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The germline mutation rate determines the pace of genome evolution and is an evolving parameter itself 1 . However, little is known about what determines its evolution, as most studies of mutation rates have focused on single species with different methodologies 2 . Here we quantify germline mutation rates across vertebrates by sequencing and comparing the high-coverage genomes of 151 parent–offspring trios from 68 species of mammals, fishes, birds and reptiles. We show that the per-generation mutation rate varies among species by a factor of 40, with mutation rates being higher for males than for females in mammals and birds, but not in reptiles and fishes. The generation time, age at maturity and species-level fecundity are the key life-history traits affecting this variation among species. Furthermore, species with higher long-term effective population sizes tend to have lower mutation rates per generation, providing support for the drift barrier hypothesis 3 . The exceptionally high yearly mutation rates of domesticated animals, which have been continually selected on fecundity traits including shorter generation times, further support the importance of generation time in the evolution of mutation rates. Overall, our comparative analysis of pedigree-based mutation rates provides ecological insights on the mutation rate evolution in vertebrates. Using sequencing and comparing high-coverage genomes, the germline mutation rates across vertebrates are quantified.

The high mutation rate of RNA viruses is credited with their evolvability and virulence. This Primer, however, discusses recent evidence that this is, in part, a byproduct of selection for faster genomic replication.

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans 1 – 7 . Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans 8 , although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined—including variation of around 30-fold in lifespan and around 40,000-fold in body mass—the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing. Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.

Abstract The rate of spontaneous mutation is a key factor in determining the capacity of a population to adapt to a novel environment, for example, a bacterial population exposed to antibiotics. Genetic and environmental factors controlling the mutation rate commonly also cause shifts in the relative rates of different mutational classes, i.e. the mutational spectrum. When the mutational spectrum is altered, the relatively enriched and depleted mutations may differ in their fitness effects. Here, we explore how a reduced mutation rate and altered mutational spectrum can contribute to adaptation in Escherichia coli. We measure mutation rates across a set of Nudix hydrolase deletants, finding multiple strains with an antimutator phenotype. We focus on the antimutator ΔnudJ, which can cause a 6-fold mutation rate reduction relative to the wildtype, with an altered mutational spectrum biased towards A > C transversions. Its reduced mutation rate, most pronounced at low population densities, appears to occur via NudJ's role in nucleotide and/or prenyl metabolism, with a reduced internal ATP pool. Its effects may be reversed by mutations to genes, including waaZ, affecting the outer membrane. Not only does nudJ deletion reduce the probability of antibiotic resistance arising at all but through enhancing an existing hotspot for low fitness A > C rifampicin resistance mutations reduces the expected fitness of strains when resistance does arise. Thus, our findings with ΔnudJ suggest future anti-evolution drug strategies could suppress spontaneous resistance evolution not only through minimizing resistance mutations but also by specifically limiting access to the fittest mutations.

Viral quasispecies refers to a population structure that consists of extremely large numbers of variant genomes, termed mutant spectra, mutant swarms or mutant clouds. Fueled by high mutation rates, mutants arise continually, and they change in relative frequency as viral replication proceeds. The term quasispecies was adopted from a theory of the origin of life in which primitive replicons) consisted of mutant distributions, as found experimentally with present day RNA viruses. The theory provided a new definition of wild type, and a conceptual framework for the interpretation of the adaptive potential of RNA viruses that contrasted with classical studies based on consensus sequences. Standard clonal analyses and deep sequencing methodologies have confirmed the presence of myriads of mutant genomes in viral populations, and their participation in adaptive processes. The quasispecies concept applies to any biological entity, but its impact is more evident when the genome size is limited and the mutation rate is high. This is the case of the RNA viruses, ubiquitous in our biosphere, and that comprise many important pathogens. In virology, quasispecies are defined as complex distributions of closely related variant genomes subjected to genetic variation, competition and selection, and that may act as a unit of selection. Despite being an integral part of their replication, high mutation rates have an upper limit compatible with inheritable information. Crossing such a limit leads to RNA virus extinction, a transition that is the basis of an antiviral design termed lethal mutagenesis.

Mutations are the ultimate source of all genetic variation. However, few direct estimates of the contribution of mutation to molecular genetic variation are available. To address this issue, we first analyzed the rate and spectrum of mutations in the Arabidopsis thaliana reference accession after 25 generations of single-seed descent. We then compared the mutation profile in these mutation accumulation (MA) lines against genetic variation observed in the 1001 Genomes Project. The estimated haploid single nucleotide mutation (SNM) rate for A. thaliana is 6.95 × 10−9 (SE ± 2.68 × 10−10) per site per generation, with SNMs having higher frequency in transposable elements (TEs) and centromeric regions. The estimated indel mutation rate is 1.30 × 10−9 (±1.07 × 10−10) per site per generation, with deletions being more frequent and larger than insertions. Among the 1694 unique SNMs identified in the MA lines, the positions of 389 SNMs (23%) coincide with biallelic SNPs from the 1001 Genomes population, and in 289 (17%) cases the changes are identical. Of the 329 unique indels identified in the MA lines, 96 (29%) overlap with indels from the 1001 Genomes dataset, and 16 indels (5% of the total) are identical. These overlap frequencies are significantly higher than expected, suggesting that de novo mutations are not uniformly distributed and arise at polymorphic sites more frequently than assumed. These results suggest that high mutation rate potentially contributes to high polymorphism and low mutation rate to reduced polymorphism in natural populations providing insights of mutational inputs in generating natural genetic diversity.

Persisters are transiently antibiotic-tolerant cells that complicate the treatment of bacterial infections. Both theory and experiments have suggested that persisters facilitate genetic resistance by constituting an evolutionary reservoir of viable cells. Here, we provide evidence for a strong positive correlation between persistence and the likelihood to become genetically resistant in natural and lab strains of E. coli . This correlation can be partly attributed to the increased availability of viable cells associated with persistence. However, our data additionally show that persistence is pleiotropically linked with mutation rates. Our theoretical model further demonstrates that increased survival and mutation rates jointly affect the likelihood of evolving clinical resistance. Overall, these results suggest that the battle against antibiotic resistance will benefit from incorporating anti-persister therapies.

Abstract Mutation rate is a fundamental parameter in population genetics. Apart from being an important scaling parameter for demographic and phylogenetic inference, it allows one to understand at what rate new genetic diversity is generated and what the expected level of genetic diversity is in a population at equilibrium. However, except for well-established model organisms, accurate estimates of de novo mutation rates are available for a very limited number of organisms from the wild. We estimated mutation rates (µ) in two marine populations of the nine-spined stickleback (Pungitius pungitius) with the aid of several 2- and 3-generational family pedigrees, deep (>50×) whole-genome resequences and a high-quality reference genome. After stringent filtering, we discovered 308 germline mutations in 106 offspring translating to µ = 4.83 × 10−9 and µ = 4.29 × 10−9 per base per generation in the two populations, respectively. Up to 20% of the mutations were shared by full-sibs showing that the level of parental mosaicism was relatively high. Since the estimated µ was 3.1 times smaller than the commonly used substitution rate, recalibration with µ led to substantial increase in estimated divergence times between different stickleback species. Our estimates of the de novo mutation rate should provide a useful resource for research focused on fish population genetics and that of sticklebacks in particular.

Given the disposability of somatic tissue, selection can favor a higher mutation rate in the early segregating soma than in germline, as seen in some animals. Although in plants intra-organismic mutation rate heterogeneity is poorly resolved, the same selectionist logic can predict a lower rate in shoot than in root and in longer-lived terminal tissues (e.g., leaves) than in ontogenetically similar short-lived ones (e.g., petals), and that mutation rate heterogeneity should be deterministic with no significant differences between biological replicates. To address these expectations, we sequenced 754 genomes from various tissues of eight plant species. Consistent with a selectionist model, the rate of mutation accumulation per unit time in shoot apical meristem is lower than that in root apical tissues in perennials, in which a high proportion of mutations in shoots are themselves transmissible, but not in annuals, in which somatic mutations tend not to be transmissible. Similarly, the number of mutations accumulated in leaves is commonly lower than that within a petal of the same plant, and there is no more heterogeneity in accumulation rates between replicate branches than expected by chance. High mutation accumulation in runners of strawberry is, we argue, the exception that proves the rule, as mutation transmission patterns indicate that runner has a restricted germline. However, we also find that in vitro callus tissue has a higher mutation rate (per unit time) than the wild-grown comparator, suggesting nonadaptive mutational \"fragility\". As mutational fragility does not obviously explain why the shoot-root difference varies with plant longevity, we conclude that some mutation rate variation between tissues is consistent with selectionist theory but that a mechanistic null of mutational fragility should be considered.

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases. A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.