Convergent Losses of TLR5 Suggest Altered Extracellular Flagellin Detection in Four Mammalian Lineages

Toll-like receptors (TLRs) play an important role for the innate immune system by detecting pathogen-associated molecular patterns. TLR5 encodes the major extracellular receptor for bacterial flagellin and frequently evolves under positive selection, consistent with coevolutionary arms races between the host and pathogens. Furthermore, TLR5 is inactivated in several vertebrates and a TLR5 stop codon polymorphism is widespread in human populations. Here, we analyzed the genomes of 120 mammals and discovered that TLR5 is convergently lost in four independent lineages, comprising Guinea pigs, Yangtze river dolphin, pinnipeds, and pangolins. Validated inactivating mutations, absence of protein-coding transcript expression, and relaxed selection on the TLR5 remnants confirm these losses. PCR analysis further confirmed the loss of TLR5 in the pinniped stem lineage. Finally, we show that TLR11, encoding a second extracellular flagellin receptor, is also absent in these four lineages. Independent losses of TLR5 and TLR11 suggest that a major pathway for detecting flagellated bacteria is not essential for different mammals and predicts an impaired capacity to sense extracellular flagellin.