| Summary: | One of the main mechanisms of inducing an antiviral response depends on 2′-5′-oligoadenylate synthetases (OAS), which sense double-stranded RNA in the cytoplasm and activate RNase L. Mutations leading to the loss of functional <i>OAS1</i> and <i>OAS2</i> genes have been identified as important modifiers of the human immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we performed comparative genomics to search for inactivating mutations of <i>OAS</i> genes in other species of mammals and to establish a model for the diversifying evolution of the <i>OAS</i> gene family. We found that a recombination of the <i>OAS</i> and <i>OAS-like</i> (<i>OASL</i>) loci has led to the loss of <i>OAS2</i> in camelids, which also lack <i>OAS3</i>. Both paralogs of <i>OASL</i> and <i>OAS3</i> are absent in Asian pangolins. An evolutionarily ancient <i>OAS</i> paralog, which we tentatively name <i>OAS4</i>, has been lost in pangolins, bats and humans. A previously unknown <i>OAS</i> gene, tentatively named <i>OAS5</i>, is present in Yangochiroptera, a suborder of bats. These differences in the <i>OAS</i> gene repertoire may affect innate immune responses to coronaviruses and other RNA viruses.
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