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Genetics Aug 2023The mutation rate plays an important role in adaptive evolution. It can be modified by mutator and anti-mutator alleles. Recent empirical evidence hints that the...
The mutation rate plays an important role in adaptive evolution. It can be modified by mutator and anti-mutator alleles. Recent empirical evidence hints that the mutation rate may vary among genetically identical individuals: evidence from bacteria suggests that the mutation rate can be affected by expression noise of a DNA repair protein and potentially also by translation errors in various proteins. Importantly, this non-genetic variation may be heritable via a transgenerational epigenetic mode of inheritance, giving rise to a mutator phenotype that is independent from mutator alleles. Here, we investigate mathematically how the rate of adaptive evolution is affected by the rate of mutation rate phenotype switching. We model an asexual population with two mutation rate phenotypes, non-mutator and mutator. An offspring may switch from its parental phenotype to the other phenotype. We find that switching rates that correspond to so-far empirically described non-genetic systems of inheritance of the mutation rate lead to higher rates of adaptation on both artificial and natural fitness landscapes. These switching rates can maintain within the same individuals both a mutator phenotype and intermediary mutations, a combination that facilitates adaptation. Moreover, non-genetic inheritance increases the proportion of mutators in the population, which in turn increases the probability of hitchhiking of the mutator phenotype with adaptive mutations. This in turns facilitates the acquisition of additional adaptive mutations. Our results rationalize recently observed noise in the expression of proteins that affect the mutation rate and suggest that non-genetic inheritance of this phenotype may facilitate evolutionary adaptive processes.
Topics: Mutation Rate; Mutation; Phenotype; Adaptation, Physiological; Bacteria
PubMed: 37293818
DOI: 10.1093/genetics/iyad111 -
Viruses Mar 2015The question of the origin of smallpox, one of the major menaces to humankind, is a constant concern for the scientific community. Smallpox is caused by the agent... (Review)
Review
The question of the origin of smallpox, one of the major menaces to humankind, is a constant concern for the scientific community. Smallpox is caused by the agent referred to as the variola virus (VARV), which belongs to the genus Orthopoxvirus. In the last century, smallpox was declared eradicated from the human community; however, the mechanisms responsible for the emergence of new dangerous pathogens have yet to be unraveled. Evolutionary analyses of the molecular biological genomic data of various orthopoxviruses, involving a wide range of epidemiological and historical information about smallpox, have made it possible to date the emergence of VARV. Comparisons of the VARV genome to the genomes of the most closely related orthopoxviruses and the examination of the distribution their natural hosts' ranges suggest that VARV emerged 3000 to 4000 years ago in the east of the African continent. The VARV evolution rate has been estimated to be approximately 2 × 10-6 substitutions/site/year for the central conserved genomic region and 4 × 10-6 substitutions/site/year for the synonymous substitutions in the genome. Presumably, the introduction of camels to Africa and the concurrent changes to the climate were the particular factors that triggered the divergent evolution of a cowpox-like ancestral virus and thereby led to the emergence of VARV.
Topics: Africa, Eastern; Evolution, Molecular; Humans; Mutation Rate; Variola virus
PubMed: 25763864
DOI: 10.3390/v7031100 -
Genetics May 2023Population bottlenecks are commonplace in experimental evolution, specifically in serial passaging experiments where microbial populations alternate between growth and...
Population bottlenecks are commonplace in experimental evolution, specifically in serial passaging experiments where microbial populations alternate between growth and dilution. Natural populations also experience such fluctuations caused by seasonality, resource limitation, or host-to-host transmission for pathogens. Yet, how unlimited growth with periodic bottlenecks influence the adaptation of populations is not fully understood. Here, we study theoretically the effects of bottlenecks on the accessibility of evolutionary paths and on the rate of evolution. We model an asexual population evolving on a minimal fitness landscape consisting of two types of beneficial mutations with the empirically supported trade-off between mutation rate and fitness advantage, in the regime where multiple beneficial mutations may segregate simultaneously. In the limit of large population sizes and small mutation rates, we show the existence of a unique most likely evolutionary scenario, determined by the size of the wild-type population at the beginning and at the end of each cycle. These two key demographic parameters determine which adaptive paths may be taken by the evolving population by controlling the supply of mutants during growth and the loss of mutants at the bottleneck. We do not only show that bottlenecks act as a deterministic control of evolutionary paths but also that each possible evolutionary scenario can be forced to occur by tuning demographic parameters. This work unveils the effects of demography on adaptation of periodically bottlenecked populations and can guide the design of evolution experiments.
Topics: Mutation Rate; Mutation; Adaptation, Physiological; Population Density
PubMed: 36728496
DOI: 10.1093/genetics/iyad001 -
Scientific Reports Jul 2022Sexual selection is the process by which traits providing a mating advantage are favoured. Theoretical treatments of the evolution of sex by sexual selection propose...
Sexual selection is the process by which traits providing a mating advantage are favoured. Theoretical treatments of the evolution of sex by sexual selection propose that it operates by reducing the load of deleterious mutations. Here, we postulate instead that sexual selection primarily acts through females preferentially mating with males carrying beneficial mutations. We used simulation and analytical modelling to investigate the evolutionary dynamics of beneficial mutations in the presence of sexual selection. We found that female choice for males with beneficial mutations had a much greater impact on genetic quality than choice for males with low mutational load. We also relaxed the typical assumption of a fixed mutation rate. For deleterious mutations, mutation rate should always be minimized, but when rare beneficial mutations can occur, female choice for males with those rare beneficial mutations could overcome a decline in average fitness and allow an increase in mutation rate. We propose that sexual selection for beneficial mutations could overcome the 'two-fold cost of sex' much more readily than choice for males with low mutational load and may therefore be a more powerful explanation for the prevalence of sexual reproduction than the existing theory. If sexual selection results in higher fitness at higher mutation rates, and if the variability produced by mutation itself promotes sexual selection, then a feedback loop between these two factors could have had a decisive role in driving adaptation.
Topics: Animals; Female; Male; Mutation; Mutation Rate; Reproduction; Selection, Genetic; Sexual Behavior, Animal; Sexual Selection
PubMed: 35871224
DOI: 10.1038/s41598-022-16002-y -
Nucleic Acids Research Aug 2023Single nucleotide mutation rates have critical implications for human evolution and genetic diseases. Importantly, the rates vary substantially across the genome and the...
Single nucleotide mutation rates have critical implications for human evolution and genetic diseases. Importantly, the rates vary substantially across the genome and the principles underlying such variations remain poorly understood. A recent model explained much of this variation by considering higher-order nucleotide interactions in the 7-mer sequence context around mutated nucleotides. This model's success implicates a connection between DNA shape and mutation rates. DNA shape, i.e. structural properties like helical twist and tilt, is known to capture interactions between nucleotides within a local context. Thus, we hypothesized that changes in DNA shape features at and around mutated positions can explain mutation rate variations in the human genome. Indeed, DNA shape-based models of mutation rates showed similar or improved performance over current nucleotide sequence-based models. These models accurately characterized mutation hotspots in the human genome and revealed the shape features whose interactions underlie mutation rate variations. DNA shape also impacts mutation rates within putative functional regions like transcription factor binding sites where we find a strong association between DNA shape and position-specific mutation rates. This work demonstrates the structural underpinnings of nucleotide mutations in the human genome and lays the groundwork for future models of genetic variations to incorporate DNA shape.
Topics: Humans; Mutation Rate; Genome, Human; Mutation; DNA; Nucleotides
PubMed: 37395403
DOI: 10.1093/nar/gkad551 -
Bioinformatics (Oxford, England) Jun 2023Modern methods for computation-intensive tasks in sequence analysis (e.g. read mapping, sequence alignment, genome assembly, etc.) often first transform each sequence...
MOTIVATION
Modern methods for computation-intensive tasks in sequence analysis (e.g. read mapping, sequence alignment, genome assembly, etc.) often first transform each sequence into a list of short, regular-length seeds so that compact data structures and efficient algorithms can be employed to handle the ever-growing large-scale data. Seeding methods using kmers (substrings of length k) have gained tremendous success in processing sequencing data with low mutation/error rates. However, they are much less effective for sequencing data with high error rates as kmers cannot tolerate errors.
RESULTS
We propose SubseqHash, a strategy that uses subsequences, rather than substrings, as seeds. Formally, SubseqHash maps a string of length n to its smallest subsequence of length k, k < n, according to a given order overall length-k strings. Finding the smallest subsequence of a string by enumeration is impractical as the number of subsequences grows exponentially. To overcome this barrier, we propose a novel algorithmic framework that consists of a specifically designed order (termed ABC order) and an algorithm that computes the minimized subsequence under an ABC order in polynomial time. We first show that the ABC order exhibits the desired property and the probability of hash collision using the ABC order is close to the Jaccard index. We then show that SubseqHash overwhelmingly outperforms the substring-based seeding methods in producing high-quality seed-matches for three critical applications: read mapping, sequence alignment, and overlap detection. SubseqHash presents a major algorithmic breakthrough for tackling the high error rates and we expect it to be widely adapted for long-reads analysis.
AVAILABILITY AND IMPLEMENTATION
SubseqHash is freely available at https://github.com/Shao-Group/subseqhash.
Topics: Algorithms; Mutation Rate; Probability; Sequence Alignment
PubMed: 37387132
DOI: 10.1093/bioinformatics/btad218 -
The ISME Journal Jun 2021Deep-sea hydrothermal vents resemble the early Earth, and thus the dominant Thermococcaceae inhabitants, which occupy an evolutionarily basal position of the archaeal...
Deep-sea hydrothermal vents resemble the early Earth, and thus the dominant Thermococcaceae inhabitants, which occupy an evolutionarily basal position of the archaeal tree and take an obligate anaerobic hyperthermophilic free-living lifestyle, are likely excellent models to study the evolution of early life. Here, we determined that unbiased mutation rate of a representative species, Thermococcus eurythermalis, exceeded that of all known free-living prokaryotes by 1-2 orders of magnitude, and thus rejected the long-standing hypothesis that low mutation rates were selectively favored in hyperthermophiles. We further sequenced multiple and diverse isolates of this species and calculated that T. eurythermalis has a lower effective population size than other free-living prokaryotes by 1-2 orders of magnitude. These data collectively indicate that the high mutation rate of this species is not selectively favored but instead driven by random genetic drift. The availability of these unusual data also helps explore mechanisms underlying microbial genome size evolution. We showed that genome size is negatively correlated with mutation rate and positively correlated with effective population size across 30 bacterial and archaeal lineages, suggesting that increased mutation rate and random genetic drift are likely two important mechanisms driving microbial genome reduction. Future determinations of the unbiased mutation rate of more representative lineages with highly reduced genomes such as Prochlorococcus and Pelagibacterales that dominate marine microbial communities are essential to test these hypotheses.
Topics: Anaerobiosis; Base Sequence; Mutation Rate; Phylogeny; Seawater; Thermococcus
PubMed: 33452477
DOI: 10.1038/s41396-020-00888-5 -
Genome Biology and Evolution Mar 2022The rate of mutations varies >100-fold across the genome, altering the rate of evolution, and susceptibility to genetic diseases. The strongest predictor of mutation...
The rate of mutations varies >100-fold across the genome, altering the rate of evolution, and susceptibility to genetic diseases. The strongest predictor of mutation rate is the sequence itself, varying 75-fold between trinucleotides. The fact that DNA sequence drives its own mutation rate raises a simple but important prediction; highly mutable sequences will mutate more frequently and eliminate themselves in favor of sequences with lower mutability, leading to a lower equilibrium mutation rate. However, purifying selection constrains changes in mutable sequences, causing higher rates of mutation. We conduct a simulation using real human mutation data to test if 1) DNA evolves to a low equilibrium mutation rate and 2) purifying selection causes a higher equilibrium mutation rate in the genome's most important regions. We explore how this simple process affects sequence evolution in the genome, and discuss the implications for modeling evolution and susceptibility to DNA damage.
Topics: DNA; Evolution, Molecular; Genome; Humans; Mutation; Mutation Rate
PubMed: 35218359
DOI: 10.1093/gbe/evac032 -
Genetics May 2022A composite likelihood method is introduced for jointly estimating the intensity of selection and the rate of mutation, both scaled by the effective population size,...
A composite likelihood method is introduced for jointly estimating the intensity of selection and the rate of mutation, both scaled by the effective population size, when there is balancing selection at a single multi-allelic locus in an isolated population at demographic equilibrium. The performance of the method is tested using simulated data. Average estimated mutation rates and selection intensities are close to the true values but there is considerable variation about the averages. Allowing for both population growth and population subdivision does not result in qualitative differences but the estimated mutation rates and selection intensities do not in general reflect the current effective population size. The method is applied to 3 class I (HLA-A, HLA-B, and HLA-C) and 2 class II loci (HLA-DRB1 and HLA-DQA1) in the 1000 Genomes populations. Allowing for asymmetric balancing selection has only a slight effect on the results from the symmetric model. Mutations that restore symmetry of the selection model are preferentially retained because of the tendency of natural selection to maximize average fitness. However, slight differences in selective effects result in much longer persistence time of some alleles. Trans-species polymorphism, which is characteristic of major-histocompatibility loci in vertebrates, is more likely when there are small differences in allelic fitness than when complete symmetry is assumed. Therefore, variation in allelic fitness expands the range of parameter values consistent with observations of trans-species polymorphism.
Topics: Alleles; Animals; Gene Frequency; Genetic Variation; Haplotypes; Mutation Rate; Selection, Genetic
PubMed: 35435218
DOI: 10.1093/genetics/iyac058 -
Heredity Aug 2021Failure to maintain DNA methylation patterns during plant development can occasionally give rise to so-called "spontaneous epimutations". These stochastic methylation...
Failure to maintain DNA methylation patterns during plant development can occasionally give rise to so-called "spontaneous epimutations". These stochastic methylation changes are sometimes heritable across generations and thus accumulate in plant genomes over time. Recent evidence indicates that spontaneous epimutations have a major role in shaping patterns of methylation diversity in plant populations. Using single CG dinucleotides as units of analysis, previous work has shown that the epimutation rate is several orders of magnitude higher than the genetic mutation rate. While these large rate differences have obvious implications for understanding genome-methylome co-evolution, the functional relevance of single CG methylation changes remains questionable. In contrast to single CG, solid experimental evidence has linked methylation gains and losses in larger genomic regions with transcriptional variation and heritable phenotypic effects. Here we show that such region-level changes arise stochastically at about the same rate as those at individual CG sites, are only marginal dependent on region size and cytosine density, but strongly dependent on chromosomal location. We also find consistent evidence that region-level epimutations are not restricted to CG contexts but also frequently occur in non-CG regions at the genome-wide scale. Taken together, our results support the view that many differentially methylated regions (DMRs) in natural populations originate from epimutation events and may not be effectively tagged by proximal SNPs. This possibility reinforces the need for epigenome-wide association studies (EWAS) in plants as a way to identify the epigenetic basis of complex traits.
Topics: Arabidopsis; DNA Methylation; Epigenesis, Genetic; Genome, Plant; Mutation Rate
PubMed: 33966050
DOI: 10.1038/s41437-021-00441-w