Of all extant species, chimpanzees and other primates are most similar to humans at the protein and genomic levels. Rodent species however, are widely used as models for biomedical research. Since arrival in the genomic age has accelerated the pace of discovery and increased our knowledge of comparative genomics, the differences between humans and those species used as disease models as well as the need to understand important differences has become increasingly apparent [26
]. It has become clear that humans possess greater diversity in protein families involved in inflammation than rodent models used to model inflammatory disease. This is most evident in members of the IL-1/IL-1R family where both agonist and antagonist members are more abundant in humans than mice [27
]. Not surprisingly, humans and mice also show differences in the number of NLR proteins potentially involved in inflammasome activity [28
]. In this report we have examined the evolutionary history of pyrin-only proteins (POPs) implicated in the regulation of inflammation and find that the emergence of POPs in the mammalian genome is a very recent event occurring roughly at the divergence of Old and New World primates. Further, our evidence suggests that POP2, which can inhibit inflammasome activity, arose from gene duplication events that first gave rise to multiple paralogs of an ancestral Nlrp2/7
-like gene, followed by diversification of these genes, retrogene insertion of an NLRP2
-like paralog, and rapid loss of the signature NBD and LRR encoding regions to yield a functional POP2 gene. MqPOP2 approximates the most distant intact ancestor of POP2, predating the divergence of humans and chimps by approximately 5-10 million years, and possesses both the NF-κB p65 and inflammasome inhibitory properties reported for the human protein. Collectively, these data suggest a strong selective pressure driving the recent emergence of a small Pyrin-only protein inhibiting both NF-κB signaling and the activation of multiple inflammasomes that corresponds with the emergence of hominid and Old World primates.
The marmoset genome clearly reveals the prior insertion of a retrogene copy of an NLRP2
-like transcript at the developing POP2
locus. By the emergence Old World primates, traces of the non-PYD coding portions of the retrogene are no longer apparent. In humans, a functional polyadenylation sequence is present within the 3' UTR of POP2 [12
]. Similar sequences are present in the 3' UTR of chimp and mqPOP2. Beyond reflecting the selective pressures acting on the POP2 gene, these features lend additional support to the emerging hypothesis that retrogenes are frequently functional, add to the complexity of the genome and may confer important regulatory functions as recently demonstrated for fibroblast growth factor 4 [29
Do the recent emergence of POP2 and other inflammatory regulators (e.g. POP1, COP, and INCA) reflect an increased need to control inflammation during the most recent stages of primate evolution? This is a difficult question requiring further investigation. However, considering that a strong selective pressure likely drove the evolutionary development of POP2, it is reasonable that POP2 might act by offsetting inflammatory events that decrease reproductive success. Inflammation of the reproductive organs would be a direct example. Recently, mutations in NLRP14 (although not yet demonstrated to initiate an inflammasome) have been implicated in failed spermatogenesis and may dysregulate inflammation or promote apoptosis [21
]. Interestingly, although inducible in monocytic cells, POP2 is expressed constitutively in the testis [12
] and could thus potentially have a role in modulating NLRP14 function. As a more extreme example, NOMID, one of the most severe autoinflammatory diseases, is one outcome of mutations in NLRP3, an inflammasome-initiating protein modulated by POP2 [12
]. Approximately 20% of individuals with NOMID die before adulthood. Identification of mutations or deletions in POP2 correlating with male reproductive system failure would lend support to this idea. The involvement of NLRP2 and NLRP7 in inflammasome inhibition [30
] and a connection between their presence among maternal RNAs in oocytes and the formation of hydatiform moles [31
], a form of reproductive failure, further suggest that some NLRs may have roles in both inflammation and reproductive success. Nevertheless, as no specific disease associations have been identified for the POP2
locus, these ideas remain speculative and await the results of further studies exploring the role of POP2.
In summary, the recent emergence of the highly selected and functional POP2 gene in higher primates, apes, and humans suggests a strong selective pressure among these species for the functions of the POP2 protein. Although our understanding of the biological role of POP2 is in its infancy, its apparent biochemical roles in regulating NF-κB activity and inflammasome formation suggest a variety of possibilities that may shed light on important differences between higher primates and other mammalian species.