Two optimal mutation rates in obligate pathogens subject to deleterious mutation

Pathogen species with high mutation rates are likely to accumulate deleterious mutations that reduce their reproductive potential within the host. By altering the within-host growth rate of the pathogen, the deleterious mutation load has the potential to affect epidemiological properties such as prevalence, mean pathogen load, and the mean duration of infections. Here, I examine an epidemiological model that allows for multiple segregating mutations that affect within-host replication efficiency. The model demonstrates a complex range of outcomes depending on pathogen mutation rate, including two distinct, widely separated mutation rates associated with high pathogen prevalence. The low mutation rate prevalence peak is associated with small amounts of genetic diversity within the pathogen population, relatively stable prevalence and infection dynamics, and genetic variation partitioned between hosts. The high mutation rate peak is characterized by considerable genetic diversity both within and between hosts, relatively frequent invasions by more virulent types, and is qualitatively similar to an RNA virus quasispecies. The two prevalence peaks are separated by a valley where natural selection favors evolution toward the optimal within-host state, which is associated with high virulence and relatively rapid host mortality. Both chronic and acute infections are examined using stochastic forward simulations.     

Beneficial mutations, hitchhiking and the evolution of mutation rates in sexual populations

Natural selection acts in three ways on heritable variation for mutation rates. A modifier allele that increases the mutation rate is (i) disfavored due to association with deleterious mutations, but is also favored due to (ii) association with beneficial mutations and (iii) the reduced costs of lower fidelity replication. When a unique beneficial mutation arises and sweeps to fixation, genetic hitchhiking may cause a substantial change in the frequency of a modifier of mutation rate. In previous studies of the evolution of mutation rates in sexual populations, this effect has been underestimated. This article models the long-term effect of a series of such hitchhiking events and determines the resulting strength of indirect selection on the modifier. This is compared to the indirect selection due to deleterious mutations, when both types of mutations are randomly scattered over a given genetic map. Relative to an asexual population, increased levels of recombination reduce the effects of beneficial mutations more rapidly than those of deleterious mutations. However, the role of beneficial mutations in determining the evolutionarily stable mutation rate may still be significant if the function describing the cost of high-fidelity replication has a shallow gradient.     

Evidence for hitchhiking of deleterious mutations within the human genome

Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles.     

The approach to mutation-selection balance in an infinite asexual population, and the evolution of mutation rates

A method is described for calculating the dynamics of the distribution of fitness in an infinite asexual population which is subject to unconditionally deleterious mutations with independent effects. This method is applied to the problem of calculating the frequency of a mutator subpopulation, at equilibrium between mutation and indirect selection due to association with deleterious mutations. Many mutator alleles are produced by loss-of-function mutations in polymerase or mismatch repair genes. Previous calculations have ignored the fact that this creates a flux of higher fitness individuals into the mutator subpopulation. This flux raises the mean fitness of the mutator subpopulation, and when this factor is taken into account, the frequency of the mutator may be more than an order of magnitude greater than recent theoretical work has suggested.     

Genome-wide deleterious mutation favors dispersal and species integrity

Here I develop the idea that ubiquitous harmful genome-wide mutation with local differentiation favors dispersal, even though migration reduces average fitness. Historical contingency of the mutational process means that demes (sub-populations) differentiate from one another. Deleterious or lethal partially recessive mutations carried by migrants then do not encounter similar mutations in the recipient deme. Migrant offspring have higher fitness than offspring of residents, because migrant offspring are heterozygous rather than homozygous for harmful mutations. The advantage is inversely related to local inbreeding depression. Genome-wide deleterious mutation favors the evolution of dispersal, which in turn enhances the genetic integrity of the species.     

Evaluation of structural and evolutionary contributions to deleterious mutation prediction

Methods for automated prediction of deleterious protein mutations have utilized both structural and evolutionary information but the relative contribution of these two factors remains unclear. To address this, we have used a variety of structural and evolutionary features to create simple deleterious mutation models that have been tested on both experimental mutagenesis and human allele data. We find that the most accurate predictions are obtained using a solvent-accessibility term, the C(beta) density, and a score derived from homologous sequences, SIFT. A classification tree using these two features has a cross-validated prediction error of 20.5% on an experimental mutagenesis test set when the prior probability for deleterious and neutral cases is equal, whereas this prediction error is 28.8% and 22.2% using either the C(beta) density or SIFT alone. The improvement imparted by structure increases when fewer homologs are available: when restricted to three homologs the prediction error improves from 26.9% using SIFT alone to 22.4% using SIFT and the C(beta) density, or 24.8% using SIFT and a noisy C(beta) density term approximating the inaccuracy of ab initio structures modeled by the Rosetta method. We conclude that methods for deleterious mutation prediction should include structural information when fewer than five to ten homologs are available, and that ab initio predicted structures may soon be useful in such cases when high-resolution structures are unavailable.     

Quantifying the slightly deleterious mutation model of molecular evolution

We have attempted to quantify the frequency and effects of slightly deleterious mutations (SDMs), those that have selective effects close to the reciprocal of the effective population size of a species, by comparing the level of selective constraint in protein-coding genes of related species that have different present-day effective population sizes. In our two comparisons, the species with the smaller effective population size showed lower constraint, implying that SDMs had become fixed. The fixation of SDMs was supported by the observation of a higher fraction of radical to conservative amino acid substitutions in species with smaller effective population sizes. The fraction of strongly deleterious mutations (which rarely become fixed) is >70% in most species. Only approximately 10% or fewer of mutations seem to behave as SDMs, but SDMs could comprise a substantial fraction of mutations in protein-coding genes that have a chance of becoming fixed between species.     

Evolution of sex: role of deleterious mutation and mobile elements

Prevalence of sexual reproduction is still enigma. The main character of sex is alleles mixing that could be advantageous either in unstable environment (in this case sex provides high temp of evolution) or in unstable genotype (in this case sex provides purge of genome from deleterious mutations). As long as not all species inhabit highly changeable environments, variation of genotypes is more important factor. As the majority of new mutations is deleterious, effective mechanism of genome purging is needed. Maintenance of "purging mechanism" may be a single role of sex. Two promising mutational hypotheses--clade selection (Muller's ratchet and Nunney's hypothesis) and mutational deterministic hypothesis of Kondrashov claim that more effective elimination of slightly-deleterious mutations provides main advantage to sexual population in comparison with asexual. Despite prima facie similarity, these hypotheses differ in mechanisms, work at different temporal scales and have different consequences. Kondrashov's hypothesis reveals short-term advantage of sexual reproduction, and thus, based on the individual selection. Clade selection displays long-term advantage of sexual reproduction that could be realized only by group selection. The role of mobile elements in evolution of sexual reproduction is also discussed. Firstly, mobile elements ("sexual molecular parasites") can complicate the problem: having been domesticated in asexual genomes and remaining active in sexual genomes they lead to higher mutational rate in sexual organisms and so violate assumption critical for both mutational hypotheses of "other things being equal". Secondly, mobile elements could be leader factor of origin of sex (hypothesis proposed by Hickey). Because theory of group selection could explain maintenance of sex, but not its origin, mobile elements could induce the origin of sex but were not able to maintain it, so the next scenario of evolution of sex is proposed: mobile elements induced origin of sex, which was established later by group selection because provided long term benefit (Muller's ratchet and Nunney's hypothesis). So, on all stages of evolution, sex was not advantageous for the organism per se.     

Tolerant versus sensitive genomes: The impact of deleterious mutation on fitness and conservation

Using two alternative mutational models, Iinvestigate equilibrium diffusion predictionsfor population fitness. In the classical``sensitive model', fitness is highly sensitiveto mutations, these usually having mildlydetrimental effects. In the ``tolerant model',most mutations have only tiny deleteriouseffects, but a small proportion is considerablydetrimental. When the same relationship betweenthe degree of dominance and the homozygousdeleterious effect of mutations is assumed,both models predict important inbreedingdepression after bottlenecking in largepopulations, although the sensitive oneaccounts for a higher average degree ofdominance. Under the sensitive model, the rateof fitness decline due to deleterious fixationis large for effective population sizes in the tens, and could be important in thelong term for effective sizes about 100, inagreement with previously published results.This suggests that conservation programs shouldact to avoid mutational meltdown. Under thetolerant model, however, the fitness declinedue to deleterious fixation is generally low,indicating that conservation programs shouldgive priority to avoid quick inbreeding, lossof genetic variability and adaptation tocaptive conditions, even if this reduces thestrength of selection against new mutations.     

Evolutionary changes in mutation rates and spectra and their influence on the adaptation of pathogens

The evolutionary tuning of mutational processes may play a key role in prokaryotic evolution, particularly among pathogens. In this paper we review the evidence that genetic systems controlling the rate and spectrum of heritable mutations have evolved to optimize levels of adaptive variation and rates of genetic change.     

Evidence for inefficient selection against deleterious mutations in cytochrome oxidase I of asexual bdelloid rotifers

Evolutionary theory predicts that natural selection should be less efficient in asexually than in sexually reproducing organisms. Obligate asexuals are expected to adapt slowly to changing environments and to accumulate mildly deleterious mutations to their genomes, potentially explaining their typically short evolutionary lifespans. One group of animals that appear to challenge these ideas is the bdelloid rotifers, a large and ancient clade of obligate asexuals. Previous work has found no evidence for inefficient selection against deleterious mutations in protein-coding genes of bdelloids. However, these studies relied mostly on between-species comparisons and were therefore unable to detect mildly deleterious mutations that persist within populations but are removed by selection over longer time periods. Here, we test for inefficient purifying selection acting on the cytochrome oxidase I (cox1) mitochondrial gene in 3 clades of bdelloids. Patterns of variation are compared to those of two facultatively sexual clades: a monogonont rotifer (Brachionus) and a branchiopod crustacean (Daphnia). As predicted due to the strict linkage between mitochondrial and nuclear genomes, bdelloids exhibit higher frequencies of putatively deleterious amino acid polymorphism within populations than the two facultatively sexual clades. While the monophyly and age of bdelloids makes it hard to rule out other explanations for the observed differences, several possible confounding factors, such as differences in effective population size or patterns of codon usage, are shown not to explain the observed differences. We therefore conclude that bdelloid mitochondrial DNA variation does display the signature of inefficient selection expected of obligate asexuals.     

The influence of the PO1A1 mutation upon recombination in Escherichia coli K12.

Genetic recombination in Escherichia coli is a highly regulated process involving multiple gene products. We have investigated the role of DNA polymerase I in this process by studying the effect of the po1A1 mutation upon DNA transfer and conjugation in otherwise isogenic suppressor-free strains of E. coli K-12. It was found that the po1A1 mutation greatly reduces recombination in Hfr crosses (a factor of 20 in Pol+ x Po1A1 crosses and more than a factor of 100 in Po1A1 X Po1A1 crosses). However, since the po1A1 mutation reduces the strains capacity to act as a recipient for an F-prime and the analysis of recombination transfer gradients revealed no differences between Po1+ and Po1- strains, it is concluded that DNA polymerase I probably affects the transfer and/or stability of donor DNA rather than the recombinational process itself.