Repeated MDA5 Gene Loss in Birds: An Evolutionary Perspective.

Two key cytosolic receptors belonging to the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family sense the viral RNA-derived danger signals: RIG-I and melanoma differentiation-associated protein 5 (MDA5). Their activation establishes an antiviral state by downstream signaling that ultimately activates interferon-stimulated genes (ISGs). While in rare cases gene loss has been detected in mammalian and avian species, most notably in the chicken, pseudogenization has only been detected once in mammals. We have screened over a hundred publicly available avian genome sequences and describe an independent disruption of in two unrelated avian lineages, the storks (Ciconiiformes) and the rallids (Gruiformes). The results of our RELAX analysis confirmed the absence of negative selection in the pseudogene. In contrast to our prediction, we have shown, using multiple dN/dS-based approaches, that the loss does not appear to have resulted in any compensatory evolution in the gene, which may partially share its ligand-binding specificity. Together, our results indicate that the pseudogenization may have important functional effects on immune responsiveness in these two avian clades.