The selective footprints of viral pressures at the human RIG-I-like receptor family

The RIG-I-like receptors (RLRs)--RIG-I, IFIH1 (or MDA5) and LGP2--are thought to be key actors in the innate immune system, as they play a major role in sensing RNA viruses in the cytosol of host cells. Despite the increasingly recognized importance of the RLR family in antiviral immunity, no population genetic studies have yet attempted to compare the evolutionary history of its different members in humans. Here, we characterized the levels of naturally occurring genetic variation in the RLRs in a panel of individuals of different ethnic origins, to assess to what extent natural selection has acted on this family of microbial sensors. Our results show that amino acid-altering variation at RIG-I, particularly in the helicase domain, has been under stronger evolutionary constraint than that at IFIH1 and LGP2, reflecting an important role for RIG-I in sensing numerous RNA viruses and/or functional constraints related to the binding of viral substrates. Such evolutionary constraints have been much more relaxed at IFIH1 and LGP2, which appear to have evolved adaptively in specific human populations. Notably, we identified several mutations showing signatures of positive selection, including two non-synonymous polymorphisms in IFIH1 (R460H and R843H) and one in LGP2 (Q425R), suggesting a selective advantage related to the sensing of RNA viruses by IFIH and to the regulatory functions of LGP2. In light of the fact that some of these mutations have been associated with altered risks of developing autoimmune disorders, our study provides an additional example of the evolutionary conflict between infection and autoimmunity.