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Heterozygosity increases microsatellite mutation rate - PubMed

Heterozygosity increases microsatellite mutation rate

William Amos. Biol Lett. 2016 Jan.

Abstract

Whole genome sequencing of families of Arabidopsis has recently lent strong support to the heterozygote instability (HI) hypothesis that heterozygosity locally increases mutation rate. However, there is an important theoretical difference between the impact on base substitutions, where mutation rate increases in regions surrounding a heterozygous site, and the impact of HI on sequences such as microsatellites, where mutations are likely to occur at the heterozygous site itself. At microsatellite loci, HI should create a positive feedback loop, with heterozygosity and mutation rate mutually increasing each other. Direct support for HI acting on microsatellites is limited and contradictory. I therefore analysed AC microsatellites in 1163 genome sequences from the 1000 genomes project. I used the presence of rare alleles, which are likely to be very recent in origin, as a surrogate measure of mutation rate. I show that rare alleles are more likely to occur at locus-population combinations with higher heterozygosity even when all populations carry exactly the same number of alleles.

Keywords: heterozygosity; heterozygote instability; human; microsatellite; mutation rate; tandem repeat.

© 2016 The Author(s).

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Figures

Figure 1.
Figure 1.

Relationship between rare alleles and drift. Stochastic simulations were conducted of a single homogeneous population in which individuals mate randomly and carry two loci. One locus experiences a single unique mutation at each generation. The other locus does not mutate but evolves purely through drift. The simulated data are scanned for rare alleles, defined as alleles present in fewer than five copies in a sample of 1000 individuals. The graph depicts the cumulative distribution of rare alleles, quantified in terms of the amount of drift that has occurred since the progenitor mutation, and expressed as the change in frequency of alleles at the drifting locus (y-axis). A large majority of rare alleles represent mutations that occurred over a timescale during which the drifting locus alleles change in frequency by only 1 or 2%.

Figure 2.
Figure 2.

Difference in heterozygosity between population groups with and without rare alleles, partitioned by population group. Rare alleles are defined as alleles present at fewer than five copies and restricted to one population group. At each locus, excluding the rare allele itself, all populations carry the same number and identity of alleles. Data were transformed such that mean heterozygosity within each population group was zero with unit standard deviation. The vertical axis is difference in heterozygosity between the population group with a rare allele and the average heterozygosity among the remaining three population groups. Population groups are Europe (EUR, N = 1348 loci), East Asia (EAS, N = 947 loci), Africa (AFR, N = 2697 loci) and Central Southern Asia (CSA, N = 1529 loci). Bars denote means±1 s.e. of the mean. All data points are significantly positive. Total sample size = 6521 loci. For AT and AG repeats, see the electronic supplementary material, ESM4a.

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