/10.1038/s42003-022-03961-1

Interpretive Summary: Analyses of transcription will benefit our understanding of genetic bases for complex traits. In this study, we demonstrated that the conservation of human functional variants and their effects across livestock species. Farmers, breeders, scientists, and policy planners who need to improve animal health and production based on genome-enabled animal selection will benefit from this study.

Technical Abstract: Despite the clear potential of livestock models of human functional variants to provide important insights into the biological mechanisms driving human diseases and traits, their use to date has been limited. Generating such models via genome editing is costly and time consuming, and it is unclear which variants will have conserved effects across species. In this study we address these issues by studying naturally occurring livestock models of human functional variants. We show that orthologues of over 1.6 million human variants are already segregating in domesticated mammalian species, including several hundred previously directly linked to human traits and diseases. Models of variants linked to particular phenotypes, including metabolomic disorders and height, are preferentially shared across species, meaning studying the genetic basis of these phenotypes is particularly tractable in livestock. Using machine learning we demonstrate it is possible to identify human variants that are more likely to have an existing livestock orthologue, and, importantly, we show that the effects of functional variants are often conserved in livestock, acting on orthologous genes with the same direction of effect. Consequently, this work demonstrates the substantial potential of naturally occurring livestock carriers of orthologues of human functional variants to disentangle their functional impacts.