Likelihood-based estimation of microsatellite mutation rates.
Microsatellites are widely used in genetic analyses, many of which require reliable estimates of microsatellite mutation rates, yet the factors determining mutation rates are uncertain. The most straightforward and conclusive method by which to study mutation is direct observation of allele transmissions in parent-child pairs, and studies of this type suggest a positive, possibly exponential, relationship between mutation rate and allele size, together with a bias toward length increase. Except for microsatellites on the Y chromosome, however, previous analyses have not made full use of available data and may have introduced bias: mutations have been identified only where child genotypes could not be generated by transmission from parents' genotypes, so that the probability that a mutation is detected depends on the distribution of allele lengths and varies with allele length. We introduce a likelihood-based approach that has two key advantages over existing methods. First, we can make formal comparisons between competing models of microsatellite evolution; second, we obtain asymptotically unbiased and efficient parameter estimates. Application to data composed of 118,866 parent-offspring transmissions of AC microsatellites supports the hypothesis that mutation rate increases exponentially with microsatellite length, with a suggestion that contractions become more likely than expansions as length increases. This would lead to a stationary distribution for allele length maintained by mutational balance. There is no evidence that contractions and expansions differ in their step size distributions.
Whittaker
John C
JC
School of Applied Statistics, University of Reading, United Kingdom. j.whittaker@ic.ac.uk
Harbord
Roger M
RM
Boxall
Nicola
N
Mackay
Ian
I
Dawson
Gary
G
Sibly
Richard M
RM
D000483:Alleles; D002874:Chromosome Mapping; D019143:Evolution, Molecular; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D018895:Microsatellite Repeats; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA
D005819:Genetic Markers