Mutating away from your enemies: The evolution of mutation rate in a host–parasite system

The rate at which mutations occur in nature is itself under natural selection. While a general reduction of mutation rates is advantageous for species inhabiting constant environments, higher mutation rates can be advantageous for those inhabiting fluctuating environments that impose on-going directional selection. Analogously, species involved in antagonistic co-evolutionary arms races, such as hosts and parasites, can also benefit from higher mutation rates. We use modifier theory, combined with simulations, to investigate the evolution of mutation rate in such a host–parasite system. We derive an expression for the evolutionary stable mutation rate between two alleles, each of whose fitness depends on the current genetic composition of the other species. Recombination has been shown to weaken the strength of selection acting on mutation modifiers, and accordingly, we find that the evolutionarily attracting mutation rate is lower when recombination between the selected and the modifier locus is high. Cyclical dynamics are potentially commonplace for loci governing antagonistic species interactions. We characterize the parameter space where such cyclical dynamics occur and show that the evolution of large mutation rates tends to inhibit cycling and thus eliminates further selection on modifiers of the mutation rate. We then find using computer simulations that stochastic fluctuations in finite populations can increase the size of the region where cycles occur, creating selection for higher mutation rates. We finally use simulations to investigate the model behaviour when there are more than two alleles, finding that the region where cycling occurs becomes smaller and the evolutionarily attracting mutation rate lower when there are more alleles.     

Experimental evolution and the dynamics of genomic mutation rate modifiers

Because genes that affect mutation rates are themselves subject to mutation, mutation rates can be influenced by natural selection and other evolutionary forces. The population genetics of mutation rate modifier alleles has been a subject of theoretical interest for many decades. Here, we review experimental contributions to our understanding of mutation rate modifier dynamics. Numerous evolution experiments have shown that mutator alleles (modifiers that elevate the genomic mutation rate) can readily rise to high frequencies via genetic hitchhiking in non-recombining microbial populations. Whereas these results certainly provide an explanatory framework for observations of sporadically high mutation rates in pathogenic microbes and in cancer lineages, it is nonetheless true that most natural populations have very low mutation rates. This raises the interesting question of how mutator hitchhiking is suppressed or its phenotypic effect reversed in natural populations. Very little experimental work has addressed this question; with this in mind, we identify some promising areas for future experimental investigation.     

Gene flow and selection interact to promote adaptive divergence in regions of low recombination

Adaptation to new environments often occurs in the face of gene flow. Under these conditions, gene flow and recombination can impede adaptation by breaking down linkage disequilibrium between locally adapted alleles. Theory predicts that this decay can be halted or slowed if adaptive alleles are tightly linked in regions of low recombination, potentially favouring divergence and adaptive evolution in these regions over others. Here, we compiled a global genomic data set of over 1,300 individual threespine stickleback from 52 populations and compared the tendency for adaptive alleles to occur in regions of low recombination between populations that diverged with or without gene flow. In support of theory, we found that putatively adaptive alleles (F_ST and d_XY outliers) tend to occur more often in regions of low recombination in populations where divergent selection and gene flow have jointly occurred. This result remained significant when we employed different genomic window sizes, controlled for the effects of mutation rate and gene density, controlled for overall genetic differentiation, varied the genetic map used to estimate recombination and used a continuous (rather than discrete) measure of geographic distance as proxy for gene flow/shared ancestry. We argue that our study provides the first statistical evidence that the interaction of gene flow and selection biases divergence toward regions of low recombination.     

Are humans increasing bacterial evolvability?

Attempts to control bacterial pathogens have led to an increase in antibiotic-resistant cells and the genetic elements that confer resistance phenotypes. These cells and genes are disseminated simultaneously with the original selective agents via human waste streams. This might lead to a second, unintended consequence of antimicrobial therapy; an increase in the evolvability of all bacterial cells. The genetic variation upon which natural selection acts is a consequence of mutation, recombination and lateral gene transfer (LGT). These processes are under selection, balancing genomic integrity against the advantages accrued by genetic innovation. Saturation of the environment with selective agents might cause directional selection for higher rates of mutation, recombination and LGT, producing unpredictable consequences for humans and the biosphere.     

A Darwinian evolutionary system. I. Definition and basic properties

Biological evolution as conceived by the present synthetic theory of evolution is modelled by a mathematical system which consists of three arrays: the genotype and phenotype population and their environment, and four operators: selection, mutation, recombination, and alteration (describing the change of the environment by the population). An evolutionary process then could be represented as the cyclic iteration of these operations on the respective arrays. Some simple versions of this system were investigated by computer simulation. They exhibited the following properties. (i) Population fitness increased with the generation number. (ii) The evolutionary rate increased with variance of fitness. (iii) The evolutionary rate increased with the number of individuals, and decreased with the number of loci. (iv) The evolutionary rate increased with the selection pressure. (v) For a given system in a given state there existed an optimal mutation rate. (vi) Free recombination was optimal. (vii) The mutational load of fitness increased with the mutation rate, but was independent of the selection pressure; contrary to this, the mutational load of the population “morph” decreased with the selection pressure, i.e. one could compensate for the deleterious effect of mutation by strong selection. These rules applied to haploids with equal, unequal, non-epistatic, and epistatic gene effect, and also to diploids. It was found that epistatic gene effect for relatively low mutation rates slows down evolution, whereas unequal gene effect enhances it. Diploids were not found to be superior to haploids in evolutionary terms, except in the case of diploids with dominant gene action for very small population sizes. The results are discussed with regard to their applicability to the simulation of more complex evolutionary phenomena.     

The Optimum Recombination Rate That Realizes the Fastest Evolution of a Novel Functional Combination of Many Genes

The effect of genetic recombination (or crossover) by sexual reproduction on the time until a novel set of genes performing a combined function appears, spreads, and becomes fixed is studied. First, we study a haploid finite population with many binary loci, in which only one sequence (called a functional gene set) is significantly advantageous over the others. The time for evolution of the function (T_d) is defined as the mean number of generations until the advantageous sequence dominates in an initially random population. When the sequence diversity is initially stored sufficiently, the evolution timeT_dis roughly the product of the waiting time until the appearance of the advantageous sequence (creation timeT_c) and the average number of appearances of the advantageous sequence from its absence until its fixation (destruction numberN_d). Mutation and crossover reduce the former but enlarge the latter. If the mutation rate is low, there is an intermediate optimal rate of crossover that achieves the minimumT_d. In contrast, if the mutation rate is sufficiently high,T_dis smallest without crossover. Second, the breakdown of established functions by recurrent deleterious mutation in an infinite population is examined. The number of functional genes maintained decreases monotonically with the recurrent deleterious mutation rate. Thus in higher organisms having many functional sets of genes in the genome, the mutation rate must be kept very low to preserve them, and hence a high crossover rate made possible by sexual reproduction is important in accelerating the evolution of novel functional sets of genes. Implications of this long-term advantage of recombination in the maintenance of sexual reproduction in higher organisms are discussed.     

Estimating the Relative Roles of Recombination and Point Mutation in the Generation of Single Locus Variants in Campylobacter jejuni and Campylobacter coli

Single locus variants (SLVs) are bacterial sequence types that differ at only one of the seven canonical multilocus sequence typing (MLST) loci. Estimating the relative roles of recombination and point mutation in the generation of new alleles that lead to SLVs is helpful in understanding how organisms evolve. The relative rates of recombination and mutation for Campylobacter jejuni and Campylobacter coli were estimated at seven different housekeeping loci from publically available MLST data. The probability of recombination generating a new allele that leads to an SLV is estimated to be roughly seven times more than that of mutation for C. jejuni, but for C. coli recombination and mutation were estimated to have a similar contribution to the generation of SLVs. The majority of nucleotide differences (98?% for C. jejuni and 85?% for C. coli) between strains that make up an SLV are attributable to recombination. These estimates are much larger than estimates of the relative rate of recombination to mutation calculated from more distantly related isolates using MLST data. One explanation for this is that purifying selection plays an important role in the evolution of Campylobacter. A simulation study was performed to test the performance of our method under a range of biologically realistic parameters. We found that our method performed well when the recombination tract length was longer than 3?kb. For situations in which recombination may occur with shorter tract lengths, our estimates are likely to be an underestimate of the ratio of recombination to mutation, and of the importance of recombination for creating diversity in closely related isolates. A parametric bootstrap method was applied to calculate the uncertainty of these estimates.     

Emergence and Maintenance of Sex among Diploid Organisms Aided by Assortative Mating

Using computer simulations I studied the simultaneous effect of variable environments, mutation rates, ploidy, number of loci subject to evolution and random and assortative mating on various reproductive systems. The simulations showed that mutants for sex and recombination are evolutionarily stable, displacing alleles for monosexuality in diploid populations mating assortatively under variable selection pressure. Assortative mating reduced excessive allelic variance induced by recombination and sex, especially among diploids. Results suggest a novel adaptive value for sex and recombination. They show that the adaptive value of diploidy and that of the segregation of sexes is different to that of sex and recombination. The results suggest that the emergence of sex had to be preceded by the emergence of diploid monosexual organisms and provide an explanation for the emergence and maintenance of sex among diploids and for the scarcity of sex among haploid organisms.     

The evolution of plastic recombination

Empirical data suggest that recombination rates may change in response to stress. To study the evolution of plastic recombination, we develop a modifier model using the same theoretical framework used to study conventional (nonplastic) modifiers, thus allowing direct comparison. We examine the evolution of plastic recombination in both haploid and diploid systems. In haploids, a plastic modifier spreads by forming associations with selectively favored alleles. Relative to nonplastic effects, selection on the plastic effects of a modifier is both much stronger and less sensitive to the specifics of the selection regime (e.g., epistasis). In contrast, the evolution of plastic recombination in diploids is much more restricted. Selection on plasticity requires the ability to detect DNA damage or cis-trans effects as may occur through maternal effects on fitness.     

The evolution of intratetrad mating rates

Intratetrad mating, the fusion of gametes formed in a single meiosis, has unusual consequences for genetic diversity, especially in genome regions linked to mating type loci. Here we investigate the fate of modifier alleles that alter the rate of intratetrad mating, under models of heterozygote advantage and of genetic load resulting from recurrent mutation. In both cases, intratetrad mating is favored if the recombination rate between the selected locus and mating type is less than the frequency of lethal recessive alleles at that locus in the population. Positive feedback often accelerates the invasion of modifiers to the intratetrad mating rate. Recombination rate and intratetrad mating rate exert indirect selection on one another, resulting in a cascading decline in outcrossing, even in the absence of any cost of sex. However, under recurrent mutation, alleles for obligate intratetrad mating invade only very slowly, perhaps explaining why outcrossing can persist at low frequencies in a largely intratetrad mating population.     

Lateral gene transfer in vitro in the intracellular pathogen Chlamydia trachomatis

Genetic recombinants that resulted from lateral gene transfer (LGT) have been detected in sexually transmitted disease isolates of Chlamydia trachomatis, but a mechanism for LGT in C. trachomatis has not been described. We describe here a system that readily detects C. trachomatis LGT in vitro and that may facilitate discovery of its mechanisms. Host cells were simultaneously infected in the absence of antibiotics with an ofloxacin-resistant mutant and a second mutant that was resistant to lincomycin, trimethoprim, or rifampin. Selection for doubly resistant C. trachomatis isolates in the progeny detected apparent recombinant frequencies of 10(-4) to 10(-3), approximately 10(4) times more frequent than doubly resistant spontaneous mutants in progeny from uniparental control infections. Polyclonal doubly resistant populations and clones isolated from them in the absence of antibiotics had the specific resistance-conferring mutations present in the parental mutants; absence of the corresponding normal nucleotides indicated that they had been replaced by homologous recombination. These results eliminate spontaneous mutation, between-strain complementation, and heterotypic resistance as general explanations of multiply resistant C. trachomatis that originated in mixed infections in our experiments and demonstrate genetic stability of the recombinants. The kind of LGT we observed might be useful for creating new strains for functional studies by creating new alleles or combinations of alleles of polymorphic loci and might also disseminate antibiotic resistance genes in vivo. The apparent absence of phages and conjugative plasmids in C. trachomatis suggests that the LGT may have occurred by means of natural DNA transformation. Therefore, the experimental system may have implications for genetically altering C. trachomatis by means of DNA transfer.     

Frequent recombination shapes the epidemic population structure of Planktothrix (Cyanoprokaryota) in Italian subalpine lakes

The planktonic genus Planktothrix, as other cyanobacteria, shows signals of both homologous and nonhomologous recombination. However, the frequency of recombination and its effect on Planktothrix population structuring is unknown. We isolated 290 Planktothrix strains from seven neighboring lakes in the subalpine Italian region and analyzed these using multilocus sequence typing. Four of six loci analyzed were polymorphic, resulting in 20 distinct multilocus genotypes. Association indices among alleles at different loci were suggestive of an “epidemic population structure,” resulting from an explosive (and temporary) dominance of one genotype against a panmictic background. ClonalFrame analyses supported this view by detecting: (i) three major clades affected by three distinct recombination events, (ii) a recombination rate about equal to the mutation rate, and (iii) the fact that recombination had an impact on introducing molecular diversity more than double the mutation rate. Furthermore, analysis of molecular variance over an annual cycle in three of seven lakes revealed that both local clonal expansion and recombination processes affected among‐lake diversity. Our observations suggest that recombination affects microevolution of Planktothrix and that an epidemic structure can emerge in populations of this genus.     

Coevolution of self-fertilization and inbreeding depression. I. Mutation-selection balance at one and two loci

Simple theories for the evolution of breeding systems suggest that the fate of an allele that modifies the rate of self-fertilization hinges only on the degree to which selfing reduces opportunities for outcrossing ("pollen discounting") and the extent of inbreeding depression. These theories predict that outcrossing evolves whenever deleterious mutations have a more severe effect in combination than expected from their individual effects. We study the evolutionary dynamics of a modifier of the rate of self-fertilization in populations subject to complete pollen discounting and recurrent mutations which impair viability at a single locus in diploids and at two loci in haploids. Our analysis indicates that genetic associations arising immediately upon the introduction of a rare modifier allele generate substantial quantitative and qualitative departures from expectation. Higher rates of segregation under selfing in our one-locus diploid model generate positive associations between enhancers of selfing and wild-type viability alleles, which in turn favor the evolution of selfing under a wider range of conditions than expected. Greater opportunities for recombination under outcrossing in our two-locus haploid model generate positive associations between enhancers of outcrossing and wild-type viability alleles. These associations favor the evolution of outcrossing under a wider range of conditions, and introduce the possibility of stable mixed mating systems involving both selfing and outcrossing. Our explicit analysis of genetic associations between loci affecting viability and the rate of self-fertilization indicates that modifiers that enhance the production of offspring with very high (and very low) viability by promoting segregation or recombination develop positive associations with high viability. This advantage of producing extremes can compensate for an initial disadvantage in offspring number.     

Assortative mating for fitness and the evolution of recombination

To understand selection on recombination, we need to consider how linkage disequilibria develop and how recombination alters these disequilibria. Any factor that affects the development of disequilibria, including nonrandom mating, can potentially change selection on recombination. Assortative mating is known to affect linkage disequilibria but its effects on the evolution of recombination have not been previously studied. Given that assortative mating for fitness can arise indirectly via a number of biologically realistic scenarios, it is plausible that weak assortative mating occurs across a diverse set of taxa. Using a modifier model, we examine how assortative mating for fitness affects the evolution of recombination under two evolutionary scenarios: selective sweeps and mutation-selection balance. We find there is no net effect of assortative mating during a selective sweep. In contrast, assortative mating could have a large effect on recombination when deleterious alleles are maintained at mutation-selection balance but only if assortative mating is sufficiently strong. Upon considering reasonable values for the number of loci affecting fitness components, the strength of selection, and the mutation rate, we conclude that the correlation in fitness between mates is unlikely to be sufficiently high for assortative mating to affect the evolution of recombination in most species.     

Evolution of the individual

This article studies the transition in evolution from single cells to multicellular organisms as a case study in the origin of individuality. The issues considered are applicable to all major transitions in the units of selection that involve the emergence of cooperation and the regulation of conflict. Explicit genetic models of mutation and selection both within and between organisms are studied. Cooperation among cells increases when the fitness covariance at the level of the organism overcomes within-organism change toward defection. Selection and mutation during development generate significant levels of within-organism variation and lead to variation in organism fitness at equilibrium. This variation selects for gem-line modifiers and other mediators of within-organism conflict, increasing the heritability of fitness at the organism level. The evolution of these modifiers is the first new function at the emerging organism level and a necessary component of the evolution of individuality.     

Mating system and recombination affect molecular evolution in four Triticeae species.

Mating systems and recombination are thought to have a deep impact on the organization and evolution of genomes. Because of the decline in effective population size and the interference between linked loci, the efficacy of selection is expected to be reduced in regions with low recombination rates and in the whole genome of self-fertilizing species. At the molecular level, relaxed selection is expected to result in changes in the rate of protein evolution and the pattern of codon bias. It is increasingly recognized that recombination also affects non-selective processes such as the biased gene conversion towards GC alleles (bGC). Like selection, this kind of meiotic drive in favour of GC over AT alleles is expected to be reduced in weakly recombining regions and genomes. Here, we investigated the effect of mating system and recombination on molecular evolution in four Triticeae species: two outcrossers (Secale cereale and Aegilops speltoides) and two selfers (Triticum urartu and Triticum monococcum). We found that GC content, possibly driven by bGC, is affected by mating system and recombination as theoretically predicted. Selection efficacy, however, is only weakly affected by mating system and recombination. We investigated the possible reasons for this discrepancy. A surprising one is that, in outcrossing lineages, selection efficacy could be reduced because of high substitution rates in favour of GC alleles. Outcrossers, but not selfers, would thus suffer from a 'GC-induced' genetic load. This result sheds new light on the evolution of mating systems.     

Mutation Accumulation May Only Be a Minor Force in Shaping Life-History Traits,Even when Reproduction Is Sexual

In a previous theoretical study we investigated whether adaptive or non-adaptive processes are more important in the evolution of senescence. We built a model that combined both processes and found that mutation accumulation is important only at those ages where mortality has a negligible impact on fitness. This model, however, was limited to haploid organisms. Here we extend our model by introducing diploidy and sexual reproduction. We assume that only recessive (mutated) homozygotes experience detrimental effects. Our results corroborate our previous conclusions, confirming that life histories are largely determined by adaptive processes. We also found that the equilibrium frequencies of mutated alleles are at higher values than in haploid model, because mutations in heterozygotes are hidden for directional selection. Nevertheless, the equilibrium frequencies of recessive homozygotes that make mutations visible to selection are very similar to the equilibrium frequencies of these alleles in our haploid model. Diploidy and sexual reproduction with recombination slows down approaching selection-mutation balance.     

IS LIFE IMPOSSIBLE? INFORMATION,SEX, AND THE ORIGIN OF COMPLEX ORGANISMS

The earliest organisms are thought to have had high mutation rates. It has been asserted that these high mutation rates would have severely limited the information content of early genomes. This has led to a well‐known “paradox” because, in contemporary organisms, the mechanisms that suppress mutations are quite complex and a substantial amount of information is required to construct these mechanisms. The paradox arises because it is not clear how efficient error‐suppressing mechanisms could have evolved, and thus allowed the evolution of complex organisms, at a time when mutation rates were too high to permit the maintenance of very substantial amounts of information within genomes. Here, we use concepts from the formal theory of information to calculate the amount of genomic information that can be maintained. We identify conditions under which much higher levels of genomic information can be maintained than previously considered possible among origin‐of‐life researchers. In particular, we find that the highest levels of information are maintained when many genotypes produce identical phenotypes, and when reproduction occasionally involves recombination between multiple parental genomes. There is a good reason to believe that these conditions are relevant for very early organisms, and thus the results presented may provide a solution to a long‐standing logical problem associated with the early evolution of life.     

In vitro recombinants of antibiotic-resistant Chlamydia trachomatis strains have statistically more breakpoints than clinical recombinants for the same sequenced loci and exhibit selection at unexpected loci

Lateral gene transfer (LGT) is essential for generating between-strain genomic recombinants of Chlamydia trachomatis to facilitate the organism's evolution. Because there is no reliable laboratory-based gene transfer system for C. trachomatis, in vitro generation of recombinants from antibiotic-resistant strains is being used to study LGT. However, selection pressures imposed on in vitro recombinants likely affect statistical properties of recombination relative to naturally occurring clinical recombinants, including prevalence at particular loci. We examined multiple loci for 16 in vitro-derived recombinants of ofloxacin- and rifampin-resistant L(1) and D strains, respectively, grown with both antibiotics, and compared these with the same sequenced loci among 11 clinical recombinants. Breakpoints and recombination frequency were examined using phylogenetics, bioinformatics, and statistics. In vitro and clinical isolates clustered perfectly into two groups, without misclassification, using Ward's minimum variance based on breakpoint data. As expected, gyrA (confers ofloxacin resistance) and rpoB (confers rifampin resistance) had significantly more breakpoints among in vitro recombinants than among clinical recombinants (P < 0.0001 and P = 0.02, respectively, using the Wilcoxon rank sum test). Unexpectedly, trpA also had significantly more breakpoints for in vitro recombinants (P < 0.0001). There was also significant selection at other loci. The strongest bias was for ompA in strain D (P = 3.3 × 10(-8)). Our results indicate that the in vitro model differs statistically from natural recombination events. Additional genomic studies are needed to determine the factors responsible for the observed selection biases at unexpected loci and whether these are important for LGT to inform approaches for genetically manipulating C. trachomatis.     

The evolution of recombination in a heterogeneous environment

Most models describing the evolution of recombination have focused on the case of a single population, implicitly assuming that all individuals are equally likely to mate and that spatial heterogeneity in selection is absent. In these models, the evolution of recombination is driven by linkage disequilibria generated either by epistatic selection or drift. Models based on epistatic selection show that recombination can be favored if epistasis is negative and weak compared to directional selection and if the recombination modifier locus is tightly linked to the selected loci. In this article, we examine the joint effects of spatial heterogeneity in selection and epistasis on the evolution of recombination. In a model with two patches, each subject to different selection regimes, we consider the cases of mutation-selection and migration-selection balance as well as the spread of beneficial alleles. We find that including spatial heterogeneity extends the range of epistasis over which recombination can be favored. Indeed, recombination can be favored without epistasis, with negative and even with positive epistasis depending on environmental circumstances. The selection pressure acting on recombination-modifier loci is often much stronger with spatial heterogeneity, and even loosely linked modifiers and free linkage may evolve. In each case, predicting whether recombination is favored requires knowledge of both the type of environmental heterogeneity and epistasis, as none of these factors alone is sufficient to predict the outcome.