Timing of replication is a determinant of neutral substitution rates but does not explain slow Y chromosome evolution...

Mutation rates, assayed as substitution rates of putatively neutral sites, are highly variable around mammalian genomes: There is heterogeneity between genes, between autosomes, and between X, Y, and autosomes. The differences between X, Y, and autosomes are typically assumed to reflect the greater number of cell divisions in the male germ-line. Such an effect can neither account for within-autosome differences nor does it predict the differences between X, Y, and autosome observed in rodents. It has recently been proposed that in primates, the time during S-phase when a gene is replicated is an important determinant of neutral rates of evolution. Here we ask 1) whether we can replicate this result in rodents, 2) whether different autosomes replicate on average at different times, and 3) whether this might explain differences in their substitution rates. Finally we ask 4) whether X, Y, and autosome replicate at different times and 5) whether any difference might explain why the number of replication events alone cannot explain their substitution rates. We find that, as in primates, autosomal intronic rates of evolution increase significantly during S-phase. Different autosomes do have different average replication times, and together with rearrangement, this is a significant predictor of between-autosome differences in substitution rate. Although we find that autosomal, X-, and Y-linked genes replicate at different times, it is paradoxical that the Y-linked genes replicate latest, and replicate more often, but are not especially fast evolving. These results support the hypothesis that replication timing is an important source of substitution rate heterogeneity.