Transposable elements and fitness in Drosophila melanogaster

Transposable elements constitute a significant fraction of the Drosophila melanogaster genome. The five families of moderately repeated transposable elements identified to date occupy dispersed and variable genomic locations, but have relatively constant copy numbers per individual. What effect to these elements have on the fitness of the individuals harboring them? Experimental evidence relating to this question is reviewed. The relevant data fall into two broad categories. The first involves the determination of the distribution of transposable elements in natural populations, by restriction mapping or in situ hybridization, and the comparison of the observed distribution with different theoretical expectations. The second approach is to study directly the effects of new transposable element-induced mutations on fitness. The P family of transposable elements is a particularly efficient mutagen, and the results of experiments in which initially P-free chromosomes are contaminated with P elements are discussed with regard to P-induced fitness mutations.     

Experimental genomic evolution: extensive compensation for loss of DNA ligase activity in a virus

Deletion of the viral ligase gene drastically reduced the fitness of bacteriophage T7 on a ligase-deficient host. Viral evolution recovered much of this fitness during long-term passage, but the final fitness remained below that of the intact virus. Compensatory changes occurred chiefly in genes involved in DNA metabolism: the viral endonuclease, helicase, and DNA polymerase. Two other compensatory changes of unknown function also occurred. Using a method to distinguish compensatory mutations from other beneficial mutations, five additional substitutions from the recovery were shown to enhance adaptation to culture conditions and were not compensatory for the deletion. In contrast to the few previous studies of viral recovery from deletions, the compensatory changes in T7 did not restore the deletion or duplicate major regions of the genome. The ability of this deleted genome to recover much of the lost fitness via mutations in its remaining genes reveals a considerable evolutionary potential to modify the interactions of its elements in maintaining an essential set of functions.     

The dynamical way to mutation-selection balance of an infinite population evolving on a truncated fitness landscape

This paper presents the exact analytical solution, valid for all generations and initial conditions, for the frequency distribution of haploids with infinite-sites genome carrying a given number of mutations in a population evolving deterministically on a truncated fitness landscape. This landscape is a generalization of the single sharp peak one, widely used in quasispecies theory, although here there are no reverse mutations.     

Positive and negative selection in murine ultraconserved noncoding elements

There are many more selectively constrained noncoding than coding nucleotides in the mammalian genome, but most mammalian noncoding DNA is subject to weak selection, on average. One of the most striking discoveries to have emerged from comparisons among mammalian genomes is the hundreds of noncoding elements of more than 200 bp in length that show absolute conservation among mammalian orders. These elements represent the tip of the iceberg of a much larger class of conserved noncoding elements (CNEs). Much evidence suggests that CNEs are selectively constrained and not mutational cold-spots, and there is evidence that some CNEs play a role in the regulation of development. Here, we quantify negative and positive selection acting in murine CNEs by analyzing within-species nucleotide variation and between-species divergence of CNEs that we identified using a phylogenetically independent comparison. The distribution of fitness effects of new mutations in CNEs, inferred from within-species polymorphism, suggests that CNEs receive a higher number of strongly selected deleterious mutations and many fewer nearly neutral mutations than amino acid sites of protein-coding genes or regulatory elements close to genes. However, we also show that CNEs experience a far higher proportion of adaptive substitutions than any known category of genomic sites in murids. The absolute rate of adaptation of CNEs is similar to that of amino acid sites of proteins. This result suggests that there is widespread adaptation in mammalian conserved noncoding DNA elements, some of which have been implicated in the regulation of crucially important processes, including development.     

Diverse phenotypic and genetic responses to short‐term selection in evolving Escherichia coli populations

Beneficial mutations fuel adaptation by altering phenotypes that enhance the fit of organisms to their environment. However, the phenotypic effects of mutations often depend on ecological context, making the distribution of effects across multiple environments essential to understanding the true nature of beneficial mutations. Studies that address both the genetic basis and ecological consequences of adaptive mutations remain rare. Here, we characterize the direct and pleiotropic fitness effects of a collection of 21 first‐step beneficial mutants derived from naïve and adapted genotypes used in a long‐term experimental evolution of Escherichia coli. Whole‐genome sequencing was able to identify the majority of beneficial mutations. In contrast to previous studies, we find diverse fitness effects of mutations selected in a simple environment and few cases of genetic parallelism. The pleiotropic effects of these mutations were predominantly positive but some mutants were highly antagonistic in alternative environments. Further, the fitness effects of mutations derived from the adapted genotypes were dramatically reduced in nearly all environments. These findings suggest that many beneficial variants are accessible from a single point on the fitness landscape, and the fixation of alternative beneficial mutations may have dramatic consequences for niche breadth reduction via metabolic erosion.     

Evolution of Mutational Robustness in the Yeast Genome: A Link to Essential Genes and Meiotic Recombination Hotspots

Deleterious mutations inevitably emerge in any evolutionary process and are speculated to decisively influence the structure of the genome. Meiosis, which is thought to play a major role in handling mutations on the population level, recombines chromosomes via non-randomly distributed hot spots for meiotic recombination. In many genomes, various types of genetic elements are distributed in patterns that are currently not well understood. In particular, important (essential) genes are arranged in clusters, which often cannot be explained by a functional relationship of the involved genes. Here we show by computer simulation that essential gene (EG) clustering provides a fitness benefit in handling deleterious mutations in sexual populations with variable levels of inbreeding and outbreeding. We find that recessive lethal mutations enforce a selective pressure towards clustered genome architectures. Our simulations correctly predict (i) the evolution of non-random distributions of meiotic crossovers, (ii) the genome-wide anti-correlation of meiotic crossovers and EG clustering, (iii) the evolution of EG enrichment in pericentromeric regions and (iv) the associated absence of meiotic crossovers (cold centromeres). Our results furthermore predict optimal crossover rates for yeast chromosomes, which match the experimentally determined rates. Using a Saccharomyces cerevisiae conditional mutator strain, we show that haploid lethal phenotypes result predominantly from mutation of single loci and generally do not impair mating, which leads to an accumulation of mutational load following meiosis and mating. We hypothesize that purging of deleterious mutations in essential genes constitutes an important factor driving meiotic crossover. Therefore, the increased robustness of populations to deleterious mutations, which arises from clustered genome architectures, may provide a significant selective force shaping crossover distribution. Our analysis reveals a new aspect of the evolution of genome architectures that complements insights about molecular constraints, such as the interference of pericentromeric crossovers with chromosome segregation.     

Rate of deleterious mutation and the distribution of its effects on fitness in vesicular stomatitis virus

Despite their importance, the parameters describing the spontaneous deleterious mutation process have not been well described in many organisms. If mutations are important for the evolution of every living organism, their importance becomes critical in the case of RNA-based viruses, in which the frequency of mutation is orders of magnitude larger than in DNA-based organisms. The present work reports minimum estimates of the deleterious mutation rate, as well as the characterization of the distribution of deleterious mutational effects on the total fitness of the vesicular stomatitis virus (VSV). The estimates are based on mutation-accumulation experiments in which selection against deleterious mutations was minimized by recurrently imposing genetic bottlenecks of size one. The estimated deleterious mutation rate was 1.2 mutations per genome and generation, with a mean fitness effect of –0.39% per generation. At the end of the mutation-accumulation experiment, the average reduction in fitness was 38% and the distribution of accumulated deleterious effects was, on average, left-skewed. The magnitude of the skewness depends on the initial fitness of the clone analysed. The implications of our findings for the evolutionary biology of RNA viruses are discussed.     

Deleterious Mutations, Apparent Stabilizing Selection and the Maintenance of Quantitative Variation

Apparent stabilizing selection on a quantitative trait that is not causally connected to fitness can result from the pleiotropic effects of unconditionally deleterious mutations, because as N. Barton noted, "...individuals with extreme values of the trait will tend to carry more deleterious alleles...." We use a simple model to investigate the dependence of this apparent selection on the genomic deleterious mutation rate, U; the equilibrium distribution of K, the number of deleterious mutations per genome; and the parameters describing directional selection against deleterious mutations. Unlike previous analyses, we allow for epistatic selection against deleterious alleles. For various selection functions and realistic parameter values, the distribution of K, the distribution of breeding values for a pleiotropically affected trait, and the apparent stabilizing selection function are all nearly Gaussian. The additive genetic variance for the quantitative trait is kQa2, where k is the average number of deleterious mutations per genome, Q is the proportion of deleterious mutations that affect the trait, and a2 is the variance of pleiotropic effects for individual mutations that do affect the trait. In contrast, when the trait is measured in units of its additive standard deviation, the apparent fitness function is essentially independent of Q and a2; and beta, the intensity of selection, measured as the ratio of additive genetic variance to the "variance" of the fitness curve, is very close to s = U/k, the selection coefficient against individual deleterious mutations at equilibrium. Therefore, this model predicts appreciable apparent stabilizing selection if s exceeds about 0.03, which is consistent with various data. However, the model also predicts that beta must equal Vm/VG, the ratio of new additive variance for the trait introduced each generation by mutation to the standing additive variance. Most, although not all, estimates of this ratio imply apparent stabilizing selection weaker than generally observed. A qualitative argument suggests that even when direct selection is responsible for most of the selection observed on a character, it may be essentially irrelevant to the maintenance of variation for the character by mutation-selection balance. Simple experiments can indicate the fraction of observed stabilizing selection attributable to the pleiotropic effects of deleterious mutations.     

Stress-induced modulators of repeat instability and genome evolution

Evolution hinges on the ability of organisms to adapt to their environment. A key regulator of adaptability is mutation rate, which must be balanced to maintain genome fidelity while permitting sufficient plasticity to cope with environmental changes. Multiple mechanisms govern an organism's mutation rate. Constitutive mechanisms include mutator alleles that drive global, permanent increases in mutation rates, but these changes are confined to the subpopulation that carries the mutator allele. Other mechanisms focus mutagenesis in time and space to improve the chances that adaptive mutations can spread through the population. For example, environmental stress can induce mechanisms that transiently relax the fidelity of DNA repair to bring about a temporary increase in mutation rates during times when an organism experiences a reduced fitness for its surroundings, as has been demonstrated for double-strand break repair in Escherichia coli. Still, other mechanisms control the spatial distribution of mutations by directing changes to especially mutable sequences in the genome. In eukaryotic cells, for example, the stress-sensitive chaperone Hsp90 can regulate the length of trinucleotide repeats to fine-tune gene function and can regulate the mobility of transposable elements to enable larger functional changes. Here, we review the regulation of mutation rate, with special emphasis on the roles of tandem repeats and environmental stress in genome evolution.     

Evolutionary dynamics of tumor progression with random fitness values

Most human tumors result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Mutations that confer a fitness advantage to the cell are known as driver mutations and are causally related to tumorigenesis. Other mutations, however, do not change the phenotype of the cell or even decrease cellular fitness. While much experimental effort is being devoted to the identification of the functional effects of individual mutations, mathematical modeling of tumor progression generally considers constant fitness increments as mutations are accumulated. In this paper we study a mathematical model of tumor progression with random fitness increments. We analyze a multi-type branching process in which cells accumulate mutations whose fitness effects are chosen from a distribution. We determine the effect of the fitness distribution on the growth kinetics of the tumor. This work contributes to a quantitative understanding of the accumulation of mutations leading to cancer.     

Distributions of beneficial fitness effects in RNA

Beneficial mutations are the driving force of evolution by natural selection. Yet, relatively little is known about the distribution of the fitness effects of beneficial mutations in populations. Recent work of Gillespie and Orr suggested some of the first generalizations for the distributions of beneficial fitness effects and, surprisingly, they depend only weakly on biological details. In particular, the theory suggests that beneficial mutations obey an exponential distribution of fitness effects, with the same exponential parameter across different regions of genotype space, provided only that few possible beneficial mutations are available to that genotype. Here we tested this hypothesis with a quasi-empirical model of RNA evolution in which fitness is based on the secondary structures of molecules and their thermodynamic stabilities. The fitnesses of randomly selected genotypes appeared to follow a Gumbel-type distribution and thus conform to a basic assumption of adaptation theory. However, the observed distributions of beneficial fitness effects conflict with specific predictions of the theory. In particular, the distributions of beneficial fitness effects appeared exponential only when the vast majority of small-effect beneficial mutations were ignored. Additionally, the distribution of beneficial fitness effects varied with the fitness of the parent genotype. We believe that correlation of the fitness values among similar genotypes is likely the cause of the departure from the predictions of recent adaptation theory. Although in conflict with the current theory, these results suggest that more complex statistical generalizations about beneficial mutations may be possible.     

The contribution of the mitochondrial genome to sex‐specific fitness variance

Maternal inheritance of mitochondrial DNA (mtDNA) facilitates the evolutionary accumulation of mutations with sex‐biased fitness effects. Whereas maternal inheritance closely aligns mtDNA evolution with natural selection in females, it makes it indifferent to evolutionary changes that exclusively benefit males. The constrained response of mtDNA to selection in males can lead to asymmetries in the relative contributions of mitochondrial genes to female versus male fitness variation. Here, we examine the impact of genetic drift and the distribution of fitness effects (DFE) among mutations—including the correlation of mutant fitness effects between the sexes—on mitochondrial genetic variation for fitness. We show how drift, genetic correlations, and skewness of the DFE determine the relative contributions of mitochondrial genes to male versus female fitness variance. When mutant fitness effects are weakly correlated between the sexes, and the effective population size is large, mitochondrial genes should contribute much more to male than to female fitness variance. In contrast, high fitness correlations and small population sizes tend to equalize the contributions of mitochondrial genes to female versus male variance. We discuss implications of these results for the evolution of mitochondrial genome diversity and the genetic architecture of female and male fitness.     

Negative clonal selection in tumor evolution

Development of cancer requires the acquisition of multiple oncogenic mutations and selection of the malignant clone. Cancer evolves within a finite host lifetime and mechanisms of carcinogenesis that accelerate this process may be more likely to contribute to the development of clinical cancers. Mutator mutations are mutations that affect genome stability and accelerate the acquisition of oncogenic mutations. However, mutator mutations will also accelerate the accumulation of mutations that decrease cell proliferation, increase apoptosis, or affect other key fitness parameters. These "reduced-fitness" mutations may mediate "negative clonal selection," i.e., selective elimination of premalignant mutator clones. Target reduced-fitness loci may be "recessive" (both copies must be mutated to reduce fitness) or "dominant" (single-copy mutation reduces fitness). A direct mathematical analysis is applied to negative clonal selection, leading to the conclusion that negative clonal selection against mutator clones is unlikely to be a significant effect under realistic conditions. In addition, the relative importance of dominant and recessive reduced-fitness mutations is quantitatively defined. The relative predominance of mutator mutations in clinical cancers will depend on several variables, including the tolerance of the genome for reduced-fitness mutations, particularly the number and potency of dominant reduced-fitness loci.     

Effects of genotype on rates of substitution during experimental evolution

Rates of molecular evolution may vary widely between populations, yet the causes of this variation are still incompletely understood. Genetic differences between populations may make an important contribution to variation in rates of evolution, owing to differences in fitness, population size, mutation rates, or in the distribution of fitness effects (DFEs) of available beneficial mutations. By whole genome sequencing of Escherichia coli populations experimentally evolved in the presence of a quinolone antibiotic, we found that rates of substitution varied by genotype, with evidence for a contribution from a genotype's starting fitness. Subsequent targeted sequencing showed that genotypes with high average substitution rates were more likely to undergo the simultaneous fixation of several mutations, consistent with theoretical models of multiple mutation dynamics. Moreover, patterns of substitution were indicative of epistatic relationships between known resistance mutations.     

A resolution of the mutation load paradox in humans

Current information on the rate of mutation and the fraction of sites in the genome that are subject to selection suggests that each human has received, on average, at least two new harmful mutations from its parents. These mutations were subsequently removed by natural selection through reduced survival or fertility. It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation () for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10's or even 100's of new deleterious mutations per genome each generation.     

Note on the computation of critical effective population sizes.

This work extends the work of Whitlock in examining the critical effective population sizes from the fixation of both deleterious and beneficial mutations under drift and selection to prevent mutation breakdown of the population. The validity of approximations for the probability of fixation depends on the nature of the assumed distribution for the fitness effect of both types of mutations. Using no approximation for the probability of fixation and assuming a heavy tailed fitness effect distribution, the current model indicates that the coefficients of variation for the fitness effect distributions of both types of mutations and the fitness effect distribution mean for the beneficial mutations are important predictors of the critical effective population size. The current model further predicts that very small populations can be sustained if the fitness effect variances for both types of mutations and the mean for beneficial mutations are large.     

Fitness change in relation to mutation number in spontaneous mutation accumulation lines of Chlamydomonas reinhardtii

Although all genetic variation ultimately stems from mutations, their properties are difficult to study directly. Here, we used multiple mutation accumulation (MA) lines derived from five genetic backgrounds of the green algae Chlamydomonas reinhardtii that have been previously subjected to whole genome sequencing to investigate the relationship between the number of spontaneous mutations and change in fitness from a nonevolved ancestor. MA lines were on average less fit than their ancestors and we detected a significantly negative correlation between the change in fitness and the total number of accumulated mutations in the genome. Likewise, the number of mutations located within coding regions significantly and negatively impacted MA line fitness. We used the fitness data to parameterize a maximum likelihood model to estimate discrete categories of mutational effects, and found that models containing one to two mutational effect categories (one neutral and one deleterious category) fitted the data best. However, the best‐fitting mutational effects models were highly dependent on the genetic background of the ancestral strain.