Sub-lethal insecticide stress alters epimutation rate but not genetic mutation rate in the pest insect Myzus persicae.

1. The frequency of seed-color mutation of Rr: Cornell, which occurs at the rate of 18.2 x 10-4 in the Cornell stock, was reduced to 0 in the F1 of a cross with a multiple linkage tester stock. The number of Rr:Cornell gametes tested for mutation in the F1 was sufficient to have yielded 22 mutations at the rate characteristic of the Cornell stock. 2. The backcross, F1 x Cornell stock, yielded 30 mutations (rate 9.2 x 10-4). The incidence of these mutations in relation to the segregation for the various marker genes indicates the presence of dominant genes favoring seed-color mutation of Rr:Cornell in the Y-marked segment and the J-marked segment of the tester stock. Similarly, the Rg-marked segment shows an effect unfavorable to the occurrence of the mutation. 3. The increase in mutation rate associated with the presence of the J segment appears to be highly significant statistically (P < .01). Since the statistical comparison assumes that sampling error due to individual plant variability is negligible, and since the results of the experiment as a whole indicate that plant variability may be very great, the evidence for the occurrence of this modifier is not considered conclusive. 4. The increase in mutation rate associated with the Y-segment was not quite significant in the backcross generation, but was clearly confirmed in the self-progeny of a backcross plant. The ratio of mutation rate in the y y vs. the Y y class was 1.0:2.3 in the backcross generation and 1.0:3.5 in the following generation. 5. The decrease in mutation rate associated with the Rg segment was significant in the backcross generation (P < .05) and was supported, in numbers inadequate for significance, in the second backcross generation. The location of a modifier in this segment is supported also by significant evidence of the same sort from a cross of Cornell with another stock. The ratio of mutation rate in the Rr Rr vs. the Rr Rg class was 3.5:1.0 in the backcross generation of the cross with the linkage tester stock, and 4.4:1.0 in the backcross generation of the other cross mentioned. 6. The effect of the modifiers upon mutation frequency appears to be cumulative, so far as may be judged from the limited data.

Editor's evaluation: Future COVID19 surges prediction based on SARS-CoV-2 mutations surveillance

Ionizing radiation and genetic risks VIII. The concept of mutation component and its use in risk estimation for multifactorial diseases

DNA polymerase zeta (Polzeta) participates in translesion DNA synthesis and is involved in the generation of the majority of mutations induced by DNA damage. The mechanisms that license access of Polzeta to the primer terminus and regulate the extent of its participation in genome replication are poorly understood. The Polzeta-dependent damage-induced mutagenesis requires monoubiquitination of proliferating cell nuclear antigen (PCNA) that is triggered by exposure to mutagens. We show that Polzeta contributes to DNA replication and causes mutagenesis not only in response to DNA damage but also in response to malfunction of normal replicative machinery due to mutations in replication genes. These replication defects lead to ubiquitination of PCNA even in the absence of DNA damage. Unlike damage-induced mutagenesis, the Polzeta-dependent spontaneous mutagenesis in replication mutants is reduced in strains defective in both ubiquitination and sumoylation of Lys164 of PCNA. Additionally, studies of a PCNA mutant defective for functional interactions with Polzeta, but not for monoubiquitination by the Rad6/Rad18 complex demonstrate a role for PCNA in regulating the mutagenic activity of Polzeta separate from its modification at Lys164.

Ionizing radiation and genetic risks VII. The concept of mutation component and its use in risk estimation for Mendelian diseases

We accumulated mutations for 1952 generations in 79 initially identical, haploid lines of the fission yeast Schizosaccharomyces pombe, and then performed whole-genome sequencing to determine the mutation rates and spectrum. We captured 696 spontaneous mutations across the 79 mutation accumulation (MA) lines. We compared the mutation spectrum and rate to a recently published equivalent experiment on the same species, and to another model ascomycetous yeast, the budding yeast Saccharomyces cerevisiae. While the two species are approximately 600 million years diverged from each other, they share similar life histories, genome size and genomic G/C content. We found that Sc. pombe and S. cerevisiae have similar mutation rates, but Sc. pombe exhibits a stronger insertion bias. Intriguingly, we observed an increased mutation rate at cytosine nucleotides, specifically CpG nucleotides, which is also seen in S. cerevisiae. However, the absence of methylation in Sc. pombe and the pattern of mutation at these sites, primarily C → A as opposed to C → T, strongly suggest that the increased mutation rate is not caused by deamination of methylated cytosines. This result implies that the high mutability of CpG dinucleotides in other species may be caused in part by a methylation-independent mechanism. Many of our findings mirror those seen in the recent study, despite the use of different passaging conditions, indicating that MA is a reliable method for estimating mutation rates and spectra.

Decision letter: Limited role of generation time changes in driving the evolution of the mutation spectrum in humans

Editor's evaluation: Limited role of generation time changes in driving the evolution of the mutation spectrum in humans

Author response: Limited role of generation time changes in driving the evolution of the mutation spectrum in humans

Mutation rates vary between species, between strains within species and between regions within a genome. What are the determinants of these forms of variation? Here, via parent–offspring sequencing of the peach we ask whether (i) woody perennials tend to have lower per unit time mutation rates compared to annuals, and (ii) hybrid strains have high mutation rates. Between a leaf from a low heterozygosity individual, derived from an intraspecific cross, to a leaf of its selfed progeny, the mutation rate is 7.77 × 10−9 point mutations per bp per generation, similar to Arabidopsis thaliana (7.0–7.4 × 10−9 point mutations per bp per generation). This suggests a low per unit time mutation rate as the generation time is much longer in peach. This is supported by our estimate of 9.48 × 10−9 point mutations per bp per generation from a 200-year-old low heterozygosity peach to its progeny. From a more highly heterozygous individual derived from an interspecific cross to its selfed progeny, the mutation rate is 1.38 × 10−8 mutations per site per generation, consistent with raised rates in hybrids. Our data thus suggest that (i) peach has an approximately order of magnitude lower mutation rate per unit time than Arabidopsis, consistent with reports of low evolutionary rates in woody perennials, and (ii) hybridization may, indeed, be associated with increased mutation rates as considered over a century ago.

RMplex reveals population differences in RM Y-STR mutation rates and provides improved father-son differentiation in Japanese

Mutation is fundamental to evolution, because it generates the genetic variation on which selection can act. In nature, genetic changes often increase the mutation rate in systems that range from viruses and bacteria to human tumors. Such an increase promotes the accumulation of frequent deleterious or neutral alleles, but it can also increase the chances that a population acquires rare beneficial alleles. Here, we study how up to 100-fold increases in Escherichia coli’s genomic mutation rate affect adaptive evolution. To do so, we evolved multiple replicate populations of asexual E. coli strains engineered to have four different mutation rates for 3000 generations in the laboratory. We measured the ability of evolved populations to grow in their original environment and in more than 90 novel chemical environments. In addition, we subjected the populations to whole genome population sequencing. Although populations with higher mutation rates accumulated greater genetic diversity, this diversity conveyed benefits only for modestly increased mutation rates, where populations adapted faster and also thrived better than their ancestors in some novel environments. In contrast, some populations at the highest mutation rates showed reduced adaptation during evolution, and failed to thrive in all of the 90 alternative environments. In addition, they experienced a dramatic decrease in mutation rate. Our work demonstrates that the mutation rate changes the global balance between deleterious and beneficial mutational effects on fitness. In contrast to most theoretical models, our experiments suggest that this tipping point already occurs at the modest mutation rates that are found in the wild.

BackgroundThe accumulation of deleterious mutations can drastically reduce population mean fitness. Self-fertilization is thought to be an effective means of purging deleterious mutations. However, widespread linkage disequilibrium generated and maintained by self-fertilization is predicted to reduce the efficacy of purging when mutations are present at multiple loci.Methodology/Principal FindingsWe tested the ability of self-fertilizing populations to purge deleterious mutations at multiple loci by exposing obligately self-fertilizing populations of Caenorhabditis elegans to a range of elevated mutation rates and found that mutations accumulated, as evidenced by a reduction in mean fitness, in each population. Therefore, purging in obligate selfing populations is overwhelmed by an increase in mutation rate. Surprisingly, we also found that obligate and predominantly self-fertilizing populations exposed to very high mutation rates exhibited consistently greater fitness than those subject to lesser increases in mutation rate, which contradicts the assumption that increases in mutation rate are negatively correlated with fitness. The high levels of genetic linkage inherent in self-fertilization could drive this fitness increase.ConclusionsCompensatory mutations can be more frequent under high mutation rates and may alleviate a portion of the fitness lost due to the accumulation of deleterious mutations through epistatic interactions with deleterious mutations. The prolonged maintenance of tightly linked compensatory and deleterious mutations facilitated by self-fertilization may be responsible for the fitness increase as linkage disequilibrium between the compensatory and deleterious mutations preserves their epistatic interaction.

Minisatellite germline mutation rate in the Techa River population

BLM has been implicated in DNA double-strand break (DSB) repair, but its precise role remains obscure. To explore this, we generated BLM(-/-) and BLM(-/-)LIG4(-/-) cells from the human pre-B cell line Nalm-6. BLM(-/-) cells exhibited retarded growth, increased mutation rates, and hypersensitivity to agents that block replication fork progression. Interestingly, these phenotypes were significantly suppressed by deletion of LIG4, suggesting that nonhomologous end-joining (NHEJ) is unfavorable for integrity and survival of cells lacking BLM. We propose that the absence of BLM leads to accumulation of replication-associated, one-ended DSBs, which are deleterious to cells and lead to genomic instability when repaired by NHEJ. In addition, the NHEJ pathway per se was marginally affected by BLM deficiency, as evidenced by x-ray sensitivity and I-SceI-based DSB repair assays. More intriguingly, however, these experiments revealed the presence of an alternative, DNA ligase IV-independent end-joining pathway, which was significantly affected by the loss of BLM. Collectively, our results provide the first evidence for genetic interactions between BLM and NHEJ in human cells.