Short Indels Are Subject to Insertion-Biased Gene Conversion

Leushkin, Evgeny; Bazykin, Georgii A.

doi:10.1111/evo.12129

Cited by 15 publications

(24 citation statements)

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“…Furthermore, the analysis of polymorphic indels showed that this correlation is not due to a mutagenic effect of recombination, but to an increased rate of fixation of insertions in regions of high recombination. These observations suggest that in Drosophila , BGC might favor insertions over deletions (Leushkin and Bazykin 2013). The authors also observed a negative correlation between rDI (measured on fixed small indels) and recombination in human and in yeast (although the correlation is much weaker than in Drosophila ).…”

Section: Discussionmentioning

confidence: 94%

“…An alternative possibility is that the fixation bias in favor of insertions results from BGC (Lamb 1985; Duret and Galtier 2009; Leushkin and Bazykin 2013). For example, if the repair of gaps in heteroduplex DNA tends to favor long alleles over short alleles then one would expect to see an increase in the probability of transmission of long alleles, specifically in regions of high recombination.…”

Section: Resultsmentioning

confidence: 99%

“…2 A ). Thus, if BGC is affecting indels in humans, as proposed by Leushkin and Bazykin (2013), its impact appears to be much weaker than on SNPs. In any case, the difference in eDAF between insertions and deletions is almost as strong in regions of very low crossover rates as in regions of high crossover rates (fig.…”

Section: Discussionmentioning

confidence: 98%

“…Leushkin and Bazykin (2013) recently reported that in Drosophila , the rDI ratio (inferred from the analysis of small indels within noncoding regions) is negatively correlated with recombination, specifically for fixed indels. Furthermore, the analysis of polymorphic indels showed that this correlation is not due to a mutagenic effect of recombination, but to an increased rate of fixation of insertions in regions of high recombination.…”

Section: Discussionmentioning

confidence: 99%

“…For example, there is evidence that the length of introns is under selective pressure: A minimum intron size is necessary for efficient splicing (Parsch 2003), but long introns appear to be counterselected in highly expressed genes (possibly to minimize the cost of the transcription (Castillo-Davis et al 2002). It is also in principle possible that indel mutations are affected by the process of biased gene conversion (BGC), which might increase the probability of fixation of insertion over deletions (or vice versa) in regions of high recombination rate (Lamb 1985; Duret and Galtier 2009; Leushkin and Bazykin 2013). Finally, it is possible that genome-wide variation in gene density predominantly reflects variation in the underlying indel mutation patterns.…”

Section: Introductionmentioning

confidence: 99%

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Strong Heterogeneity in Mutation Rate Causes Misleading Hallmarks of Natural Selection on Indel Mutations in the Human Genome

Kvikstad

Duret

2013

Molecular Biology and Evolution

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Elucidating the mechanisms of mutation accumulation and fixation is critical to understand the nature of genetic variation and its contribution to genome evolution. Of particular interest is the effect of insertions and deletions (indels) on the evolution of genome landscapes. Recent population-scaled sequencing efforts provide unprecedented data for analyzing the relative impact of selection versus nonadaptive forces operating on indels. Here, we combined McDonald–Kreitman tests with the analysis of derived allele frequency spectra to investigate the dynamics of allele fixation of short (1–50 bp) indels in the human genome. Our analyses revealed apparently higher fixation probabilities for insertions than deletions. However, this fixation bias is not consistent with either selection or biased gene conversion and varies with local mutation rate, being particularly pronounced at indel hotspots. Furthermore, we identified an unprecedented number of loci with evidence for multiple indel events in the primate phylogeny. Even in nonrepetitive sequence contexts (a priori not prone to indel mutations), such loci are 60-fold more frequent than expected according to a model of uniform indel mutation rate. This provides evidence of as yet unidentified cryptic indel hotspots. We propose that indel homoplasy, at known and cryptic hotspots, produces systematic errors in determination of ancestral alleles via parsimony and advise caution interpreting classic selection tests given the strong heterogeneity in indel rates across the genome. These results will have great impact on studies seeking to infer evolutionary forces operating on indels observed in closely related species, because such mutations are traditionally presumed homoplasy-free.

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Section: Discussionmentioning

confidence: 94%