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Measuring epistasis in fitness landscapes: the correlation of fitness effects of mutations

Genotypic fitness landscapes are constructed by assessing the fitness of all possible combinations of a given number of mutations. In the last years, several experimental fitness landscapes have been completely resolved. As fitness landscapes are high-dimensional, simple measures of their structure are used as statistics in empirical applications. Epistasis is one of the most relevant features of fitness landscapes. Here we propose a new natural measure of the amount of epistasis based on the correlation of fitness effects of mutations. This measure has a natural interpretation, captures well the interaction between mutations and can be obtained analytically for most landscape models. We discuss how this measure is related to previous measures of epistasis (number of peaks, roughness/slope, fraction of sign epistasis, Fourier-Walsh spectrum) and how it can be easily extended to landscapes with missing data or with fitness ranks only. Furthermore, the dependence of the correlation of fitness effects on mutational distance contains interesting information about the patterns of epistasis. This dependence can be used to uncover the amount and nature of epistatic interactions in a landscape or to discriminate between different landscape models.

Evolutionary Biology

Core Genes Evolve Rapidly in the Long-term Evolution Experiment with Escherichia coli

Bacteria can evolve rapidly under positive selection owing to their vast numbers, allowing their genes to diversify by adapting to different environments. We asked whether the same genes that are fast evolving in the long-term evolution experiment with Escherichia coli (LTEE) have also diversified extensively in nature. We identified ~2000 core genes shared among 60 E. coli strains. During the LTEE, core genes accumulated significantly more nonsynonymous mutations than flexible (i.e., noncore) genes. Furthermore, core genes under positive selection in the LTEE are more conserved in nature than the average core gene. In some cases, adaptive mutations appear to fine-tune protein functions, rather than merely knocking them out. The LTEE conditions are novel for E. coli, at least in relation to the long sweep of its evolution in nature. The constancy and simplicity of the environment likely favor the complete loss of some unused functions and the fine-tuning of others.\n\nCompeting Interests StatementWe, the authors, declare that we have no conflicts of interest.

Evolutionary Biology

Evolution in Eggs and Phases: experimental evolution of fecundity and reproductive timing in Caenorhabditis elegans

To examine the role of natural selection on fecundity in a variety of Caenorhabditis elegans genetic backgrounds, we used an experimental evolution protocol to evolve 14 distinct genetic strains over 15-20 generations. Beginning with three founder worms for each strain, we were able to generate 790 distinct genealogies, which provided information on both the effects of natural selection and the evolvability of each strain. Among these genotypes are a wildtype (N2) and a collection of mutants with targeted mutations in the daf-c, daf-d, and AMPK pathways. The overarching goal of our analysis is two-fold: to observe differences in reproductive fitness and observe related changes in reproductive timing. This yields two outcomes. The first is that the majority of selective effects on fecundity occur during the first few generations of evolution, while the negative selection for reproductive timing occurs on longer timescales. The second finding reveals that positive selection on fecundity results in positive and negative selection on reproductive timing, both of which are strain-dependent. Using a derivative of population size per generation called the reproductive carry-over (RCO) measure, it is found that the fluctuation and shape of the probability distribution may be informative in terms of developmental selection. While these consist of general patterns that transcend mutations in a specific gene, changes in the RCO measure may nevertheless be products of selection. In conclusion, we discuss the broader implications of these findings, particularly in the context of genotype-fitness maps and the role of uncharacterized mutations in individual variation and evolvability.

Evolutionary Biology

Assortative mating can impede or facilitate fixation of underdominant alleles

Although underdominant mutations have undoubtedly fixed between divergent species, classical models of population genetics suggest underdominant alleles should be purged quickly, except in small or subdivided populations. Here we study the fixation of underdominant alleles at loci that also influence mate choice, such as loci encoding coloration patterns visible to mates and predators alike. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans the two classical extremes of random mating (n = 1) and complete assortment (n [->] {infty}), and yet it produces a complex form of sexual selection that depends non-monotonically on the number of mating opportunities, n. The resulting interaction between viability selection and sexual selection can either inhibit or facilitate fixation of underdominant alleles, compared to random mating. As the number of mating opportunities increases, underdominant alleles can fix at rates that even approach the neutral substitution rate. This result is counterintuitive because sexual selection and underdominance each suppress rare alleles in this model, and yet in combination they can promote the fixation of rare alleles. This phenomenon constitutes a new mechanism for the fixation of underdominant alleles in large populations, and it illustrates how incorporating life history characteristics can alter the predictions of population-genetic models for evolutionary change.

Evolutionary Biology

Transposable Element Evolution in the Allotetraploid Capsella bursa-pastoris

Premise of the studyShifts in ploidy affect the evolutionary dynamics of genomes in a myriad of ways. Population genetic theory predicts that transposable element (TE) proliferation may follow because the genome wide efficacy of selection should be reduced and the increase in gene copies may mask the deleterious effects of TE insertions. Moreover, in allopolyploids TEs may further accumulate because of hybrid breakdown of TE silencing. However, to date the evidence of TE proliferation following an increase in ploidy is mixed, and the relative importance of relaxed selection vs. silencing breakdown remains unclear.\n\nMethodsWe used high-coverage whole genome sequence data to evaluate the abundance, genomic distribution, and population frequencies of TEs in the self-fertilizing recent allotetraploid Capsella bursa-pastoris (Brassicaceae). We then compared the C. bursa-pastoris TE profile with that of its two parental diploid species, outcrossing C. grandiflora and self-fertilizing C. orientalis.\n\nKey resultsWe found no evidence that C. bursa-pastoris has experienced a large genome wide proliferation of TEs relative to its parental species. However, when centromeric regions are excluded, we find evidence of significantly higher abundance of retrotransposons in C. bursa-pastoris along the gene-rich chromosome arms, compared to C.grandiflora and C. orientalis.\n\nConclusionsThe lack of a genome-wide effect of allopolyploidy on TE abundance, combined with the increases TE abundance in gene-rich regions suggest that relaxed selection rather than hybrid breakdown of host silencing explains the TE accumulation in C. bursa-pastoris

Evolutionary Biology

Horizontal transfer in bacterial Methionyl tRNA synthetase is very common shown by Genus and phyla level phylogenetic analysis.

Methionyl tRNA synthetase is single copy informational gene in Salmonella typhimurium. Informational genes are more conserved than operational genes. In this study we had analyzed HGT events within MetG sequences of different bacterial genera. A species tree based on 16srRNA sequences of the same genus was drawn evaluated against the generally accepted species tree of the bacteria. MetG phylogenetic tree was evaluated against the 16srRNAS tree and HGT event identified. Similarly phyla trees were made and HGT event identified. 24 HGT events were identified between genus and 11 within phyla. MetG is a considered as conserved gene finding so many HGT event in this gene indicate that horizontal gene transfer is very common in this gene. Manual tree making for phyla could help to understand phylogenetic relationships between very large trees.

Evolutionary Biology

Resolving the conflict between associative overdominance and background selection

In small populations, genetic linkage between a polymorphic neutral locus and loci subject to selection, either against partially recessive mutations or in favor of heterozygotes, may result in an apparent selective advantage to heterozygotes at the neutral locus (associative overdominance), and a retardation of the rate of loss of variability by genetic drift at this locus. In large populations, selection against deleterious mutations has previously been shown to reduce variability at linked neutral loci (background selection). We describe analytical, numerical and simulation studies that shed light on the conditions under which retardation versus acceleration of loss of variability occurs at a neutral locus linked to a locus under selection. We consider a finite, randomly mating population initiated from an infinite population in equilibrium at a locus under selection, with no linkage disequilibrium. With mutation and selection, retardation only occurs when S, the product of twice the effective population size and the selection coefficient, is of order one. With S >> 1, background selection always causes an acceleration of loss of variability. Apparent heterozygote advantage at the neutral locus is, however, always observed when mutations are partially recessive, even if there is an accelerated rate of loss of variability. With heterozygote advantage at the selected locus, there is nearly always a retardation of loss of variability. The results shed light on experiments on the loss of variability at marker loci in laboratory populations, and on the results of computer simulations of the effects of multiple selected loci on neutral variability.

Evolutionary Biology

Have coral snake mimics diversified more than non-mimics?

Dipsadidae is the most diversified family of snakes, composed of species showing an impressive variety of color patterns. Some species are cryptic whereas others have contrasting patterns comprised by bright colors alternated with darker shades, including particular combinations of vivid colors characteristic of coral snakes (Elapidae). Species with such patterns are thought to be mimics of coral snakes based on their color pattern similarity, predator avoidance of such patterns in field experiments, and the geographical concordance between models and mimics. Here we test whether color patterns associated with coral snake mimicry and contrasting color patterns in general influenced the diversification dynamics of the group. We compile the largest database of color patterns among reptiles to date, with color descriptions for the majority (594 species) of dipsadids. We used trait-dependent diversification models along with extensive simulations to deal with the recently described statistical bias associated with such methods. Despite the apparent survival advantage associated with coral snake mimicry, we show that there is no detectable influence of color types in the dynamics of diversification in Dipsadidae. We discuss insights into the function of color patterns and argue that non-mimic contrasting patterns might serve as pre-adaptations to mimicry of coral snakes.\n\nData archival locationBEAST XML file and BiSSE MCMC results: http://dx.doi.org/10.6084/m9.figshare.831493\n\nR code for analyses and simulations: https://github.com/Caetanods/Dipsadidae_color_evolution

Evolutionary Biology

Positive selection on a regulatory insertion-deletion polymorphism in FADS2 influences apparent endogenous synthesis of arachidonic acid

Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22 bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the U.S. A much higher I/I genotype frequency was found in Indians (68%) than in the U.S. (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African and some East Asian populations. Basal plasma phospholipid arachidonic acid status was 8% greater in I/I compared to D/D individuals. The biochemical pathway product-precursor difference, arachidonic acid minus linoleic acid, was 31% and 13% greater for I/I and I/D compared to D/D, respectively. Our study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

Evolutionary Biology

Does linked selection explain the narrow range of genetic diversity across species?

The relatively narrow range of genetic polymorphism levels across species has been a major source of debate since the inception of molecular population genetics. Recently Corbett-Detig et al found evidence that linked selection strongly constrains levels of polymorphism in species with large census sizes. Here I reexamine this claim and find weak support for this conclusion. While linked selection is an important determinant of polymorphism levels along the genome in many species, we currently lack compelling evidence that it is a major determinant of polymorphism levels among obligately sexual species.

Evolutionary Biology

Accelerating Wright-Fisher Forward Simulations on the Graphics Processing Unit

Forward Wright-Fisher simulations are powerful in their ability to model complex demography and selection scenarios, but suffer from slow execution on the CPU, thus limiting their usefulness. The single-locus Wright-Fisher forward algorithm is, however, exceedingly parallelizable, with many steps which are so-called embarrassingly parallel, consisting of a vast number of individual computations that are all independent of each other and thus capable of being performed concurrently. The rise of modern Graphics Processing Units (GPUs) and programming languages designed to leverage the inherent parallel nature of these processors have allowed researchers to dramatically speed up many programs that have such high arithmetic intensity and intrinsic concurrency. The presented GPU Optimized Wright-Fisher simulation, or GO Fish for short, can be used to simulate arbitrary selection and demographic scenarios while running over 250-fold faster than its serial counterpart on the CPU. Even modest GPU hardware can achieve an impressive speedup of well over two orders of magnitude. With simulations so accelerated, one can not only do quick parametric bootstrapping of previously estimated parameters, but also use simulated results to calculate the likelihoods and summary statistics of demographic and selection models against real polymorphism data - all without restricting the demographic and selection scenarios that can be modeled or requiring approximations to the single-locus forward algorithm for efficiency. Further, as many of the parallel programming techniques used in this simulation can be applied to other computationally intensive algorithms important in population genetics, GO Fish serves as an exciting template for future research into accelerating computation in evolution. GO Fish is part of the Parallel PopGen Package available at: http://dl42.github.io/ParallelPopGen/

Evolutionary Biology

Older fathers’ children have lower evolutionary fitness across four centuries and in four populations

Higher paternal age at offspring conception increases de novo genetic mutations (Kong et al., 2012). Based on evolutionary genetic theory we predicted that the offspring of older fathers would be less likely to survive and reproduce, i.e. have lower fitness. In a sibling control study, we find clear support for negative paternal age effects on offspring survival, mating and reproductive success across four large populations with an aggregate N > 1.3 million in main analyses. Compared to a sibling born when the father was 10 years younger, individuals had 4-13% fewer surviving children in the four populations. Three populations were pre-industrial (1670-1850) Western populations and showed a pattern of paternal age effects across the offsprings lifespan. In 20th-century Sweden, we found no negative paternal age effects on child survival or marriage odds. Effects survived tests for competing explanations, including maternal age and parental loss. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time. We can use this understanding to predict the effect of increasingly delayed reproduction on offspring genetic load, mortality and fertility.

Evolutionary Biology

Epistasis and the dynamics of reversion in molecular evolution

Recent studies of protein evolution contend that the longer an amino acid substitution is present at a site, the less likely it is to revert to the amino acid previously occupying that site. Here we study this phenomenon of decreasing reversion rates rigorously, and in a much more general context. We show that, under weak mutation and for arbitrary fitness landscapes, reversion rates decrease with time for any site that is involved in at least one epistatic interaction. Specifically, we prove that, at stationarity, the hazard function of the distribution of waiting times until reversion is strictly decreasing for any such site. Thus, in the presence of epistasis, the longer a particular character has been absent from a site, the less likely the site will revert to its prior state. We also explore several examples of this general result, which share a common pattern whereby the probability of having reverted increases rapidly at short times to some substantial value before becoming almost flat after a few substitutions at other sites. This pattern indicates a characteristic tendency for reversion to occur either almost immediately after the initial substitution or only after a very long time.

Evolutionary Biology

Evolutionary consequences of DNA methylation in a basal metazoan

Gene body methylation (gbM) is an ancestral and widespread feature in Eukarya, yet its adaptive value and evolutionary implications remain unresolved. The occurrence of gbM within protein coding sequences is particularly puzzling, because methylation causes cytosine hypermutability and hence is likely to produce deleterious amino acid substitutions. We investigate this enigma using an evolutionarily basal group of Metazoa, the stony corals (order Scleractinia, class Anthozoa, phylum Cnidaria). We show that gbM correlates with breadth and abundance of transcription and with slow sequence evolution. We also show a strong correlation between gbM and codon bias due to systematic replacement of CpG bearing codons. We suggest that the ancestral function of gene body methylation is tied to selective pressure for accurate and stable gene expression, and that mutation caused by gbM may be a previously unrecognized driver of adaptive codon evolution.

Evolutionary Biology

Antimicrobial functions of lactoferrin promote genetic conflicts in ancient primates and modern humans

Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic conflicts with pathogens remain unclear. Here we show that lactoferrin has been subject to recurrent episodes of positive selection during primate divergence predominately at antimicrobial peptide surfaces consistent with long-term antagonism by pathogens. An abundant lactoferrin polymorphism in human populations and Neanderthals also exhibits signatures of positive selection across primates, linking ancient host-microbe conflicts to modern human genetic variation. Rapidly evolving sites in lactoferrin further correspond to molecular interfaces with pathogenic bacteria causing meningitis, pneumonia, and sepsis. Because microbes actively target lactoferrin to acquire iron, we propose that the emergence of antimicrobial activity provided a pivotal mechanism of adaptation sparking evolutionary conflicts via acquisition of new protein functions.

Evolutionary Biology

Genetics of cortico-cerebellar expansion in anthropoid primates: a comparative approach

What adaptive changes in brain structure and function underpin the evolution of increased cognitive performance in humans and our close relatives? Identifying the genetic basis of brain evolution has become a major tool in answering this question. Numerous cases of positive selection, altered gene expression or gene duplication have been identified that may contribute to the evolution of the neocortex, which is widely assumed to play a predominant role in cognitive evolution. However, the neocortex co-evolves with other, functionally inter-dependent, regions of the brain, most notably the cerebellum. The cerebellum is linked to a range of cognitive tasks and expanded rapidly during hominoid evolution, independently of neocortex size. Here we demonstrate that, across primates, genes with known roles in cerebellum development are just as likely to be targeted by selection as genes linked to cortical development. In fact, cerebellum genes are more likely to have evolved adaptively during hominoid evolution, consistent with phenotypic data suggesting an accelerated rate of cerebellar expansion in apes. Finally, we present evidence that selection targeted genes with specific effects on either the neocortex or cerebellum, not both. This suggests cortico-cerebellar co-evolution is maintained by selection acting on independent developmental programs.

Evolutionary Biology

Adaptive divergence in brain composition between ecologically distinct incipient species

During ecological speciation diverging populations are exposed to contrasting sensory and spatial information that present new behavioral and perceptive challenges. Here, we investigate how brain composition evolves during the early stages of speciation. The incipient species pair, Heliconius erato cyrbia and H. himera, have parapatric ranges across an environmental and altitudinal gradient. Despite continuing gene-flow, these species have divergent ecological, behavioral and physiological traits. We demonstrate that these incipient species also differ significantly in brain composition, especially in the size of sensory structures. H. erato has larger visual components whilst H. himera invests more heavily in olfaction. These differences are not explained by environmentally-induced plasticity, but reflect non-allometric shifts in brain structure. Our results suggest the adaptive evolution of brain structure and function play an important role in facilitating the emergence of ecologically distinct species, and imply that plasticity alone may be insufficient to meet the demands of novel environments.

Evolutionary Biology

Replicator Dynamics with Feedback-Evolving Games: Towards a Co-Evolutionary Game Theory

A tragedy of the commons occurs when individuals take actions to maximize their payoffs even as their combined payoff is less than the global maximum had the players coordinated. The originating example is that of over-grazing of common pasture lands. In game theoretic treatments of this example there is rarely consideration of how individual behavior subsequently modifies the commons and associated payoffs. Here, we generalize evolutionary game theory by proposing a class of replicator dynamics with feedback-evolving games in which environment-dependent payoffs and strategies coevolve. We initially apply our formulation to a system in which the payoffs favor unilateral defection and cooperation, given replete and depleted environments respectively. Using this approach we identify and characterize a new class of dynamics: an oscillatory tragedy of the commons in which the system cycles between deplete and replete environmental states and cooperation and defection behavior states. We generalize the approach to consider outcomes given all possible rational choices of individual behavior in the depleted state when defection is favored in the replete state. In so doing we find that incentivizing cooperation when others defect in the depleted state is necessary to avert the tragedy of the commons. In closing, we propose new directions for the study of control and influence in games in which individual actions exert a substantive effect on the environmental state.

Evolutionary Biology