Tim Connallon

SEX LINKAGE, SEX-SPECIFIC SELECTION, AND THE ROLE OF RECOMBINATION IN THE EVOLUTION OF SEXUALLY DIMORPHIC GENE EXPRESSION

Sex‐biased genes—genes that are differentially expressed within males and females—are nonrandomly distributed across animal genomes, with sex chromosomes and autosomes often carrying markedly different concentrations of male‐ and female‐biased genes. These linkage patterns are often gene‐ and lineage‐dependent, differing between functional genetic categories and between species. Although sex‐specific selection is often hypothesized to shape the evolution of sex‐linked and autosomal gene content, population genetics theory has yet to account for many of the gene‐ and lineage‐specific idiosyncrasies emerging from the empirical literature. With the goal of improving the connection between evolutionary theory and a rapidly growing body of genome‐wide empirical studies, we extend previous population genetics theory of sex‐specific selection by developing and analyzing a biologically informed model that incorporates sex linkage, pleiotropy, recombination, and epistasis, factors that are likely to vary between genes and between species. Our results demonstrate that sex‐specific selection and sex‐specific recombination rates can generate, and are compatible with, the gene‐ and species‐specific linkage patterns reported in the genomics literature. The theory suggests that sexual selection may strongly influence the architectures of animal genomes, as well as the chromosomal distribution of fixed substitutions underlying sexually dimorphic traits.

The Resolution of Sexual Antagonism by Gene Duplication

Disruptive selection between males and females can generate sexual antagonism, where alleles improving fitness in one sex reduce fitness in the other. This type of genetic conflict arises because males and females carry nearly identical sets of genes: opposing selection, followed by genetic mixing during reproduction, generates a population genetic “tug-of-war” that constrains adaptation in either sex. Recent verbal models suggest that gene duplication and sex-specific cooption of paralogs might resolve sexual antagonism and facilitate evolutionary divergence between the sexes. However, this intuitive proximal solution for sexual dimorphism potentially belies a complex interaction between mutation, genetic drift, and positive selection during duplicate fixation and sex-specific paralog differentiation. The interaction of these processes—within the explicit context of duplication and sexual antagonism—has yet to be formally described by population genetics theory. Here, we develop and analyze models of gene duplication and sex-specific differentiation between paralogs. We show that sexual antagonism can favor the fixation and maintenance of gene duplicates, eventually leading to the evolution of sexually dimorphic genetic architectures for male and female traits. The timescale for these evolutionary transitions is sensitive to a suite of genetic and demographic variables, including allelic dominance, recombination, sex linkage, and population size. Interestingly, we find that female-beneficial duplicates preferentially accumulate on the X chromosome, whereas male-beneficial duplicates are biased toward autosomes, independent of the dominance parameters of sexually antagonistic alleles. Although this result differs from previous models of sexual antagonism, it is consistent with several findings from the empirical genomics literature.

FITNESS CONSEQUENCES OF SEX-SPECIFIC SELECTION

Theory suggests that sex‐specific selection can facilitate adaptation in sexually reproducing populations. However, sexual conflict theory and recent experiments indicate that sex‐specific selection is potentially costly due to sexual antagonism: alleles harmful to one sex can accumulate within a population because they are favored in the other sex. Whether sex‐specific selection provides a net fitness benefit or cost depends, in part, on the relative frequency and strength of sexually concordant versus sexually antagonistic selection throughout a species’ genome. Here, we model the net fitness consequences of sex‐specific selection while explicitly considering both sexually concordant and sexually antagonistic selection. The model shows that, even when sexual antagonism is rare, the fitness costs that it imposes will generally overwhelm fitness benefits of sexually concordant selection. Furthermore, the cost of sexual antagonism is, at best, only partially resolved by the evolution of sex‐limited gene expression. To evaluate the key parameters of the model, we analyze an extensive dataset of sex‐specific selection gradients from wild populations, along with data from the experimental evolution literature. The model and data imply that sex‐specific selection may likely impose a net cost on sexually reproducing species, although additional research will be required to confirm this conclusion.

A General Population Genetic Framework for Antagonistic Selection That Accounts for Demography and Recurrent Mutation

Antagonistic selection—where alleles at a locus have opposing effects on male and female fitness (“sexual antagonism”) or between components of fitness (“antagonistic pleiotropy”)—might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range—a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The “efficacy” of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (Nes >> 1, where Ne is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection.

Association between sex-biased gene expression and mutations with sex-specific phenotypic consequences in Drosophila.

Genome-wide mRNA transcription profiles reveal widespread molecular sexual dimorphism or “sex-biased” gene expression, yet the relationship between molecular and phenotypic sexual dimorphism remains unclear. A major unresolved question is whether sex-biased genes typically perform male- and female-specific functions (whether these genes have sex-biased phenotypic or fitness consequences) or have similar functional importance for both sexes. To elucidate the relationship between sex-biased transcription and sex-biased fitness consequences, we analyzed a large data set of lethal, visible, and sterile mutations that have been mapped to the Drosophila melanogaster genome. The data permitted us to classify genes according to their sex-specific mutational effects and to infer the relationship between sex-biased transcription level and sex-specific fitness consequences. We find that mutations in female-biased genes are (on average) more deleterious to females than to males and that mutations in male-biased genes tend to be more deleterious to males than to females. Nevertheless, mutations in most sex-biased genes have similar phenotypic consequences for both sexes, which suggests that sex-biased transcription is not necessarily associated with functional genetic differentiation between males and females. These results have interesting implications for the evolution of sexual dimorphism and sex-specific adaptation.

Balancing Selection in Species with Separate Sexes: Insights from Fisher’s Geometric Model

How common is balancing selection, and what fraction of phenotypic variance is attributable to balanced polymorphisms? Despite decades of research, answers to these questions remain elusive. Moreover, there is no clear theoretical prediction about the frequency with which balancing selection is expected to arise within a population. Here, we use an extension of Fisher’s geometric model of adaptation to predict the probability of balancing selection in a population with separate sexes, wherein polymorphism is potentially maintained by two forms of balancing selection: (1) heterozygote advantage, where heterozygous individuals at a locus have higher fitness than homozygous individuals, and (2) sexually antagonistic selection (a.k.a. intralocus sexual conflict), where the fitness of each sex is maximized by different genotypes at a locus. We show that balancing selection is common under biologically plausible conditions and that sex differences in selection or sex-by-genotype effects of mutations can each increase opportunities for balancing selection. Although heterozygote advantage and sexual antagonism represent alternative mechanisms for maintaining polymorphism, they mutually exist along a balancing selection continuum that depends on population and sex-specific parameters of selection and mutation. Sexual antagonism is the dominant mode of balancing selection across most of this continuum.

Gene Duplication, Gene Conversion and the Evolution of the Y Chromosome

Nonrecombining chromosomes, such as the Y, are expected to degenerate over time due to reduced efficacy of natural selection compared to chromosomes that recombine. However, gene duplication, coupled with gene conversion between duplicate pairs, can potentially counteract forces of evolutionary decay that accompany asexual reproduction. Using a combination of analytical and computer simulation methods, we explicitly show that, although gene conversion has little impact on the probability that duplicates become fixed within a population, conversion can be effective at maintaining the functionality of Y-linked duplicates that have already become fixed. The coupling of Y-linked gene duplication and gene conversion between paralogs can also prove costly by increasing the rate of nonhomologous crossovers between duplicate pairs. Such crossovers can generate an abnormal Y chromosome, as was recently shown to reduce male fertility in humans. The results represent a step toward explaining some of the more peculiar attributes of the human Y as well as preliminary Y-linked sequence data from other mammals and Drosophila. The results may also be applicable to the recently observed pattern of tetraploidy and gene conversion in asexual, bdelloid rotifers.

Modeling the Manipulation of Natural Populations by the Mutagenic Chain Reaction

The use of recombinant genetic technologies for population manipulation has mostly remained an abstract idea due to the lack of a suitable means to drive novel gene constructs to high frequency in populations. Recently Gantz and Bier showed that the use of CRISPR/Cas9 technology could provide an artificial drive mechanism, the so-called mutagenic chain reaction (MCR), which could lead to rapid fixation of even a deleterious introduced allele. We establish the near equivalence of this system to other gene drive models and review the results of simple models showing that, when there is a fitness cost to the MCR allele, an internal equilibrium may exist that is usually unstable. In this case, introductions must be at a frequency above this critical point for the successful invasion of the MCR allele. We obtain estimates of fixation and invasion probabilities for the appropriate scenarios. Finally, we discuss how polymorphism in natural populations may introduce sources of natural resistance to MCR invasion. These modeling results have important implications for application of MCR in natural populations.

ASSOCIATION BETWEEN SEX RATIO DISTORTION AND SEXUALLY ANTAGONISTIC FITNESS CONSEQUENCES OF FEMALE CHOICE

Genetic variation can be beneficial to one sex yet harmful when expressed in the other—a condition referred to as sexual antagonism. Because X chromosomes are transmitted from fathers to daughters, and sexually antagonistic fitness variation is predicted to often be X-linked, mates of relatively low-fitness males might produce high-fitness daughters whereas mates of high-fitness males produce low-fitness daughters. Such fitness consequences have been predicted to influence the evolution of female mating biases and the offspring sex ratio. Females might evolve to prefer mates that provide good genes for daughters or might adjust offspring sex ratios in favor of the sex with the highest relative fitness. We test these possibilities in a laboratory-adapted population of Drosophila melanogaster, and find that females preferentially mate with males carrying genes that are deleterious for daughters. Preferred males produce equal numbers of sons and daughters, whereas unpreferred males produce female-biased sex ratios. As a consequence, mean offspring fitness of unpreferred males is higher than offspring fitness of preferred males. This observation has several interesting implications for sexual selection and the maintenance of population genetic variation for fitness.

Antagonistic versus nonantagonistic models of balancing selection: characterizing the relative timescales and hitchhiking effects of partial selective sweeps.

Antagonistically selected alleles‐–those with opposing fitness effects between sexes, environments, or fitness components‐–represent an important component of additive genetic variance in fitness‐related traits, with stably balanced polymorphisms often hypothesized to contribute to observed quantitative genetic variation. Balancing selection hypotheses imply that intermediate‐frequency alleles disproportionately contribute to genetic variance of life‐history traits and fitness. Such alleles may also associate with population genetic footprints of recent selection, including reduced genetic diversity and inflated linkage disequilibrium at linked, neutral sites. Here, we compare the evolutionary dynamics of different balancing selection models, and characterize the evolutionary timescale and hitchhiking effects of partial selective sweeps generated under antagonistic versus nonantagonistic (e.g., overdominant and frequency‐dependent selection) processes. We show that the evolutionary timescales of partial sweeps tend to be much longer, and hitchhiking effects are drastically weaker, under scenarios of antagonistic selection. These results predict an interesting mismatch between molecular population genetic and quantitative genetic patterns of variation. Balanced, antagonistically selected alleles are expected to contribute more to additive genetic variance for fitness than alleles maintained by classic, nonantagonistic mechanisms. Nevertheless, classical mechanisms of balancing selection are much more likely to generate strong population genetic signatures of recent balancing selection.