On aging and age-specific effects of spontaneous mutations.

Evolutionary theory assumes that mutations that cause aging either have beneficial early-life effects that gradually become deleterious with advancing age (antagonistic pleiotropy [AP]) or that they only have deleterious effects at old age (mutation accumulation [MA]). Mechanistically, aging is predicted to result from damage accumulating in the soma. While this scenario is compatible with AP, it is not immediately obvious how damage would accumulate under MA. In a modified version of the MA theory, it has been suggested that mutations with weakly deleterious effects at young age can also contribute to aging, if they generate damage that gradually accumulates with age. Mutations with increasing deleterious effects have recently gained support from theoretical work and studies of large-effect mutations. Here we address if spontaneous mutations also have negative effects that increase with age. We accumulate mutations with early-life effects in Drosophila melanogaster across 27 generations and compare their relative effects on fecundity early and late in life. Our mutation accumulation lines on average have substantially lower early-life fecundity compared to controls. These effects were further maintained throughout life, but they did not increase with age. Our results suggest that most spontaneous mutations do not contribute to damage accumulation and aging.

Age-specific effects of deletions: implications for aging theories.

The evolution of aging requires mutations with late-life deleterious effects. Classic theories assume these mutations either have neutral (mutation accumulation) or beneficial (antagonistic pleiotropy) effects early in life, but it is also possible that they start out as mildly harmful and gradually become more deleterious with age. Despite a wealth of studies on the genetics of aging, we still have a poor understanding of how common mutations with age-specific effects are and what aging theory they support. To advance our knowledge on this topic, we measure a set of genomic deletions for their heterozygous effects on juvenile performance, fecundity at 3 ages, and adult survival. Most deletions have age-specific effects, and these are commonly harmful late in life. Many of the deletions assayed here would thus contribute to aging if present in a population. Taking only age-specific fecundity into account, some deletions support antagonistic pleiotropy, but the majority of them better fit a scenario where their negative effects on fecundity become progressively worse with age. Most deletions have a negative effect on juvenile performance, a fact that strengthens the conclusion that deletions primarily contribute to aging through negative effects that amplify with age.

Ageing desexualizes the Drosophila brain transcriptome.

General evolutionary theory predicts that individuals in low condition should invest less in sexual traits compared to individuals in high condition. Whether this positive association between condition and investment also holds between young (high condition) and senesced (low condition) individuals is however less clear, since elevated investment into reproduction may be beneficial when individuals approach the end of their life. To address how investment into sexual traits changes with age, we study genes with sex-biased expression in the brain, the tissue from which sexual behaviours are directed. Across two distinct populations of Drosophila melanogaster, we find that old brains display fewer sex-biased genes, and that expression of both male-biased and female-biased genes converges towards a sexually intermediate phenotype owing to changes in both sexes with age. We further find that sex-biased genes in general show heightened age-dependent expression in comparison to unbiased genes and that age-related changes in the sexual brain transcriptome are commonly larger in males than females. Our results hence show that ageing causes a desexualization of the fruit fly brain transcriptome and that this change mirrors the general prediction that low condition individuals should invest less in sexual phenotypes.

A genome-wide test for paternal indirect genetic effects on lifespan in Drosophila melanogaster.

Exposing sires to various environmental manipulations has demonstrated that paternal effects can be non-trivial also in species where male investment in offspring is almost exclusively limited to sperm. Whether paternal effects also have a genetic component (i.e. paternal indirect genetic effects (PIGEs)) in such species is however largely unknown, primarily because of methodological difficulties separating indirect from direct effects of genes. PIGEs may nevertheless be important since they have the capacity to contribute to evolutionary change. Here we use Drosophila genetics to construct a breeding design that allows testing nearly complete haploid genomes (more than 99%) for PIGEs. Using this technique, we estimate the variance in male lifespan due to PIGEs among four populations and compare this to the total paternal genetic variance (the sum of paternal indirect and direct genetic effects). Our results indicate that a substantial part of the total paternal genetic variance results from PIGEs. A screen of 38 haploid genomes, randomly sampled from a single population, suggests that PIGEs also influence variation in lifespan within populations. Collectively, our results demonstrate that PIGEs may constitute an underappreciated source of phenotypic variation.

Deleterious mutations show increasing negative effects with age in Drosophila melanogaster.

BACKGROUND: In order for aging to evolve in response to a declining strength of selection with age, a genetic architecture that allows for mutations with age-specific effects on organismal performance is required. Our understanding of how selective effects of individual mutations are distributed across ages is however poor. Established evolutionary theories assume that mutations causing aging have negative late-life effects, coupled to either positive or neutral effects early in life. New theory now suggests evolution of aging may also result from deleterious mutations with increasing negative effects with age, a possibility that has not yet been empirically explored. RESULTS: To directly test how the effects of deleterious mutations are distributed across ages, we separately measure age-specific effects on fecundity for each of 20 mutations in Drosophila melanogaster. We find that deleterious mutations in general have a negative effect that increases with age and that the rate of increase depends on how deleterious a mutation is early in life. CONCLUSIONS: Our findings suggest that aging does not exclusively depend on genetic variants assumed by the established evolutionary theories of aging. Instead, aging can result from deleterious mutations with negative effects that amplify with age. If increasing negative effect with age is a general property of deleterious mutations, the proportion of mutations with the capacity to contribute towards aging may be considerably larger than previously believed.

Heightened condition-dependence of the sexual transcriptome as a function of genetic quality in Drosophila melanogaster head tissue.

Theory suggests sexual traits should show heightened condition-dependent expression. This prediction has been tested extensively in experiments where condition has been manipulated through environmental quality. Condition-dependence as a function of genetic quality has, however, only rarely been addressed, despite its central importance in evolutionary theory. To address the effect of genetic quality on expression of sexual and non-sexual traits, we here compare gene expression in Drosophila melanogaster head tissue between flies with intact genomes (high condition) and flies carrying a major deleterious mutation (low condition). We find that sex-biased genes show heightened condition-dependent expression in both sexes, and that expression in low condition males and females regresses towards a more similar expression profile. As predicted, sex-biased expression was more sensitive to condition in males compared to females, but surprisingly female-biased, rather than male-biased, genes show higher sensitivity to condition in both sexes. Our results thus support the fundamental predictions of the theory of condition-dependence when condition is a function of genetic quality.

Evolution Under Dietary Restriction Decouples Survival From Fecundity in Drosophila melanogaster Females.

One of the key tenets of life-history theory is that reproduction and survival are linked and that they trade-off with each other. When dietary resources are limited, reduced reproduction with a concomitant increase in survival is commonly observed. It is often hypothesized that this dietary restriction effect results from strategically reduced investment in reproduction in favor of somatic maintenance to survive starvation periods until resources become plentiful again. We used experimental evolution to test this "waiting-for-the-good-times" hypothesis, which predicts that selection under sustained dietary restriction will favor increased investment in reproduction at the cost of survival because "good-times" never come. We assayed fecundity and survival of female Drosophila melanogaster fruit flies that had evolved for 50 generations on three different diets varying in protein content-low (classic dietary restriction diet), standard, and high-in a full-factorial design. High-diet females evolved overall increased fecundity but showed reduced survival on low and standard diets. Low-diet females evolved reduced survival on low diet without corresponding increase in reproduction. In general, there was little correspondence between the evolution of survival and fecundity across all dietary regimes. Our results contradict the hypothesis that resource reallocation between fecundity and somatic maintenance underpins life span extension under dietary restriction.

Host diet mediates a negative relationship between abundance and diversity of Drosophila gut microbiota.

Nutrient supply to ecosystems has major effects on ecological diversity, but it is unclear to what degree the shape of this relationship is general versus dependent on the specific environment or community. Although the diet composition in terms of the source or proportions of different nutrient types is known to affect gut microbiota composition, the relationship between the quantity of nutrients supplied and the abundance and diversity of the intestinal microbial community remains to be elucidated. Here, we address this relationship using replicate populations of Drosophila melanogaster maintained over multiple generations on three diets differing in the concentration of yeast (the only source of most nutrients). While a 6.5-fold increase in yeast concentration led to a 100-fold increase in the total abundance of gut microbes, it caused a major decrease in their alpha diversity (by 45-60% depending on the diversity measure). This was accompanied by only minor shifts in the taxonomic affiliation of the most common operational taxonomic units (OTUs). Thus, nutrient concentration in host diet mediates a strong negative relationship between the nutrient abundance and microbial diversity in the Drosophila gut ecosystem.

Genetic Quality Affects the Rate of Male and Female Reproductive Aging Differently in Drosophila melanogaster.

Males and females often maximize fitness by pursuing different reproductive strategies, with males commonly assumed to benefit more from increased resource allocation into current reproduction. Such investment should trade off with somatic maintenance and may explain why males frequently live shorter than females. It also predicts that males should experience faster reproductive aging. Here we investigate whether reproductive aging and life span respond to condition differently in male and female Drosophila melanogaster, as predicted if sexual selection has shaped male and female resource-allocation patterns. We manipulate condition through genetic quality by comparing individuals inbred or outbred for a major autosome. While genetic quality had a similar effect on condition in both sexes, condition had a much larger general effect on male reproductive output than on female reproductive output, as expected when sexual selection on vigor acts more strongly on males. We find no differences in reproductive aging between the sexes in low condition, but in high condition reproductive aging is relatively faster in males. No corresponding sex-specific change was found for life span. The sex difference in reproductive aging appearing in high condition was specifically due to a decreased aging rate in females rather than any change in males. Our results suggest that females age slower than males in high condition primarily because sexual selection has favored sex differences in resource allocation under high condition, with females allocating relatively more toward somatic maintenance than males.

Sex differences in life span: Females homozygous for the X chromosome do not suffer the shorter life span predicted by the unguarded X hypothesis.

Life span differs between the sexes in many species. Three hypotheses to explain this interesting pattern have been proposed, involving different drivers: sexual selection, asymmetrical inheritance of cytoplasmic genomes, and hemizygosity of the X(Z) chromosome (the unguarded X hypothesis). Of these, the unguarded X has received the least experimental attention. This hypothesis suggests that the heterogametic sex suffers a shortened life span because recessive deleterious alleles on its single X(Z) chromosome are expressed unconditionally. In Drosophila melanogaster, the X chromosome is unusually large (∼20% of the genome), providing a powerful model for evaluating theories involving the X. Here, we test the unguarded X hypothesis by forcing D. melanogaster females from a laboratory population to express recessive X-linked alleles to the same degree as males, using females exclusively made homozygous for the X chromosome. We find no evidence for reduced life span or egg-to-adult viability due to X homozygozity. In contrast, males and females homozygous for an autosome both suffer similar, significant reductions in those traits. The logic of the unguarded X hypothesis is indisputable, but our results suggest that the degree to which recessive deleterious X-linked alleles depress performance in the heterogametic sex appears too small to explain general sex differences in life span.

Ageing: Why Males Curtail the Longevity of Their Mates.

Male nematodes secrete pheromones that accelerate the somatic senescence of potential mates. A new study shows that this harm most likely is an unintended by-product of the males' aim to speed up sexual maturation and delay reproductive senescence of future partners.

Autosomal and X-Linked Additive Genetic Variation for Lifespan and Aging: Comparisons Within and Between the Sexes in Drosophila melanogaster.

Theory makes several predictions concerning differences in genetic variation between the X chromosome and the autosomes due to male X hemizygosity. The X chromosome should: (i) typically show relatively less standing genetic variation than the autosomes, (ii) exhibit more variation in males compared to females because of dosage compensation, and (iii) potentially be enriched with sex-specific genetic variation. Here, we address each of these predictions for lifespan and aging in Drosophila melanogaster To achieve unbiased estimates of X and autosomal additive genetic variance, we use 80 chromosome substitution lines; 40 for the X chromosome and 40 combining the two major autosomes, which we assay for sex-specific and cross-sex genetic (co)variation. We find significant X and autosomal additive genetic variance for both traits in both sexes (with reservation for X-linked variation of aging in females), but no conclusive evidence for depletion of X-linked variation (measured through females). Males display more X-linked variation for lifespan than females, but it is unclear if this is due to dosage compensation since also autosomal variation is larger in males. Finally, our results suggest that the X chromosome is enriched for sex-specific genetic variation in lifespan but results were less conclusive for aging overall. Collectively, these results suggest that the X chromosome has reduced capacity to respond to sexually concordant selection on lifespan from standing genetic variation, while its ability to respond to sexually antagonistic selection may be augmented.

Evolution under dietary restriction increases male reproductive performance without survival cost.

Dietary restriction (DR), a reduction in nutrient intake without malnutrition, is the most reproducible way to extend lifespan in a wide range of organisms across the tree of life, yet the evolutionary underpinnings of the DR effect on lifespan are still widely debated. The leading theory suggests that this effect is adaptive and results from reallocation of resources from reproduction to somatic maintenance, in order to survive periods of famine in nature. However, such response would cease to be adaptive when DR is chronic and animals are selected to allocate more resources to reproduction. Nevertheless, chronic DR can also increase the strength of selection resulting in the evolution of more robust genotypes. We evolved Drosophila melanogaster fruit flies on 'DR', 'standard' and 'high' adult diets in replicate populations with overlapping generations. After approximately 25 generations of experimental evolution, male 'DR' flies had higher fitness than males from 'standard' and 'high' populations. Strikingly, this increase in reproductive success did not come at a cost to survival. Our results suggest that sustained DR selects for more robust male genotypes that are overall better in converting resources into energy, which they allocate mostly to reproduction.

Sexually antagonistic epigenetic marks that canalize sexually dimorphic development.

The sexes share the same autosomal genomes, yet sexual dimorphism is common due to sex-specific gene expression. When present, XX and XY karyotypes trigger alternate regulatory cascades that determine sex-specific gene expression profiles. In mammals, secretion of testosterone (T) by the testes during foetal development is the master switch influencing the gene expression pathways (male vs. female) that will be followed, but many genes have sex-specific expression prior to T secretion. Environmental factors, like endocrine disruptors and mimics, can interfere with sexual development. However, sex-specific ontogeny can be canalized by the production of epigenetic marks (epimarks) generated during early ontogeny that increase sensitivity of XY embryos to T and decrease sensitivity of XX embryos. Here, we integrate and synthesize the evidence indicating that canalizing epimarks are produced during early ontogeny. We will also describe the evidence that such epimarks sometimes carry over across generations and produce mosaicism in which some traits are discordant with the gonad. Such carryover epimarks are sexually antagonistic because they benefit the individual in which they were formed (via canalization) but harm opposite-sex offspring when they fail to erase across generations and produce gonad-trait discordances. SA-epimarks have the potential to: i) magnify phenotypic variation for many sexually selected traits, ii) generate overlap along many dimensions of the masculinity/femininity spectrum, and iii) influence medically important gonad-trait discordances like cryptorchidism, hypospadias and idiopathic hirsutism.

Sexual selection has minimal impact on effective population sizes in species with high rates of random offspring mortality: An empirical demonstration using fitness distributions.

The effective population size (N(e)) is a fundamental parameter in population genetics that influences the rate of loss of genetic diversity. Sexual selection has the potential to reduce N(e) by causing the sex-specific distributions of individuals that successfully reproduce to diverge. To empirically estimate the effect of sexual selection on N(e), we obtained fitness distributions for males and females from an outbred, laboratory-adapted population of Drosophila melanogaster. We observed strong sexual selection in this population (the variance in male reproductive success was ∼14 times higher than that for females), but found that sexual selection had only a modest effect on N(e), which was 75% of the census size. This occurs because the substantial random offspring mortality in this population diminishes the effects of sexual selection on N(e), a result that necessarily applies to other high fecundity species. The inclusion of this random offspring mortality creates a scaling effect that reduces the variance/mean ratios for male and female reproductive success and causes them to converge. Our results demonstrate that measuring reproductive success without considering offspring mortality can underestimate Ne and overestimate the genetic consequences of sexual selection. Similarly, comparing genetic diversity among different genomic components may fail to detect strong sexual selection.

Why organisms age: Evolution of senescence under positive pleiotropy?

Two classic theories maintain that aging evolves either because of alleles whose deleterious effects are confined to late life or because of alleles with broad pleiotropic effects that increase early-life fitness at the expense of late-life fitness. However, empirical studies often reveal positive pleiotropy for fitness across age classes, and recent evidence suggests that selection on early-life fitness can decelerate aging and increase lifespan, thereby casting doubt on the current consensus. Here, we briefly review these data and promote the simple argument that aging can evolve under positive pleiotropy between early- and late-life fitness when the deleterious effect of mutations increases with age. We argue that this hypothesis makes testable predictions and is supported by existing evidence.

Sex-specific trans-regulatory variation on the Drosophila melanogaster X chromosome.

The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change.

Sexually antagonistic zygotic drive: a new form of genetic conflict between the sex chromosomes.

Sisters and brothers are completely unrelated with respect to the sex chromosomes they inherit from their heterogametic parent. This has the potential to result in a previously unappreciated form of genetic conflict between the sex chromosomes, called sexually antagonistic zygotic drive (SA-ZD). SA-ZD can arise whenever brothers and sisters compete over limited resources or there is brother-sister mating coupled with inbreeding depression. Although theory predicts that SA-ZD should be common and influence important evolutionary processes, there is little empirical evidence for its existence. Here we discuss the current understanding of SA-ZD, why it would be expected to elude empirical detection when present, and how it relates to other forms of genetic conflict.

Heritability of life span is largely sex limited in Drosophila.

Males and females differ with respect to life span and rate of aging in most animal species. Such sexual dimorphism can be associated with a complex genetic architecture, where only part of the genetic variation is shared between the sexes. However, the extent to which this is true for life span and aging is not known, because studies of life span have given contradictory results and aging has not been studied from this perspective. Here we investigate the additive genetic architecture of life span and aging in Drosophila melanogaster. We find substantial amounts of additive genetic variation for both traits, with more than three-quarters of this variation available for sex-specific evolutionary change. This result shows that the sexes have a profoundly different additive genetic basis for these traits, which has several implications. First, it translates into an, on average, three-times-higher heritability of life span within, compared to between, the sexes. Second, it implies that the sexes are relatively free to evolve with respect to these traits. And third, as life span and aging are traits that integrate over all genetic factors that contribute to mortal disease, it also implies that the genetics of heritable disease differs vastly between the sexes.