RESUMEN
Host-pathogen interactions are generally initiated by host recognition of microbial components or danger signals triggered by microbial invasion. This recognition involves germline-encoded microbial sensors or pattern-recognition receptors (PRRs). By studying the way in which natural selection has driven the evolution of these microbial sensors in humans, we can identify genes playing an essential role and distinguish them from other, more redundant genes. We characterized the sequence diversity of the NOD-like receptor family, including the NALP and NOD/IPAF subfamilies, in various populations worldwide and compared this diversity with that of other PRR families, such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). We found that most NALPs had evolved under strong selective constraints, suggesting that their functions are essential and possibly much broader than previously thought. Conversely, most NOD/IPAF subfamily members were subject to more relaxed selective constraints, suggesting greater redundancy. Furthermore, some NALP genes, including NLRP1, NLRP14, and CIITA, were found to have evolved adaptively. We identified those variants conferring a selective advantage on some human populations as the most likely targets of positive selection. More generally, the strength of selection differed considerably between the major families of microbial sensors. Endosomal TLRs and most NALPs were found to evolve under stronger purifying selection than most NOD/IPAF subfamily members and cell-surface TLRs and RLRs, suggesting some degree of redundancy in the signaling pathways triggered by these molecules. This study provides novel perspectives and experimentally testable hypotheses concerning the relative biological relevance of the various families of microbial sensors in humans.
Asunto(s)
Evolución Molecular , Inmunidad Innata/genética , Receptores de Reconocimiento de Patrones/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Citosol/metabolismo , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , Variación Genética , Humanos , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos , Selección Genética , Receptores Toll-Like/genéticaRESUMEN
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.
Asunto(s)
ARN Helicasas DEAD-box/genética , ARN Helicasas/genética , Selección Genética/genética , Proteína 58 DEAD Box , Evolución Molecular , Humanos , Helicasa Inducida por Interferón IFIH1 , Mutación , Polimorfismo Genético/genética , ARN Viral , Receptores InmunológicosRESUMEN
Natural selection is expected to act strongly on immune system genes as hosts adapt to novel, diverse, and coevolving pathogens. Population genetic studies of host defense genes with parallel functions in model organisms have revealed distinct evolutionary histories among the different components-receptors, adaptors, and effectors-of the innate immune system. In humans, however, detailed evolutionary studies have been mainly confined to the receptors and in particular to Toll-like receptors (TLRs). By virtue of a toll/interleukin-1 receptor (TIR) domain, TLRs activate distinct signaling pathways, which are mediated by the five TIR-containing adaptors: myeloid differentiation factor-88 (MyD88), myeloid differentiation factor-88 adaptor-like protein (MAL), toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon (IFN)ß (TRIF), toll/interleukin-1 receptor domain-containing adaptor protein inducing IFNß-related adaptor molecule (TRAM), and sterile α- and armadillo motif-containing protein (SARM). Here, we have examined the extent to which natural selection has affected immune adaptors in humans, using as a paradigm the TIR-containing adaptors. To do so, we characterized their levels of naturally occurring genetic variation in various human populations. We found that MyD88 and TRIF have mainly evolved under purifying selection, suggesting that their role in the early stages of signal transduction is essential and nonredundant for host survival. In addition, the adaptors have been targeted by multiple episodes of positive selection, differing in timing and spatial location. MyD88 and SARM display signatures of a selective sweep that has occurred in all humans, whereas for the other three adaptors, we detected signatures of adaptive evolution that are restricted to specific populations. Our study provides evidence that the contemporary diversity of the five TIR-containing adaptors results from the intermingling of different selective events, swinging between constraint and adaptation.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas del Dominio Armadillo/genética , Proteínas del Citoesqueleto/genética , Variación Genética , Inmunidad Innata/genética , Glicoproteínas de Membrana/genética , Factor 88 de Diferenciación Mieloide/genética , Receptores de Interleucina-1/genética , Selección Genética , Adaptación Biológica/genética , Análisis de Varianza , Animales , Secuencia de Bases , Teorema de Bayes , Análisis por Conglomerados , Simulación por Computador , Haplotipos/genética , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Pan troglodytes/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Interleucina-1/metabolismo , Análisis de Secuencia de ADN , Transducción de Señal/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
Investigations of the legacy of natural selection in the human genome have proved particularly informative, pinpointing functionally important regions that have participated in our genetic adaptation to the environment. Furthermore, genetic dissection of the intensity and type of selection acting on human genes can be used to predict involvement in different forms and severities of human diseases. We review here the progress made in population genetics studies toward understanding the effects of selection, in its different forms and intensities, on human genome diversity. We discuss some outstanding, robust examples of genes and biological functions subject to strong dietary, climatic and pathogen selection pressures. We also explore the possible relationship between cancer and natural selection, a topic that has been largely neglected because cancer is generally seen as a late-onset disease. Finally, we discuss how the present-day incidence of some diseases of modern societies may represent a by-product of past adaptation to other selective forces and changes in lifestyle. This perspective thus illustrates the value of adopting a population genetics approach in delineating the biological mechanisms that have played a major evolutionary role in the way humans have genetically adapted to different environments and lifestyles over time.