Mutation-driven evolution: Microsatellite instability drives speciation in a mammalian taxon

Abstract

The concept of evolvability-from its evolutionary origins to molecular mechanisms-defines a fundamental problem at the intersection of biochemistry, genetics, and developmental biology. An emerging paradigm, mutation-driven evolution, posits that chromosomal dynamics (including changes in ploidy, chromosome loss, aberrant recombination, and mechanics of DNA damage and repair) underlie the origin of genetic variation as a precondition for selection. A model is provided by microsatellite instability. Although widely exploited as an experimental marker of evolutionary change with application to human disease, the potential contribution of such instability to evolvability itself is less well understood. Here, we propose that microsatellite instability within a vertebrate sex-determining gene can drive rapid adaptation and speciation. Our analysis focuses on superfamily Muroidea (order Rodentia) wherein four anomalies are observed: (1) This superfamily is unusually speciose, indeed the most species rich in Mammalia; (2) speciation has occurred rapidly (i.e., within the past 25 million years) and apparently in overlapping ranges; (3) inherited XY sex reversal has evolved independently within multiple genera; and (4) uniquely among therian mammals, male sex-determining mechanisms not dependent on Y-encoded testis-determining factor Sry have emerged. A unifying hypothesis is presented whereby these anomalies have a single molecular basis, to wit the dynamics of a Muroidea-specific microsatellite-encoded transcriptional activation domain. An ancestral microsatellite in this taxon has functioned as a "genetic capacitor" to enable cryptic variation to accumulate within Sry. On discharge, this capacitor provided a recurring source of reproductive isolation and thus enabled rapid evolution of biological novelty at the edge of sexual ambiguity.