On the evolutionary advantage of fitness-associated recombination

The adaptive value of recombination remains something of a puzzle. One of the basic problems is that recombination not only creates new and advantageous genetic combinations, but also breaks down existing good ones. A negative correlation between the fitness of an individual and its recombination rate would result in prolonged integrity of fitter genetic combinations while enabling less fit ones to produce new combinations. Such a correlation could be mediated by various factors, including stress responses, age, or direct DNA damage. For haploid population models, we show that an allele for such fitness-associated recombination (FAR) can spread both in asexual populations and in populations reproducing sexually at any uniform recombination rate. FAR also carries an advantage for the population as a whole, resulting in a higher average fitness at mutation-selection balance. These results are demonstrated in populations adapting to new environments as well as in well-adapted populations coping with deleterious mutations. Current experimental results providing evidence for the existence of FAR in nature are discussed.     

Prisoner's dilemma posed by fitness-associated recombination strategies

Genetic recombination is a central and repeated topic of study in the evolution of life. However, along with the influence of recombination on evolution, we understand surprisingly little of how selection shapes the nature of recombination. One explanation for recombination is that it allows organisms to escape from perilous situations where they experience very low fitness. As a corollary, it has been suggested that selection should favor recombination at low fitness and not at high fitness (fitness-associated recombination, FAR), and theory suggests that such strategies can indeed be selected. Here we develop models to further investigate the evolution of FAR. Consistent with previous works, we find that FAR can invade and dominate over a strategy of uniform recombination that is independent of fitness. However, our simulation results suggest that extreme FAR strategies, known as group-elitism, are not necessarily superior to other FAR strategies. Moreover, we argue that FAR domination will often occur with a net loss of mean population fitness. Interestingly, this suggests that the strategy of not recombining at high fitness will sometimes be analogous to a defector strategy from the famous "prisoner's dilemma" game: a selfish strategy that is selected but leads to a loss of mean fitness for all players.     

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.     

Correlation between recombination frequency and fitness in Drosophila melanogaster

The origin and maintenance of genetic recombination are unsettled evolutionary issues. Genetic variation affecting recombination frequency appears to be pervasive in nature, suggesting that natural selection must increase recombination frequency under some circumstances. However, theoretical arguments and experimental evidence indicate that the frequency of recombination should be reduced by natural selection.A hypothesis not previously explored is that recombination modifiers may directly affect the fitness of their carriers; rather than only indirectly (through the production of recombinant progeny) as generally assumed. We have tested this hypothesis by examining three fitness components (viability, male fertility, and female fecundity) in Drosophila melanogaster homozygous for second chromosomes isolated from a natural population. Then, we have measured the frequency of recombination in flies heterozygous for each wild second chromosome and a chromosome carrying five recessive alleles.The results indicate that genes modulating the frequency of recombination have direct effects on fitness as proposed by the hypothesis. However, the correlation between frequency of recombination and fitness is negative. Thus, the riddle of recombination remains unexplained and, in fact, more puzzling that ever.     

Intraspecific hybridization and the recovery of fitness in the native legume Chamaecrista fasciculata

Genetic incompatibilities and low offspring fitness are characteristic outcomes of hybridization between species. Yet, the creative potential of recombination following hybridization continues to be debated. Here we quantify the outcome of hybridization and recombination between adaptively divergent populations of the North American legume Chamaecrista fasciculata in a large-scale field experiment. Previously, hybrids between these populations demonstrated hybrid breakdown, suggesting the expression of adaptive epistatic interactions underlying population genetic differentiation. However, the outcome of hybridization ultimately rests on the performance of even later generation recombinants. In experiments that compared the performance of recombinant F6 and F2 generations with nonrecombinant F1 and parental genotypes, we observed that increasing recombination had contrasting effects on different life-history components. Lifetime fitness, defined as the product of survivorship and reproduction, showed a strong recovery of fitness in the F6. The overall gain in fitness with increased recombination suggests that hybridization and recombination may provide the necessary genetic variation for adaptive evolution within species. We discuss the mechanisms that may account for the gain in fitness with recombination, and explore the implications for hybrid speciation and phenotypic evolution.     

Recombination Accelerates Adaptation on a Large-Scale Empirical Fitness Landscape in HIV-1

Recombination has the potential to facilitate adaptation. In spite of the substantial body of theory on the impact of recombination on the evolutionary dynamics of adapting populations, empirical evidence to test these theories is still scarce. We examined the effect of recombination on adaptation on a large-scale empirical fitness landscape in HIV-1 based on in vitro fitness measurements. Our results indicate that recombination substantially increases the rate of adaptation under a wide range of parameter values for population size, mutation rate and recombination rate. The accelerating effect of recombination is stronger for intermediate mutation rates but increases in a monotonic way with the recombination rates and population sizes that we examined. We also found that both fitness effects of individual mutations and epistatic fitness interactions cause recombination to accelerate adaptation. The estimated epistasis in the adapting populations is significantly negative. Our results highlight the importance of recombination in the evolution of HIV-I.     

Mutation-selection balance and the evolutionary advantage of sex and recombination

Mutation-selection balance in a multi-locus system is investigated theoretically, using a modification of Bulmer's infinitesimal model of selection on a normally-distributed quantitative character, taking the number of mutations per individual (n) to represent the character value. The logarithm of the fitness of an individual with n mutations is assumed to be a quadratic, decreasing function of n. The equilibrium properties of infinitely large asexual populations, random-mating populations lacking genetic recombination, and random-mating populations with arbitrary recombination frequencies are investigated. With 'synergistic' epistasis on the scale of log fitness, such that log fitness declines more steeply as n increases, it is shown that equilibrium mean fitness is least for asexual populations. In sexual populations, mean fitness increases with the number of chromosomes and with the map length per chromosome. With 'diminishing returns' epistasis, such that log fitness declines less steeply as n increases, mean fitness behaves in the opposite way. Selection on asexual variants and genes affecting the rate of genetic recombination in random-mating populations was also studied. With synergistic epistasis, zero recombination always appears to be disfavoured, but free recombination is disfavoured when the mutation rate per genome is sufficiently small, leading to evolutionary stability of maps of intermediate length. With synergistic epistasis, an asexual mutant is unlikely to invade a sexual population if the mutation rate per diploid genome greatly exceeds unity. Recombination is selectively disadvantageous when there is diminishing returns epistasis. These results are compared with the results of previous theoretical studies of this problem, and with experimental data.     

On the evolution of recombination and meiosis.

Theories on the evolution of recombination in regard to its ability to increase mean fitness require a consistent source of negative linkage disequilibrium among loci affecting fitness to show an advantage to recombination. Here we present evidence that, at least theoretically, genetic variation for recombination can spread in very large populations under a strictly multiplicative-fitness, deleterious-allele model. The model uses only Mendelian genetics in a multi-locus context to show that a dominant gene for recombination can spread when rare and resist invasion when common. In non-equilibrium populations driven by Muller's ratchet, the gene increases its probability of fixation by increasing the probability of being associated with the best individuals. This occurs at an optimal level of recombination. Its action results in both an immediate and a long-term advantage to recombination amongst the proto-meiotic organisms modelled. The genetic mechanism lends itself naturally to a model for the evolution of meiosis, where modern-day gametes are seen as derivative of ancient unicellular organisms.     

Long-term experimental evolution in Escherichia coli. V. Effects of recombination with immigrant genotypes on the rate of bacterial evolution

This study builds upon an earlier experiment that examined the dynamics of mean fitness in evolving populations of Escherichia coli in which mutations were the sole source of genetic variation. During thousands of generations in a constant environment, the rate of improvement in mean fitness of these asexual populations slowed considerably from an initially rapid pace. In this study, we sought to determine whether sexual recombination with novel genotypes would reaccelerate the rate of adaption in these populations. To that end, treatment populations were propagated for an additional 1000 generations in the same environment as their ancestors, but they were periodically allowed to mate with an immigrant pool of genetically distinct Hfr (high frequency recombination) donors. These donors could transfer genes to the resident populations by conjugation, but the donors themselves could not grow in the experimental environment. Control populations were propagated under identical conditions, but in the absence of sexual recombination with the donors. All twelve control populations retained the ancestral alleles at every locus that was scored. In contrast, the sexual recombination treatment yielded dramatic increases in genetic variation. Thus, there was a profound effect of recombination on the rate of genetic change. However, the increased genetic variation in the treatment populations had no significant effect on the rate of adaptive evolution, as measured by changes in mean fitness relative to a common competitor. We then considered three hypotheses that might reconcile these two outcomes: recombination pressure, hitchhiking of recombinant genotypes in association with beneficial mutations, and complex selection dynamics whereby certain genotypes may have a selective advantage only within a particular milieu of competitors. The estimated recombination rate was too low to explain the observed rate of genetic change, either alone or in combination with hitchhiking effects. However, we documented comple x ecological interactions among some recombinant genotypes, suggesting that our method for estimating fitness relative to a common competitor might have underestimated the rate of adaptive evolution in the treatment populations.     

Selection for recombination in partially self-fertilizing populations

This paper confirms Holden's (1979) suggestion that certain types of fitness interactions between a pair of loci in partially self-fertilizing populations may promote selection for increased recombination between them. Our results are based on both algebraic and computer calculations of the fate of alleles at a third locus, which control the level of recombination between the selected pair. We also show that the behavior of the population mean fitness as a function of recombination fraction is not necessarily an indicator of the direction of selection on recombination in partially selfing populations.     

The Effect of Bacterial Recombination on Adaptation on Fitness Landscapes with Limited Peak Accessibility

There is ample empirical evidence revealing that fitness landscapes are often complex: the fitness effect of a newly arisen mutation can depend strongly on the allelic state at other loci. However, little is known about the effects of recombination on adaptation on such fitness landscapes. Here, we investigate how recombination influences the rate of adaptation on a special type of complex fitness landscapes. On these landscapes, the mutational trajectories from the least to the most fit genotype are interrupted by genotypes with low relative fitness. We study the dynamics of adapting populations on landscapes with different compositions and numbers of low fitness genotypes, with and without recombination. Our results of the deterministic model (assuming an infinite population size) show that recombination generally decelerates adaptation on these landscapes. However, in finite populations, this deceleration is outweighed by the accelerating Fisher-Muller effect under certain conditions. We conclude that recombination has complex effects on adaptation that are highly dependent on the particular fitness landscape, population size and recombination rate.     

Evolution in Saccharomyces cerevisiae: identification of mutations increasing fitness in laboratory populations

Since the publication of the complete sequence of the genome of Saccharomyces cerevisiae, a number of comprehensive investigations have been initiated to gain insight into cellular function. The focus of these studies has been to identify genes essential for survival in specific environments or those that when mutated cause gross phenotypic defects in growth. Here we describe Ty1-based mutational approaches designed to identify genes, which when mutated generate evolutionarily significant phenotypes causing small but positive increments on fitness. As expected, Ty1 mutations with a positive fitness effect were in the minority. However, mutations in two loci, one inactivating FAR3 and one upstream of CYR1, identified in evolving populations, were shown to have small but significantly positive fitness effects.     

Linkage Modification with Mixed Random Mating and Selfing: A Numerical Study

Although recombination cannot increase under conditions of random mating or complete selfing in regimes of constant selection, with mixed random mating and selfing, selection for increased recombination can occur. For some fitness regimes there may be selection for reduced recombination with both low and high degrees of selfing but selection for increased recombination with moderate degrees of selfing. With some fitness regimes there is a historical effect: depending on which equilibrium a population starts from, there may be selection for either increased or decreased recombination. In other cases the direction of selection may be determined by the present state of individuals within the population. If recombination is already fairly limited, there may be selection for further reduction. If recombination is already fairly frequent, there may be selection for increased recombination. For certain symmetric viability systems there may be an intermediate value of the recombination fraction between 0 and 0.5 toward which the population will evolve. Although it is not yet possible to classify precisely those fitness matrices that can exhibit selection for increased recombination, it does appear that selection for increased recombination can occur only if at least two of the double homozygotes are less fit than would be expected on the basis of a comparison of the fitnesses of the single and double heterozygotes on an additive scale.     

Mammalian wax biosynthesis. I. Identification of two fatty acyl-Coenzyme A reductases with different substrate specificities and tissue distributions

The conversion of fatty acids to fatty alcohols is required for the synthesis of wax monoesters and ether lipids. The mammalian enzymes that synthesize fatty alcohols have not been identified. Here, an in silico approach was used to discern two putative reductase enzymes designated FAR1 and FAR2. Expression studies in intact cells showed that FAR1 and FAR2 cDNAs encoded isozymes that reduced fatty acids to fatty alcohols. Fatty acyl-CoA esters were the substrate of FAR1, and the enzyme required NADPH as a cofactor. FAR1 preferred saturated and unsaturated fatty acids of 16 or 18 carbons as substrates, whereas FAR2 preferred saturated fatty acids of 16 or 18 carbons. Confocal light microscopy indicated that FAR1 and FAR2 were localized in the peroxisome. The FAR1 mRNA was detected in many mouse tissues with the highest level found in the preputial gland, a modified sebaceous gland. The FAR2 mRNA was more restricted in distribution and most abundant in the eyelid, which contains wax-laden meibomian glands. Both FAR mRNAs were present in the brain, a tissue rich in ether lipids. The data suggest that fatty alcohol synthesis in mammals is accomplished by two fatty acyl-CoA reductase isozymes that are expressed at high levels in tissues known to synthesize wax monoesters and ether lipids.     

Far3 and five interacting proteins prevent premature recovery from pheromone arrest in the budding yeast Saccharomyces cerevisiae

In budding yeast, diffusible mating pheromones initiate a signaling pathway that culminates in several responses, including cell cycle arrest. Only a handful of genes required for the interface between pheromone response and the cell cycle have been identified, among them FAR1 and FAR3; of these, only FAR1 has been extensively characterized. In an effort to learn about the mechanism by which Far3 acts, we used the two-hybrid method to identify interacting proteins. We identified five previously uncharacterized open reading frames, dubbed FAR7, FAR8, FAR9, FAR10, and FAR11, that cause a far3-like pheromone arrest defect when disrupted. Using two-hybrid and coimmunoprecipitation analysis, we found that all six Far proteins interact with each other. Moreover, velocity sedimentation experiments suggest that Far3 and Far7 to Far11 form a complex. The phenotype of a sextuple far3far7-far11 mutant is no more severe than any single mutant. Thus, FAR3 and FAR7 to FAR11 all participate in the same pathway leading to G1 arrest. These mutants initially arrest in response to pheromone but resume budding after 10 h. Under these conditions, wild-type cells fail to resume budding even after several days whereas far1 mutant cells resume budding within 1 h. We conclude that the FAR3-dependent arrest pathway is functionally distinct from that which employs FAR1.     

Synthetic shuffling and in vitro selection reveal the rugged adaptive fitness landscape of a kinase ribozyme

The relationship between genotype and phenotype is often described as an adaptive fitness landscape. In this study, we used a combination of recombination, in vitro selection, and comparative sequence analysis to characterize the fitness landscape of a previously isolated kinase ribozyme. Point mutations present in improved variants of this ribozyme were recombined in vitro in more than 10¹⁴ different arrangements using synthetic shuffling, and active variants were isolated by in vitro selection. Mutual information analysis of 65 recombinant ribozymes isolated in the selection revealed a rugged fitness landscape in which approximately one-third of the 91 pairs of positions analyzed showed evidence of correlation. Pairs of correlated positions overlapped to form densely connected networks, and groups of maximally connected nucleotides occurred significantly more often in these networks than they did in randomized control networks with the same number of links. The activity of the most efficient recombinant ribozyme isolated from the synthetically shuffled pool was 30-fold greater than that of any of the ribozymes used to build it, which indicates that synthetic shuffling can be a rich source of ribozyme variants with improved properties.     

The ecology and genetics of fitness in Chlamydomonas. VIII. The dynamics of adaptation to novel environments after a single episode of sex

According to classical evolutionary theory, sexual recombination can generate the variation necessary to adapt to changing environments and thereby confer an evolutionary advantage of sexual over asexual reproduction. Using the green alga, Chlamydomonas reinhardtii, we investigated the effect of a single sexual episode on adaptation of heterotrophic growth on different carbon sources. In an initial mixture of isolates, sex was induced and the resulting offspring constituted the sexual populations, along with any unmated vegetative cells; the unmated mixture of isolates represented the asexual populations. Mean and variance in division rates (i.e., fitness) were measured four times during approximately 50 generations of vegetative growth in the dark on all possible combinations of four carbon sources. Consistent with effects of recombination of epistatic genes in linkage disequilibrium, sexual populations initially had a higher variance in fitness, but their mean fitness was lower than that of asexual populations, possibly due to recombinational load. Subsequently, fitness of sexual populations exceeded that of asexual ones, but finally they regained parity in both mean and variance of fitness. Although recombination was not more effective on more complex substrates, these results generally support the idea that sex can accelerate adaptation to novel environments.     

Hybridization,recombination, and the genetic basis of fitness variation across environments in <Emphasis Type="Italic">Avena barbata</Emphasis>

We created Recombinant Inbred Lines (RILs) derived from a cross between ecotypes of Avena barbata associated with moist (mesic) and dry (xeric) habitats in California. Traits which were correlated with fitness across RILs mapped to the same Quantitative Trait Loci (QTLs) as fitness. However, different QTL affected fitness in different environments so that fitness was weakly correlated across environments. Recombination released considerable heritable variation both in fitness, and in ecologically relevant traits. Many traits showed transgressive segregation caused by recombination of QTL associated in repulsion phase in the parents. In addition, some traits were uncorrelated, allowing novel combinations of those traits to be created. Recombination also created heritable variation in reaction norms for at least one trait (root allocation). Altogether these results suggest that recombination can combine the most selectively advantageous genes and traits of the parents to produce broadly adapted genotypes that are capable of outperforming the parents. Indeed, two of the RILs showed higher fitness than the parental ecotypes across a range of environmental treatments in the greenhouse, but their superiority was less pronounced in the field. Although late-generation recombinants exhibited hybrid breakdown, being less fit, on average, than the mid-parent, early generation hybrids appear to exhibit hybrid vigour through the expression of dominance effects in the heterozyotes. This vigour may offset the effects of hybrid breakdown in the early generations following a cross, enhancing the opportunity for recombination to create broadly adapted genotypes. We discuss the implications of these findings to the evolution of colonizing species.     

Imperfect Genes, Fisherian Mutation and the Evolution of Sex

In this paper we present a mathematical model of mutation and selection that allows for the coexistence of multiple alleles at a locus with very small selective differences between alleles. The model also allows for the determination of fitness by multiple loci. Models of this sort are biologically plausible. However, some previous attempts to construct similar models have assumed that all mutations produce a decrease in fitness, and this has led to a tendency for the average fitness of population members to decline when population numbers are finite. In our model we incorporate some of the ideas of R. A. FISHER, so that both deleterious and beneficial mutations are possible. As a result, average fitness tends to approach a stationary distribution. We have used computer simulation methods to apply the Fisherian mutation model to the problem of the evolution of sex and recombination. The results suggest that sex and recombination can provide very large benefits in terms of average fitness. The results also suggest that obligately sexual species will win ecological competitions with species that produce a substantial fraction of their offspring asexually, so long as the number of sites under selection within the genomes of the competing species is not too small and the population sizes are not too large. Our model focuses on fertility selection in an hermaphroditic plant. However, the results are likely to generalize to a wide variety of other situations as well.