Ruminant-specific retrotransposons shape regulatory evolution of bovine immunity

Authors: KELLY, CONOR - University Of Colorado; Chitko-Mckown, Carol; CHUONG, EDWARD - University Of Colorado

Submitted to: bioRxiv
Publication Type: Pre-print Publication
Publication Acceptance Date: 10/1/2021
Publication Date: 10/1/2021
Citation: Kelly, C.J., Chitko-Mckown, C.G., Chuong, E.B. 2021. Ruminant-specific retrotransposons shape regulatory evolution of bovine immunity. bioRxiv. https://doi.org/10.1101/2021.10.01.462810.
DOI: https://doi.org/10.1101/2021.10.01.462810

Interpretive Summary: Cattle are an important livestock species and mapping important traits in their genome such as disease susceptibility is a major challenge in the bovine research community. Lineage-specific transposable elements (TEs), also known as “jumping genes” or transposons, are sequences of DNA that move from one location in the genome to another. They are now recognized to be involved in the evolution of gene regulation and variation, but this has not been explored in ruminant genomes. We performed experiments to locate type II interferon (IFN) responses which are produced by immune cells to combat viral infections. Thousands of ruminant-specific TEs which were predicted to act as IFN-inducible enhancer elements. CRISPR knockout experiments using bovine cells showed that immune factors including cytokine receptors are regulated by TE-derived enhancers. Finally, a population genomic analysis of 38 animals revealed that a subset of TE-derived enhancers were present in polymorphic insertion sites in modern cattle. Our study shows that lineage-specific TEs have shaped the evolution of ruminant IFN responses, and may continue to contribute to difference in immune gene regulation among different breeds and individual animals. Together with work in human cells, our results demonstrate that lineage-specific TEs have independently been co-opted to regulate IFN-inducible gene expression in multiple species supporting TE co-option as a mechanism driving the evolution of IFN-inducible gene networks.

Technical Abstract: Cattle are an important livestock species, and mapping the genomic architecture of agriculturally relevant traits such as disease susceptibility is a major challenge in the bovine research community. Lineage-specific transposable elements (TEs) are increasingly recognized to contribute to gene regulatory evolution and variation, but this possibility has been largely unexplored in ruminant genomes. We conducted epigenomic profiling of the type II interferon (IFN) response in bovine cells, and found thousands of ruminant-specific TEs including MER41_BT and Bov-A2 elements predicted to act as IFN-inducible enhancer elements. CRISPR knockout experiments in bovine cells established that critical immune factors including IFNAR2 and IL2RB are transcriptionally regulated by TE-derived enhancers. Finally, population genomic analysis of 38 individuals revealed that a subset of TE-derived enhancers represent polymorphic insertion sites in modern cattle. Our study reveals that lineage-specific TEs have shaped the evolution of ruminant IFN responses, and potentially continue to contribute to immune gene regulatory differences across modern breeds and individuals. Together with previous work in human cells, our findings demonstrate that lineage-specific TEs have been independently co-opted to regulate IFN-inducible gene expression in multiple species, supporting TE co-option as a recurrent mechanism driving the evolution of IFN-inducible transcriptional networks.