Inter-allelic interactions play a major role in microsatellite evolution

Abstract

Microsatellite mutations identified in pedigrees confirm that most changes involve the gain or loss of single repeats. However, an unexpected pattern is revealed when the resulting data are plotted on standardized scales that range from the shortest to longest allele at a locus. Both mutation rate and mutation bias reveal a strong dependency on allele length relative to other alleles at the same locus. We show that models in which alleles mutate independently cannot explain these patterns. Instead, both mutation probability and direction appear to involve interactions between homologues in heterozygous individuals. Simple models in which the longer homologue in heterozygotes is more likely to mutate and/or biased towards contraction readily capture the observed trends. The exact model remains unclear in all its details but inter-allelic interactions are a vital component, implying a link between demographic history and the mode and tempo of microsatellite evolution.

Genome-wide patterns ofde novotandem repeat mutations and their contribution to autism spectrum disorders

“…We find that mutations derived from maternal germlines are significantly larger than those from the paternal germline, indicating potentially different mutational forces driving TR mutations dependent on the parent of origin. Further, we replicate the previously observed bias in mutation direction toward the population mean, and find evidence that this trend may in part by driven by interaction between alleles in heterozygous parents 34 .…”

“…We further examined mutation sizes separately for mutations phased to either the maternal vs. Multiple previous studies of TR mutation reported a directionality bias in mutations, with longer alleles more likely to experience contractions and shorter alleles more likely to experience expansions 14,15,34 . While this trend could in part be driven by technical errors due to heterozygous drop out of long alleles ( Methods ), it is supported by orthogonal analysis showing variance in TR allele length saturates over time 14 .…”

“…2c ). It has been previously hypothesized that this trend could be driven in part by interaction between parent alleles 34 . To test this hypothesis, we examined the directionality bias restricting to mutations derived from parents with either homozygous vs. heterozygous genotypes.…”

Pairing and anti-pairing: a balancing act in the diploid genome

“…An analogous process in non-germline cells could further afford organisms some control over the degree of structural heterogeneity in their soma [99]. Intriguingly, studies have correlated sites of sequence heterogeneity with higher local mutation rates and, in the germline, attributed the heightened rates to an instability or compromised state of meiotic pairing [100, 101]. Here, we suggest that cells may embody a process in which they exert a directed influence on future generations by assessing parental and population heterogeneity and then modulating mutation rates (Figure 4B).…”

Interpreting short tandem repeat variations in humans using mutational constraint

“…Unstable expansions, such as those occurring in trinucleotide repeat disorders, likely mutate by different models. Our model also ignores the effect of sequence interruptions and interaction between alleles, both of which have been hypothesized to influence STR mutation patterns 19,35,37 .…”