Why are some human disease-associated mutations fixed in mice?

A recent comparative genomic analysis revealed the presence of nucleotide sequences in mouse that are known to be disease-associated in humans, yet the mouse appears normal. In this article we formulate and test several hypotheses in an attempt to explain why these apparently deleterious mutations become fixed in mice. We find that except for one case, the fixations of the disease-associated mutations occurred before the separation of Mus musculus and Mus spretus at least 1 million years ago and that the fixations are not attributable to a founder effect during the recent history of mouse breeding. About 80% of the cases involve diseases that occur before reproductive age in humans and these substitutions are unlikely to have been fixed because of the inefficiency of natural selection against late-onset diseases. We conclude that the compensatory mutation hypothesis remains the most probable explanation for the majority of the fixations of disease mutations in mice.