This study was approved by the Institut Pasteur Institutional Review Board (no

This study was approved by the Institut Pasteur Institutional Review Board (no. indicating that genetic variation at these genes has conferred a selective advantage to the host, most likely by increasing resistance to viral infection. Our population genetic analyses show that IFNs differ widely in their biological relevance, and highlight evolutionarily important determinants of host immune responsiveness. IFNs are helicoidal cytokines released by host cells in response to the presence of pathogens or tumor cells. Human IFNs have been classified into three major types on the basis of the cognate receptors through which they signal, gene sequence similarity, and chromosomal location (Pestka et al., 2004). Type I IFNs include 17 subtypes (13 subtypes of IFN- and IFNs ///), all of which bind to a receptor composed of two chains, IFNAR1 and IFNAR2 (Uz et al., 2007). The genes encoding type I IFNs are intronless and are located in a region spanning 400 kb on chromosome 9, with the exception ofIFNK, which is located 6 Mb away from the other type I IFN genes (Trent et al., 1982;Henco et al., 1985;Daz et al., 1994). There is only one type II IFN, IFN-, which signals via a receptor composed of the IFN-R1 and IFN-R2 subunits (Wheelock and Sibley, 1965;Pestka et al., 2004). The more recently described type III IFNs constitute a group of three cytokines, IL-28A, IL-28B, and IL-29 (also known as IFN-2, IFN-3, and IFN-1, respectively), the genes for which are clustered in an 50-kb region of chromosome 19 (Kotenko et al., 2003;Sheppard et al., 2003). These IFNs activate a signaling pathway similar to that of type I IFNs, but act via a different receptor composed of the type III IFN-specific IL-28RA and the IL-10RB, the latter subunit being also used by the IL-10 and IL-22 receptor (Kotenko et al., 1997;Xie et al., 2000). There is increasing evidence ZPK to suggest that Lipofermata type I and III IFNs have a different role from the type II IFN: IFN-/ and IFN- appear to have potent antiviral activities, whereas IFN- has antibacterial, antiparisitic, and antifungal properties (Pestka et al., 2004;Zhang et al., 2008). In recent years, human genetics studies of both Mendelian and complex diseases have identified several variants affecting the production of, or the response to, IFNs, shedding light on the genuine functions of IFNs in the natural setting (Zhang et al., 2008). Disorders or specific mutations in genes involved in the IFN- circuit, such as inIFNGR1andIFNGR2, confer a Mendelian predisposition to mycobacterial disease (Filipe-Santos et al., 2006), whereas the disorders or specific mutations in patients with impaired type I or type III responses are associated with a stronger predisposition to viral infections (Dupuis et al., 2003;Chapgier et al., 2006;Minegishi et al., 2006). Likewise, mutations affecting type I or type III IFN responses have been associated with various autoimmune pathologies (Crow et al., 2006a,b;Glocker et al., 2009;Rice et al., 2009). Several epidemiological genetics studies Lipofermata have recently shown that genetic variants in the region encompassing the type III IFNIL28Bgene are associated with the spontaneous clearance of hepatitis C virus (HCV) and the response to HCV therapeutic treatment (Ge et al., 2009;Suppiah et al., 2009;Tanaka et al., 2009;Thomas et al., 2009). Our Lipofermata understanding of the Lipofermata mechanisms controlling IFN production, the downstream signaling pathways associated with these molecules, and their involvement in physiology and pathology is starting to be fully appreciated, but several biological questions remain unanswered. Given that multiple IFN molecules signal through the Lipofermata same receptor (e.g., IFN-/ and IFN-), are all IFNs equally relevant to host survival? Are some IFN genes more essential for immunity to infection whereas.