The Evolution of Epistasis and the Advantage of Recombination in Populations of Bacteriophage T4

Experiments reported here test two hypotheses about the evolution of recombination: first, the Fisher-Muller concept that sexual organisms respond to selection more rapidly than do asexual ones, and second, that epistasis is more likely to evolve in the absence of recombination. Populations of bacteriophage T4 were selected by the drug proflavine in discrete generations and the change in mean population fitness was monitored. Three separate selection series yielded results supporting the Fisher-Muller hypothesis. The amount of epistasis evolved was measured by partitioning the T4 map into regions and comparing the sum of the proflavine resistances of each region with the resistance of the whole. Significantly more interactions were found in phage isolated from the populations with lower total recombination than in those from populations with higher recombination. The degree to which these experiments fit preconceived notions about natural selection suggests that microorganisms may be advantageously used in other population genetics experiments.     

Viruses and the Advantage of Sex in Anthoxanthum odoratum: A Review

Abstract The nature of the selective forces responsible for the maintenance of sexual reproduction in populations remains controversial. Theoreticians have proposed a variety of mechanisms to explain how sex is adaptive, including varying environments, sib competition, mutational damage, and pathogens. In a well-studied population of the short-lived, perennial grass Anthoxanthum odoratum in a mown North Carolina field, significant fitness advantages for sexual vs. asexual offspring have been shown. Evidence from two recent experiments implicates barley yellow dwarf luteovirus (BYDV), a single-stranded RNA virus, as a cause of the short-term advantage for sex in this population. When planted in sites close to parents, asexual offspring were twice as frequently infected as sexual offspring. In other sites, infection was more frequent among common than rare genotypes. Viruses possess a unique combination of features which make them plausible candidates to favor sexual reproduction in plants. Viruses are pervasive, have subtle but significant fitness effects, have the potential for rapid mutation and evolution, and are spread by vectors whose behaviors are host frequency dependent. The ecological and evolutionary consequences of viruses in plant populations deserve further study.     

Epistasis and the genetics of human diseases

Epistasis or modifier genes, that is, gene-gene interactions of non-allelic partners, play a major role in susceptibility to common human diseases. This old genetic concept has experienced a major renaissance recently. Interestingly, epistatic genes can make the disease less severe, or make it more severe. Hence, most diseases are of different intensities in different individuals and in different ethnicities. This phenomenon affects sickle-cell anemia carriers and other hemoglobinopathies, systemic lupus erythematosus, cystic fibrosis, complex autoimmune diseases, venous thromboembolism, and many others. It is likely, and fortunate, than 20 years form now, patients entering a medical facility will be subjected to a genomic scanning, including pathogenic genes as well as epistatic genes.     

Epistasis Detection via the Joint Cumulant

Statistics in Biosciences - Selecting influential non-linear interactive features from ultrahigh-dimensional data has been an important task in various fields. However, statistical accuracy and...     

Epistasis and the adaptability of an RNA virus

We have explored the patterns of fitness recovery in the vesicular stomatitis RNA virus. We show that, in our experimental setting, reversions to the wild-type genotype were rare and fitness recovery was at least partially driven by compensatory mutations. We compared compensatory adaptation for genotypes carrying (1) mutations with varying deleterious fitness effects, (2) one or two deleterious mutations, and (3) pairs of mutations showing differences in the strength and sign of epistasis. In all cases, we found that the rate of fitness recovery and the proportion of reversions were positively affected by population size. Additionally, we observed that mutations with large fitness effect were always compensated faster than mutations with small fitness effect. Similarly, compensatory evolution was faster for genotypes carrying a single deleterious mutation than for those carrying pairs of mutations. Finally, for genotypes carrying two deleterious mutations, we found evidence of a negative correlation between the epistastic effect and the rate of compensatory evolution.     

Transitory Derepression and the Maintenance of Conjugative Plasmids

It has been proposed that bacterial plasmids cannot be maintained by infectious transfer alone and that their persistence requires positive selection for plasmid-borne genes. To test this hypothesis, the population dynamics of two laboratory and five naturally occurring conjugative plasmids were examined in chemostat cultures of E. coli K-12. Both laboratory plasmids and three of the five wild plasmids failed to increase in frequency when introduced at low frequencies. However, two of the naturally occurring plasmids rapidly increased in frequency, and bacteria carrying them achieved dominance in the absence of selection for known plasmid-borne genes. Three hypotheses for the invasion and persistence of these two plasmids were examined. It is concluded that although these two extrachromosomal genetic elements are repressed for conjugative pili synthesis, as a consequence of high rates of transfer during periods of transitory derepression in newly formed transconjugants, they become established and are maintained by infectious transfer alone. The implications of these observations to the theory of plasmid maintenance and the evolution of repressible conjugative pili synthesis are discussed.     

Epistasis and hybrid sterility in Saccharomyces

Hybrid sterility is thought to be due to deleterious epistatic interactions between genes from different species. Here we demonstrate that dominant genic incompatibility does not contribute to sterility in hybrids between Saccharomyces cerevisiae and five closely related species. Sterile diploids were made fertile by genome doubling to produce hybrid tetraploids. Based on these and previous results, we conclude that neither genic incompatibility nor classical chromosomal speciation models apply.     

Positive Epistasis Drives the Acquisition of Multidrug Resistance

The evolution of multiple antibiotic resistance is an increasing global problem. Resistance mutations are known to impair fitness, and the evolution of resistance to multiple drugs depends both on their costs individually and on how they interact—epistasis. Information on the level of epistasis between antibiotic resistance mutations is of key importance to understanding epistasis amongst deleterious alleles, a key theoretical question, and to improving public health measures. Here we show that in an antibiotic-free environment the cost of multiple resistance is smaller than expected, a signature of pervasive positive epistasis among alleles that confer resistance to antibiotics. Competition assays reveal that the cost of resistance to a given antibiotic is dependent on the presence of resistance alleles for other antibiotics. Surprisingly we find that a significant fraction of resistant mutations can be beneficial in certain resistant genetic backgrounds, that some double resistances entail no measurable cost, and that some allelic combinations are hotspots for rapid compensation. These results provide additional insight as to why multi-resistant bacteria are so prevalent and reveal an extra layer of complexity on epistatic patterns previously unrecognized, since it is hidden in genome-wide studies of genetic interactions using gene knockouts.     

Epistasis between deleterious mutations and the evolution of recombination

Epistasis and the evolution of recombination are closely intertwined: epistasis generates linkage disequilibria (i.e. statistical associations between alleles), whereas recombination breaks them up. The mutational deterministic hypothesis (MDH) states that high recombination rates are maintained because the breaking up of linkage disequilibria generated by negative epistasis enables more efficient purging of deleterious mutations. However, recent theoretical and experimental work challenges the MDH. Experimental evidence suggests that negative epistasis, required by the MDH, is relatively uncommon. On the theoretical side, population genetic models suggest that, compared with the combined effects of drift and selection, epistasis generates a negligible amount of linkage disequilibria. Here, we assess these criticisms and discuss to what extent they invalidate the MDH as an explanation for the evolution of recombination.     

Complementation and Epistasis in Viral Coinfection Dynamics

Coinfection in RNA virus populations results in two important phenomena, complementation and recombination. Of the two, complementation has a strong effect on selection against deleterious mutations, as has been confirmed in earlier studies. As complementation delays the purging of less-fit mutations, coinfection may be detrimental to the evolution of a virus population. Here we employ both deterministic modeling and stochastic simulation to explore the mechanisms underlying the interactions between complementation and other evolutionary factors, namely, mutation, selection, and epistasis. We find that strong complementation reduces slightly the overall fitness of a virus population but substantially enhances its diversity and robustness, especially when interacting with selection and epistasis.     

Epistasis and the mutation load: a measurement-theoretical approach

An approximate solution for the mean fitness in mutation-selection balance with arbitrary order of epistatic interaction is derived. The solution is based on the assumptions of coupling equilibrium and that the interaction effects are multilinear. We find that the effect of m-order epistatic interactions (i.e., interactions among groups of m loci) on the load is dependent on the total genomic mutation rate, U, to the mth power. Thus, higher-order gene interactions are potentially important if U is large and the interaction density among loci is not too low. The solution suggests that synergistic epistasis will decrease the mutation load and that variation in epistatic effects will elevate the load. Both of these results, however, are strictly true only if they refer to epistatic interaction strengths measured in the optimal genotype. If gene interactions are measured at mutation-selection equilibrium, only synergistic interactions among even numbers of genes will reduce the load. Odd-ordered synergistic interactions will then elevate the load. There is no systematic relationship between variation in epistasis and load at equilibrium. We argue that empirical estimates of gene interaction must pay attention to the genetic background in which the effects are measured and that it may be advantageous to refer to average interaction intensities as measured in mutation-selection equilibrium. We derive a simple criterion for the strength of epistasis that is necessary to overcome the twofold disadvantage of sex.     

Epistasis and Its Implications for Personal Genetics

The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity.     

Necrotrophic Effector Epistasis in the Pyrenophora tritici-repentis-Wheat Interaction

Pyrenophora tritici-repentis, the causal agent of tan spot disease of wheat, mediates disease by the production of host-selective toxins (HST). The known toxins are recognized in an ‘inverse’ gene-for-gene manner, where each is perceived by the product of a unique locus in the host and recognition leads to disease susceptibility. Given the importance of HSTs in disease development, we would predict that the loss of any of these major pathogenicity factors would result in reduced virulence and disease development. However, after either deletion of the gene encoding the HST ToxA or, reciprocally, heterologous expression of ToxA in a race that does not normally produce the toxin followed by inoculation of ToxA-sensitive and insensitive wheat cultivars, we demonstrate that ToxA symptom development can be epistatic to other HST-induced symptoms. ToxA epistasis on certain ToxA-sensitive wheat cultivars leads to genotype-specific increases in total leaf area affected by disease. These data indicate a complex interplay between host responses to HSTs in some genotypes and underscore the challenge of identifying additional HSTs whose activity may be masked by other toxins. Also, through mycelial staining, we acquire preliminary evidence that ToxA may provide additional benefits to fungal growth in planta in the absence of its cognate recognition partner in the host.     

King's Formula for the Mutation Load with Epistasis

A formula by J. L. King gives the equilibrium mutation load as L = 2 sigma ui(1 - qi)/z - x) in which ui is the mutation rate to deleterious alleles at the ith locus, qi is the frequency of mutant alleles at this locus, x is the mean number of such mutant genes per individual before selection, z is the mean number in individuals eliminated by selection, and the summation is over all relevant loci. We show that this rule is inaccurate for intense selection and that a correct formula is L = 2 sigma ui(1 - qi) w/(z - x) = 2U w/(z - x) = 2U/(z - x + 2U) in which U is the mean number of new mutations per haploid genome in the population and w is the mean relative fitness before selection. If w/(z - x) less than 1/2, the mutation load is less than the Haldane value (U less than or equal to L less than or equal to 2U) and can be considerably less. In a diploid asexual population, however, with independent occurrence of mutations, L = 1 - e-2U regardless of the mode of selection.