Parent–progeny sequencing indicates higher mutation rates in heterozygotes

Abstract

Mutation rates vary within genomes, but the causes of this remain unclear. As many prior inferences rely on methods that assume an absence of selection, potentially leading to artefactual results, we call mutation events directly using a parent-offspring sequencing strategy focusing on Arabidopsis and using rice and honey bee for replication. Here we show that mutation rates are higher in heterozygotes and in proximity to crossover events. A correlation between recombination rate and intraspecific diversity is in part owing to a higher mutation rate in domains of high recombination/diversity. Implicating diversity per se as a cause, we find an ∼3.5-fold higher mutation rate in heterozygotes than in homozygotes, with mutations occurring in closer proximity to heterozygous sites than expected by chance. In a genome that is a patchwork of heterozygous and homozygous domains, mutations occur disproportionately more often in the heterozygous domains. If segregating mutations predispose to a higher local mutation rate, clusters of genes dominantly under purifying selection (more commonly homozygous) and under balancing selection (more commonly heterozygous), might have low and high mutation rates, respectively. Our results are consistent with this, there being a ten times higher mutation rate in pathogen resistance genes, expected to be under positive or balancing selection. Consequently, we do not necessarily need to evoke extremely weak selection on the mutation rate to explain why mutational hot and cold spots might correspond to regions under positive/balancing and purifying selection, respectively.

Spontaneous Chloroplast Mutants Mostly Occur by Replication Slippage and Show a Biased Pattern in the Plastome of Oenothera

“…The mutation spectrum in the Oenothera plastome is in sharp contrast to that detected in the nuclear genome of Arabidopsis thaliana (Ossowski et al, 2010;Yang et al, 2015) or Escherichia coli (Lee et al, 2012). Mutations in nuclear genomes are biased toward single base pair G:C to A:T transitions (with a lower frequency of transversions) that are explained by deamination of methylated cytosine and UV light-induced DNA damage.…”

High mutational rates of large-scale duplication and deletion in Daphnia pulex

“…Because of this foreign origin, there is 2× the silentsite heterozygosity on Chromosomes XIII and IX compared with all other genomic regions in asexuals (synonymous-site heterozygosity, or Π s = 0.0442 vs. 0.0223 per site) (Tucker et al 2013), suggesting that chromosomal divergence is contributing to the increased mutation rates in this region. It has been observed that mutations accumulate at higher rates in F1 hybrids (Scavetta and Tautz 2010;Yang et al 2015), and repeat regions are more likely to change in length if the homologous sequence has a drastically divergent length (Amos et al 1996). However, perhaps most pertinent to this study is that mutations have been shown to arise at a higher rate in heterozygous regions of genomes that have interspersed homozygous and heterozygous domains (Yang et al 2015).…”

“…It has been observed that mutations accumulate at higher rates in F1 hybrids (Scavetta and Tautz 2010;Yang et al 2015), and repeat regions are more likely to change in length if the homologous sequence has a drastically divergent length (Amos et al 1996). However, perhaps most pertinent to this study is that mutations have been shown to arise at a higher rate in heterozygous regions of genomes that have interspersed homozygous and heterozygous domains (Yang et al 2015). Future studies are needed to fully understand the mechanistic phenomena leading to the observed changes on D. pulex Chromosomes XIII and IX in asexual lines.…”

Genomic incompatibilities in the diploid and tetraploid offspring of the goldfish × common carp cross

“…S22) (54-57), might drive, or contribute to, the high rate of crossing-over in the offspring. Recent reports of higher mutation rates in heterozygotes support this possibility (58). Chaos caused by allopolyploidization also might result in multiple failures of chromosomal pairing (53).…”