Trends in Genetics
Volume 16, Issue 12, 1 December 2000, Pages 551-558
Journal home page for Trends in Genetics

Review
Microsatellite mutations in the germline:: implications for evolutionary inference

https://doi.org/10.1016/S0168-9525(00)02139-9Get rights and content

Abstract

Microsatellite DNA sequences mutate at rates several orders of magnitude higher than that of the bulk of DNA. Such high rates mean that spontaneous mutations that form new-length variants can realistically be seen in pedigree analysis. Data on observed mutation events from various organisms are now accumulating, allowing inferences on DNA sequence evolution to be made through an unusually direct approach. Here I discuss and integrate microsatellite mutation data in an evolutionary context. A striking feature of the mutation process is that it seems highly heterogeneous, with distinct differences between species, repeat types, loci and alleles. Age and sex also affect the mutation rate. Within genomes at equilibrium, the microsatellite-length distribution is a delicate balance between biased mutation processes and point mutations acting towards the decay of repetitive DNA. Indeed, simple repeats do not evolve simply.

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.

References (66)

  • H. Hamada

    A novel repeated element with Z-DNA-forming potential is widely found in evolutionarily diverse eukaryotic genomes

    Proc. Natl. Acad. Sci. U. S. A.

    (1982)
  • D. Tautz

    Hypervariability of simple sequences as a general source for polymorphic DNA markers

    Nucleic Acids Res.

    (1989)
  • J.L. Weber et al.

    Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction

    Am. J. Hum. Genet.

    (1989)
  • M.W. Bruford et al.

    Microsatellites and their application to population genetics studies

    Curr. Opin. Genet. Devel.

    (1993)
  • D.C. Queller

    Microsatellites and kinship

    Trends Ecol. Evol.

    (1993)
  • P. Jarne et al.

    Microsatellites, from molecular to populations and back

    Trends Ecol. Evol.

    (1996)
  • C. Schlötterer et al.

    The use of microsatellites for genetic analysis of natural populations – a critical review

  • D.B. Goldstein et al.

    Microsatellites: Evolution and Applications

    (1999)
  • M. Kimura

    The Neutral Theory of Evolution

    (1983)
  • J.L. Weber et al.

    Mutation of short tandem repeats

    Hum. Mol. Genet.

    (1993)
  • C.T. Caskey

    Triplet mutations in human disease

    Science

    (1992)
  • G.R. Sutherland et al.

    Simple tandem DNA repeats and human genetic disease

    Proc. Natl. Acad. Sci. U. S. A.

    (1995)
  • G. Levinson et al.

    Slipped-strand mispairing: a major mechanism for DNA sequence evolution

    Mol. Biol. Evol.

    (1987)
  • E. Heyer

    Estimating Y chromosome specific microsatellite mutation frequencies using deep rooting pedigrees

    Hum. Mol. Genet.

    (1997)
  • C. Schlötterer et al.

    Slippage synthesis of simple sequence DNA

    Nucleic Acids Res.

    (1992)
  • J.F. Crow

    How much do we know about spontaneous human mutation rates?

    Environ. Mol. Mutagen.

    (1993)
  • C. Schlötterer

    High mutation rate of a long microsatellite allele in Drosophila melanogaster provides evidence for allele-specific mutation rates

    Mol. Biol. Evol.

    (1998)
  • M.D. Schug

    The mutation rates of di-, tri- and tetranucleotide repeats in Drosophila melanogaster

    Mol. Biol. Evol.

    (1998)
  • J.L. Weber

    Informativeness of human (dC–dA)n and (dG–dT)n polymorphisms

    Genomics

    (1990)
  • B. Brinkmann

    Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat

    Am. J. Hum. Genet.

    (1998)
  • C.R. Primmer

    Directional evolution in germline microsatellite mutations

    Nat. Genet.

    (1996)
  • R.H. Crozier

    Mutability of microsatellites developed for the ant Camponotus consobrinus

    Mol. Ecol.

    (1999)
  • T.C. Glenn

    Allelic diversity in alligator microsatellite loci is negatively correlated with GC content of flanking sequences and evolutionary conservation of PCR amplifiability

    Mol. Biol. Evol.

    (1996)
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