Trends in Genetics
ReviewMicrosatellite mutations in the germline:: implications for evolutionary inference
Section snippets
Mutation mechanism
A model for microsatellite mutation based on replication slippage was formulated by Levinson and Gutman14 approximately 15 years ago. Replication slippage or slipped-strand mispairing refers to the out-of-register alignment of the two DNA strands following dissociation at the time when the DNA polymerase traverses the repetitive region. If the most 3′ repeat unit of the nascent strand rehybridizes with a complementary repeat unit downstream along the template strand, a loop will be formed in
Average mutation rate
Unique eukaryotic DNA sequences mutate at a rate of approximately 10−9 per nucleotide per generation20. The mutation rate of microsatellites is several orders of magnitude higher, often quoted in the range of 10−3 to 10−4 per locus per generation10. The most recent data from large-scale human genome mapping or paternity testing based on many different loci suggest an even higher mean rate of ∼2×10−3 per meiosis (Table 1). However, these estimates cannot be extrapolated directly to other
Additional mutation biases
The common observation that microsatellites rarely attain lengths over a few tens of repeat units has prompted a discussion on what factors prevent microsatellite growth. In theory, for instance, selection could act against long alleles, introducing a form of length ceiling40. However, microsatellites are typically embedded within noncoding DNA41 and there are so far no data to suggest that selection has a strong effect on microsatellite persistence or that there are selective constraints on
Sex bias
The low mutation rate of most DNA sequences generally means that the mutation process can only be studied through indirect approaches, for example, by analyses of historically accumulated mutations in population samples or in interspecific sequence comparisons. Unfortunately, in most cases this impedes analyses of two classical questions of mutation research – how the mutation rate varies in relation to sex and age. The high mutation rate of many microsatellite loci might overcome this problem,
Experiments in yeast
Direct observations on mutation events at microsatellite loci are commonly made as a by-product of large-scale genome mapping or paternity testing. This rather passive way of data collection means that experiments aimed at addressing particular questions of the microsatellite mutation process can rarely be designed. Fortunately, such experiments are possible in yeast systems. If reporter genes containing in-frame insertions of microsatellite sequence are inserted into yeast chromosomes, cells
Conclusions
An important conclusion from this review is that the microsatellite mutation process is far more complex than previously thought; a simple stepwise mutation model represents an oversimplification of the true mutation process. It will be a challenging task for population geneticists and theoreticians to develop new models of microsatellite evolution that include the combined effects of mutation biases, point mutations and purifying mutations. In fact, although rare, observations of alleles with
Acknowledgements
I thank L. Hurst for comments on the manuscript and to members of my laboratory for discussions. Financial support was obtained from the Swedish Council for Forestry and Agricultural Research, the Swedish Natural Science Research Council and the Swedish Medical Research Council.
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