Factors in uencing ascertainment bias of microsatellite allele sizes: impact on estimates of mutation rates

Microsatellite loci play an important role as markers for identi cation, disease gene mapping and evolutionary studies. Mutation rate, which is of fundamental importance, can be obtained from interspecies comparisons, which however are subject to ascertainment bias. This bias arises for example when a locus is selected based on its large allele size in one species (cognate species 1), in which it is rst discovered. This bias is re ected in average allele length in any non-cognate species 2 being smaller than that in species 1. This phenomenon was observed in various pairs of species, including comparisons of allele sizes in Human and Chimpanzee. Various mechanisms were proposed to explain observed di erences in mean allele lengths between two species. Here, we examine the framework of a single-step asymmetric and unrestricted stepwise mutation model with genetic drift. Analysis is based on coalescent theory. Analytical results are con rmed by simulations using the simuPOP software. The mechanism of ascertainment bias in this model is a tighter correlation of allele sizes within a cognate species 1 than of allele sizes in two di erent species 1 and 2. We present computations of the expected average allele size di erence, given the mutation rate, population sizes of species 1 and 2, time of separation of species 1 and 2, and the age of the allele. We show that when the past demographic histories of the cognate and non-cognate taxa are di erent, the rate and directionality of mutations impact the allele sizes in the two taxa di erently from the simple e ect of ascertainment bias. This e ect may exaggerate or reverse the e ect of di erence in mutation rates. We re-analyze literature data, which indicate that despite the bias, the microsatellite mutation rate estimate in the ancestral population is consistently greater than that in either Human or Chimpanzee and the mutation rate estimate in Human exceeds or equals that in Chimpanzee with the rate of allele length expansion in Human being greater than that in Chimpanzee. We also demonstrate that population bottlenecks and expansions in the recent human history have little impact on our conclusions.