title: Genic mutation rates in mammals: local similarity, chromosomal heterogeneity, and X-versus-autosome disparity.
abstract: The reduction of mutation rates on the mammalian X chromosome relative to autosomes is most often explained in the literature as evidence of male-driven evolution. This hypothesis attributes lowered mutation rates on the X chromosome to the fact that this chromosome spends less time in the germline of males than in the germline of females. In contrast to this majority view, two articles argued that the patterns of mutation rates across chromosomes are inconsistent with male-driven evolution. One article reported a 40% reduction in synonymous substitution rates (Ks) for X-linked genes relative to autosomes in the mouse-rat lineage. The authors argued that this reduction is too dramatic to be explained by male-driven evolution and concluded that selection has systematically reduced mutation rate on the X chromosome to a level optimal for this male-hemizygous chromosome. More recently, a second article found that chromosomal mutation rates in both the human-mouse and mouse-rat lineages were so heterogeneous that the X chromosome was not an outlier. Here again, the authors argued that this is at odds with male-driven evolution and suggested that selection has modulated chromosomal mutation rates to locally optimal levels, thus extending the argument of the first mentioned article to include autosomes. Here, we reexamine these conclusions using mouse-rat and human-mouse coding-region data. We find a more modest reduction of Ks on the X chromosome, but our results contradict the finding that the X chromosome is not distinct from autosomes. Multiple statistical tests show that Ks rates on the X chromosome differ systematically from the autosomes in both lineages. We conclude that the moderate reduction of mutation rate on the X chromosome of both lineages is consistent with male-driven evolution; however, the large variance in mutation rates across chromosomes suggests that mutation rates are affected by additional factors besides male-driven evolution. Investigation of mutation rates by synteny reveals that synteny blocks, rather than entire chromosomes, might represent the unit of mutation rate variation.
authors.affiliation: Department of Human Genetics, Howard Hughes Medical Institute, University of Chicago, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Malcom
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Wyckoff
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lahn
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D051381:Rats; D026801:Synteny; D014960:X Chromosome