Nearly all core signalling proteins in the Imd and Toll pathways are maintained as strict orthologues among Drosophila species (Sackton et al., 2007) and between Drosophila and mosquitoes (Christophides et al., 2002; Waterhouse et al., 2007), honey bees (Evans et al, 2006), and Tribolium (Zou et al, 2007). Despite this maintenance of orthology, however, these signalling genes show unexpectedly high levels of amino acid divergence between D. mela-nogaster and mosquitoes and considerable evidence of adaptive evolution within Drosophila (see Figure 13.2; see also Figure 6.3 in this volume; Schlenke and Begun, 2003; Jiggins and Kim, 2007; Sackton et al, 2007; Waterhouse et al, 2007).
The adaptive evolution of innate immune signalling pathways is illustrated dramatically by proteins in the Relish cleavage complex of the Imd signalling pathway (Figure 13.3). Relish is a nuclear factor kB (NF-kB) family transcription factor that is cytoplasmically bound in the absence of infection. Activation of the Imd signalling pathway leads to phosphorylation of Relish, caspase-mediated cleavage of the Relish inhibitory domain, and translocation of the activated transcription factor to the nucleus. Several proteins in the cleavage complex (Dredd, dFADD, IKKp, IKK,, and Relish itself) appear to be evolving adaptively in D. melanogaster, Drosophila simulans, and/or the melanogaster species group. Adaptive mutations are disproportionately located in protein domains important for the release of activated Relish: the Relish autoinhibi-tory domain and cleaved linker, the Dredd caspase domain, the dFADD death domain, and the IKKp kinase domain (Figure 13.3; Begun and Whitley, 2000; Schlenke and Begun, 2003; Jiggins and Kim, 2007; Sackton et al, 2007). Adaptive evolution of the Relish complex is not universal among Drosophila, but is restricted to certain species in the mela-nogaster group (Levine and Begun, 2007; Sackton et al., 2007). In an interesting parallel, the Relish gene of Nasutitermes termites also evolves adap-tively, again with positively selected mutations localized in and around the caspase cleavage site and linker (Bulmer and Crozier, 2006), suggesting convergence of selective pressures in these distantly related insects. Nor is adaptive evolution in Drosophila restricted to the Relish complex. Many other signal transduction genes in the Imd and Toll pathways (imd, spirit, persephone, Toll, dorsal, necrotic) also show evidence of rapid evolution in Drosophila (Schlenke and Begun, 2003; Jiggins and Kim, 2007; Sackton et al., 2007).
One hypothesis to explain the preponderance of adaptive mutations in signalling genes is that at least some pathogens may actively interfere with host immune signalling (Begun and Whitley, 2000). Such pathogens could include bacteria that inject immunomodulatory molecules into host cells, immunosuppressive fungi and parasitoid mutual-istic polydnaviruses (reviewed in Schmid-Hempel, 2008). In the Relish example, pathogen interference with the assembled cleavage complex could drive co-evolutionary adaptation in several proteins. Alternatively, interference with a single important member of the complex could drive adaptation in that member while promoting compensatory adaptations in the interacting proteins to retain host function. Such compensatory mutations may occur throughout the signalling pathway, amplifying the evidence of natural selection in this gene set (DePristo et al, 2005). The convergence of adaptive evolution of genes within the Relish complex in different insect species suggests that some of these genes are common targets of pathogens.
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