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In Drosophila, the insulin-signaling pathway controls some life history traits, such as fertility and lifespan, and it is considered to be the main metabolic pathway involved in establishing adult body size. Several observations concerning variation in body size in the Drosophila genus are suggestive of its adaptive character. Genes encoding proteins in this pathway are, therefore, good candidates to have experienced adaptive changes and to reveal the footprint of positive selection. The Drosophila insulin-like peptides (DILPs) are the ligands that trigger the insulin-signaling cascade. In Drosophila melanogaster, there are several peptides that are structurally similar to the single mammalian insulin peptide. The footprint of recent adaptive changes on nucleotide variation can be unveiled through the analysis of polymorphism and divergence. With this aim, we have surveyed nucleotide sequence variation at the dilp1-7 genes in a natural population of D. melanogaster. The comparison of polymorphism in D. melanogaster and divergence from D. simulans at different functional classes of the dilp genes provided no evidence of adaptive protein evolution after the split of the D. melanogaster and D. simulans lineages. However, our survey of polymorphism at the dilp gene regions of D. melanogaster has provided some evidence for the action of positive selection at or near these genes. The regions encompassing the dilp1-4 genes and the dilp6 gene stand out as likely affected by recent adaptive events.

The IT-insulin/target of rapamycin (TOR)-signal transduction pathway is a relatively well-characterized pathway that plays a central role in fundamental biological processes. Network-level analyses of DNA divergence in Drosophila and vertebrates have revealed a clear gradient in the levels of purifying selection along this pathway, with the downstream genes being the most constrained. Remarkably, this feature does not result from factors known to affect selective constraint such as gene expression, codon bias, protein length, and connectivity. The present work aims to establish whether the selective constraint gradient detected along the IT pathway at the between-species level can also be observed at a shorter time scale. With this purpose, we have surveyed DNA polymorphism in Drosophila melanogaster and divergence from D. simulans along the IT pathway. Our network-level analysis shows that DNA polymorphism exhibits the same polarity in the strength of purifying selection as previously detected at the divergence level. This equivalent feature detected both within species and between closely and distantly related species points to the action of a general mechanism, whose action is neither organism specific nor evolutionary time dependent. The detected polarity would be, therefore, intrinsic to the IT pathway architecture and function.

The highly conserved insulin-signaling pathway influences very diverse processes including intermediary metabolism, reproduction, aging, and growth. The first pathway component is the insulin receptor that upon insulin binding triggers the signal-transduction cascade. Its variation, like that of other pathway components, might therefore affect many organismal traits. Variation at the "Insulin-like" receptor (InR) gene was surveyed both within Drosophila melanogaster and between species across the Drosophila phylogeny. In D. melanogaster, the level and pattern of variation at the approximately 8-kb region surveyed did not provide any indication of a recent selective event in this region. Maximum likelihood (ML) analyses revealed the past action of purifying selection acting differentially both across the phylogeny and along the studied gene. Moreover, the ML analyses and the McDonald and Kreitman test revealed the footprint of positive selection driving amino acid changes to fixation in the branch separating the Sophophora and the Drosophila subgenera, and in the D. melanogaster lineage, respectively. The oldest selective events could have affected either the insulin binding or the signal-transduction capacities of the receptor, whereas mutations affecting signal transduction would seem to underlie the more recent events.