Regulatory evolution of innate immunity through co option of endogenous retroviruses
Regulatory use of endogenous retroviruses Mammalian genomes contain many endogenous retroviruses (ERVs) which have a range of evolutionary ages. The propagation and maintenance of these genetic elements have been attributed to their ability to contribute to gene regulation. Chuong et al. demonstrate that some ERV families are enriched in regulatory elements, so that they act as independently evolved enhancers for immune genes in both humans and mice (see the Perspective by Lynch) The analysis revealed a primate specific element that orchestrates the transcriptional response to interferons. Selection can therefore act on selfish genetic elements to generate novel gene networks. Science, this issue p. 1083 see also p. 1029 Endogenous retroviruses have sculpted the gene networks involved in the innate immune response. [Also see Perspective by Lynch] Endogenous retroviruses (ERVs) are abundant in mammalian genomes and contain sequences modulating transcription. The impact of ERV propagation on the evolution of gene regulation remains poorly understood. We found that ERVs have shaped the evolution of a transcriptional network underlying the interferon (IFN) response, a major branch of innate immunity, and that lineage specific ERVs have dispersed numerous IFN inducible enhancers independently in diverse mammalian genomes. CRISPR Cas9 deletion of a subset of these ERV elements in the human genome impaired expression of adjacent IFN induced genes and revealed their involvement in the regulation of essential immune functions, including activation of the AIM2 inflammasome. Although these regulatory sequences likely arose in ancient viruses, they now constitute a dynamic reservoir of IFN inducible enhancers fueling genetic innovation in mammalian immune defenses.
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