The molecular evolution of signal peptides

Signal peptides direct mature peptides to their appropriate cellular locati on, after which they are cleaved off. Very many random alternatives can ser ve the same function. Of all coding sequences, therefore, signal peptides m ight come closest to being neutrally evolving. Here we consider this issue by examining the molecular evolution of 76 mouse-rat orthologues, each with defined signal peptides. Although they do evolve rapidly, they evolve abou t half as fast as neutral sequences. This indicates that a substantial prop ortion of mutations must be under stabilizing selection. A few putative sig nal sequences lack a hydrophobic core and these tend to be more slowly evol ving than others, indicating even stronger stabilizing selection. However, closer scrutiny suggests that some of these represent mis-annotations in Ge nBank. It is also likely that some of the substitutions are not neutral. VV e find, for example, that the rate of protein evolution correlates with tha t of the mature peptide. This may be a result of compensatory evolution. We also find that signal peptides of immune genes tend to be faster evolving than the average, which suggests an association with antagonistic co-evolut ion. Previous reports also indicated that the signal peptide of the imprint ed gene, Igf2r, is also unusually fast evolving. This, it was hypothesized, might also be indicative of antagonistic co-evolution. Comparison of Igf2r 's signal peptide evolution shows that, although it is not an outlier, its rate of evolution is comparable to that of many of the faster evolving immu ne system signal sequences and 5/6 of the amino acid changes do not conserv e hydrophobicity. This is at least suggestive that there is something unusu al about Igf2r's signal sequence. (C) 2000 Elsevier Science B.V. All rights reserved.