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Senescence, the decline in fitness components of an organism with age [1], is a nearly universal characteristic of living beings [2-6]. This ubiquity is challenging because natural selection does not favor the evolution of traits decreasing fitness [1, 7, 8]. Senescence may result from two nonexclusive mechanisms: the accumulation of deleterious mu...
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... that we focused on observational components of variance, which are estimated in a statistically independent fashion by using an ANOVA design, rather than on causal components, which are estimated as linear combinations of the observational components and are, therefore, not statistically independent. Three of the four observational components of variance (VFs, VFo, and VGFs) significantly increased with age as expected under MA (Fig- ure 1E, Figure S2, and Table S3). The fourth (VGFo) did not increase and remained low at all ages. ...
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... main expectation of the AP theory is the occurrence of negative genetic correlations between early and late fitness traits as a consequence of opposite effects of pleiotropic Figure S2). (F) Age-specific heterosis (data are represented as mean 6 SEM over crosses; linear regression on cross means: Student's t test = 9.01, p < 0.0001, n = 153). ...
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... latter declines with age because of the reduced contribution of old cohorts to population growth. From this we showed that over a broad range of conditions, MA predicts stronger heterosis for lateexpressed traits than for early-expressed ones (Figure 2). This prediction does not hold under AP, as the genetic load is independent of the fitness sensitivity [17]. ...
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... results obtained with Mathematica 4.0 [S5] are shown for some representative population parameters in Figure 2. In contrast to inbreeding depression, which is mainly due to mutations of large effect maintained at low frequencies in all demes, among-population heterosis is mainly produced by mutations of moderate to low effect on fitness, which tend to be fixed by drift in a small fraction of demes and are rescued by wild-type alleles in among-deme crosses [S2, S4]. ...
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... results obtained with Mathematica 4.0 [S5] are shown for some representative population parameters in Figure 2. In contrast to inbreeding depression, which is mainly due to mutations of large effect maintained at low frequencies in all demes, among-population heterosis is mainly produced by mutations of moderate to low effect on fitness, which tend to be fixed by drift in a small fraction of demes and are rescued by wild-type alleles in among-deme crosses [S2, S4]. Over a large range of migration rates and selection coefficients, the decrease in the strength of selection (S(z)dz) with age is expected to increase heterosis for z (Figure 2). Only when the fitness effect of a mutation is very small [S(z)dz < 0.00001 for the population parameters used in Figure 2] can heterosis decrease with a decrease in S(z)dz; this is because very small mutations become effectively neutral and may go to fixation in the whole population as a result of mutation and drift. ...
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... a large range of migration rates and selection coefficients, the decrease in the strength of selection (S(z)dz) with age is expected to increase heterosis for z (Figure 2). Only when the fitness effect of a mutation is very small [S(z)dz < 0.00001 for the population parameters used in Figure 2] can heterosis decrease with a decrease in S(z)dz; this is because very small mutations become effectively neutral and may go to fixation in the whole population as a result of mutation and drift. However, this category of mutations is unlikely to contribute significantly to observable heterosis. ...
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... is important here to clearly distinguish between heterosis for trait z (Equation 3) and heterosis for fitness, which is found by multiplying Equation 3 by S(z). Heterosis for z is proportional to the variance in allele frequency, which under most circumstances is a decreasing function of S(z) (Figure 2). Heterosis for fitness is proportional to the product S(z)Var(q) which in the parameter range of Figure 2 is a nonmonotonic function of S(z) (see reference [S4]). ...
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... for z is proportional to the variance in allele frequency, which under most circumstances is a decreasing function of S(z) (Figure 2). Heterosis for fitness is proportional to the product S(z)Var(q) which in the parameter range of Figure 2 is a nonmonotonic function of S(z) (see reference [S4]). ...
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Citations
... They both suggest that aging results from mutations with late acting deleterious effects, while they differ in that Mutation Accumulation (MA; Medawar 1952) assumes aging mutations to be neutral early in life whereas antagonistic pleiotropy (AP; Williams 1957) assumes them to be beneficial. The AP and MA theories of aging have both been tested extensively, and evidence in favor of each has been found in the laboratory as well as in the wild (AP, e.g., Luckinbill et al. 1984;Rose 1984;Zwaan et al. 1995;Partridge et al. 1999;Charmantier et al. 2006;Nussey et al. 2008;Remolina et al. 2012;MA, e.g., Charlesworth & Hughes 1996;Hughes et al. 2002;Snoke & Promislow 2003;Swindell & Bouzat 2006;Borash et al. 2007;Reynolds et al. 2007;Escobar et al. 2008;Keller et al. 2008;Burke et al. 2014;Durham et al. 2014;Lohr & Haag 2015). Brengdahl et al., 2020 …we cannot resist the temptation to point out the contrast between the relative scientific standing of evolutionary biology and that of the rest of biology, where the explanation of ageing is concerned. ...
... Testing the role of the mutation accumulation mechanism on aging initially relied on studying inter-individual heterogeneity of age-related fitness reduction, a prediction of the model (Charlesworth & Hughes, 1996;Shaw et al., 1999;Wilson et al., 2007;Escobar et al., 2008). More recently, researchers have also begun employing molecular data to test the idea. ...
The mutation accumulation theory predicts that aging is caused by accumulation of late-acting deleterious variants in the germ-line, due to weak purifying selection at old age. In accordance with this model, we and others have shown that sequence conservation among old-biased genes (with higher expression in old versus young adults) is weaker than among young-biased genes across a number of mammalian and insect species. However, questions remained regarding the source and generality of this observation. It was especially unclear whether the observed patterns were driven by tissue and cell type composition shifts or by cell-autonomous expression changes during aging. How wide this trend would extend to non-mammalian metazoan aging was also uncertain. Here we analyzed bulk tissue as well as cell type-specific RNA sequencing data from diverse animal taxa across six different datasets from five species. We show that the previously reported age-related decrease in transcriptome conservation (ADICT) is commonly found in aging tissues of non-mammalian species, including non-mammalian vertebrates (chicken brain, killifish liver and skin) and invertebrates (fruit fly brain). Analyzing cell type-specific transcriptomes of adult mice, we further detect the same ADICT trend at the single cell type level. Old-biased genes are less conserved across the majority of cell types analyzed in the lung, brain, liver, muscle, kidney, and skin, and these include both tissue-specific cell types, and also ubiquitous immune cell types. Overall, our results support the notion that aging in metazoan tissues may be at least partly shaped by the mutation accumulation process.
... The classical Mutation Accumulation theory of ageing has been expanded to also incorporate mutations with much broader windows of effect (Charlesworth 2001). Several studies have tested and found support for MA, both in lab-adapted (Charlesworth and Hughes 1996;Hughes et al 2002;Snoke and Promislow 2003;Reynolds et al 2007;Burke et al 2014;Durham et al 2014) as well as wild populations (Escobar et al 2008;Keller et al 2008;Lohr and Haag 2015). Generally, ageing through mutations under a MA-scenario are considered to happen through many deleterious mutations which individually have small effects, although examples of MA mutations with large individual effects exist (Hughes and Reynolds 2005). ...
... While alternative formulations have been proposed and question these predictions (Moorad & Promislow 2009), a problem is that these alternative models make assumptions about age-specific changes in allelic effects and dominance for which there is little evidence (Hughes, 2010). Testing of this hypothesis has mostly been done in invertebrates like Drosophila with results showing that genetic variation and inbreeding effects increase dramatically with age in support of MA (Hughes, et al., 2002;Gong & Woodruff, 2006;Lesser, et al., 2006;Swindell & Bouzat, 2006;Borash, et al., 2007;Reynolds, et al., 2007;Escobar, et al., 2008;Keller, et al., 2008), though there are some exceptions (Fox & Stillwell, 2009;Fox, et al., 2006). ...
The nematode worm Caenorhabditis elegans has emerged as one of the premier model systems for ageing research. Its use has led to the discovery of many biological mechanisms of ageing conserved across species, including acceleration of ageing by insulin/IGF-1 signalling (IIS) and germline signalling. Ageing in C. elegans, however, is unusual in terms of the severity and early onset of senescent pathology, particularly affecting organs involved in reproduction. For example, in post-reproductive hermaphrodites, intestinal biomass is converted into yolk leading to intestinal atrophy and yolk steatosis. While late yolk production has long been viewed as futile, is it possible that it somehow promote fitness? Results in this thesis show that post-reproductive C. elegans hermaphrodites vent yolk that can be consumed by larvae, promoting their growth. Thus, post-reproductive mothers can contribute to reproductive fitness by converting their biomass into milk, suggesting that intestinal atrophy is a cost of lactation. This type of massive reproductive effort involving biomass repurposing leading to organ degeneration is characteristic of semelparous organisms (i.e. that exhibit only a single reproductive episode) ranging from monocarpic plants to Pacific salmon where it leads to rapid death (reproductive death). Results also show that lactation occurs in other hermaphroditic Caenorhabditis nematode species but not in females. Moreover, the latter do not exhibit intestinal atrophy or steatosis, and are longer lived suggesting that they do not undergo reproductive death. Furthermore, germline ablation strongly increases lifespan in hermaphrodites but not females; similarly, blocking sexual maturation e.g. by gonadectomy can greatly increase lifespan in other organisms that undergo reproductive death. IIS which accelerates C. elegans ageing is also shown to promote lactation. These results suggest that C. elegans hermaphrodites exhibit reproductive death, suppression of which increases lifespan. This has major implications in terms of what one can learn about human ageing from C. elegans.
... The AP and MA theories of aging have both been tested extensively, and evidence in favor of each has been found in the laboratory as well as in the wild (AP, e.g., [12][13][14][15][16][17][18], MA, e.g., [19][20][21][22][23][24][25][26][27][28][29]). The two theories make contrasting predictions about how early and late life performances are associated with one another. ...
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.
... Shaw, Promislow, Tatar, Hughes, & Geyer, 1999)] or natural populations (e.g., Soay sheep and red deer: ref. (Wilson et al., 2007)). In hermaphroditic snails, in an indirect test of the expectation regarding inbreeding depression, outbreeding was reported to mitigate age-related increase in mortality (Escobar, Jarne, Charmantier, & David, 2008). In humans, the heritability of CpG methylation patterns was shown to increase with age for about 100 genome-wide loci (although here, possible fitness consequences were not evaluated) (Robins et al., 2017). ...
Medawar's mutation accumulation hypothesis explains aging by the declining force of natural selection with age: Slightly deleterious germline mutations expressed in old age can drift to fixation and thereby lead to aging‐related phenotypes. Although widely cited, empirical evidence for this hypothesis has remained limited. Here, we test one of its predictions that genes relatively highly expressed in old adults should be under weaker purifying selection than genes relatively highly expressed in young adults. Combining 66 transcriptome datasets (including 16 tissues from five mammalian species) with sequence conservation estimates across mammals, here we report that the overall conservation level of expressed genes is lower at old age compared to young adulthood. This age‐related decrease in transcriptome conservation (ADICT) is systematically observed in diverse mammalian tissues, including the brain, liver, lung, and artery, but not in others, most notably in the muscle and heart. Where observed, ADICT is driven partly by poorly conserved genes being up‐regulated during aging. In general, the more often a gene is found up‐regulated with age among tissues and species, the lower its evolutionary conservation. Poorly conserved and up‐regulated genes have overlapping functional properties that include responses to age‐associated tissue damage, such as apoptosis and inflammation. Meanwhile, these genes do not appear to be under positive selection. Hence, genes contributing to old age phenotypes are found to harbor an excess of slightly deleterious alleles, at least in certain tissues. This supports the notion that genetic drift shapes aging in multicellular organisms, consistent with Medawar's mutation accumulation hypothesis.
... This suggests that (i) the effects depend on the offspring's genotype and not on maternal effects, and that (ii) the observed reduction results from an increased frequency of alleles that have some detectable deleterious heterozygous effect on survival and not the fixation of purely recessive deleterious alleles. The first point is reminiscent of previous studies on inbreeding depression in Physa acuta showing that juvenile survival depends on the juvenile's, rather than their mother's, inbreeding coefficient (Escobar et al. 2008;Janicke et al. 2014). The second point is further confirmed by our finding that the "hybrids" between the two independent lines exhibited a juvenile survival similar to the lines themselves and replicate the same patterns. ...
Sex allocation theory predicts that simultaneous hermaphrodites evolve to an evolutionary stable resource allocation, whereby any increase in investment to male reproduction leads to a disproportionate cost on female reproduction and vice‐versa. However, empirical evidence for sexual trade‐offs in hermaphroditic animals is still limited. Here, we tested how male and female reproductive traits evolved under conditions of reduced selection on either male or female reproduction for 40 generations in a hermaphroditic snail. This selection favors a reinvestment of resources from the sex function under relaxed selection towards the other function. We found no such evolutionary response. Instead, juvenile survival and male reproductive success significantly decreased in lines where selection on the male function (i. e., sexual selection) was relaxed, while relaxing selection on the female function had no effect. Our results suggest that most polymorphisms under selection in these lines were not sex‐antagonistic. Rather, they were deleterious mutations affecting juvenile survival (thus reducing both male and female fitness) with strong pleiotropic effects on male success in a sexual selection context. These mutations accumulated when sexual selection was relaxed, which supports the idea that sexual selection in hermaphrodites contributes to purge the mutation load from the genome as in separate‐sex organisms.
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... In humans, heritability of CpG methylation patterns was shown to increase with age for about 100 genome-wide loci also consistent with MA, although possible fitness consequences were not evaluated 12 . In an indirect test of the expectation for inbreeding depression, outbreeding was reported to reduce age-related increase in mortality in hermaphroditic snails 13 , again in line with MA. Finally, Rodríguez et al. 14 studied >2,500 human genetic variants linked to 120 genetic diseases and reported that variants associated with late-onset disease segregate at higher frequencies than those associated with early-onset disease, a third prediction under MA 14 . ...
... The MA hypothesis predicts that burden of slightly deleterious germline substitutions will increase with age due to the declining force of negative selection 3 . Our approach differs from earlier attempts to test this hypothesis [6][7][8][9][10][11]13,14 in two respects. First, instead of relying on intra-species variation to estimate mutational load, we used inter-species divergence, which may be statistically more powerful as it involves a larger number of substitutions. ...
Medawar’s mutation accumulation (MA) hypothesis explains ageing by the declining force of natural selection with age: slightly deleterious germline mutations that are functional in old age are not effectively eliminated by selection and therefore lead to ageing-related phenotypes. Although widely cited, empirical support for the MA hypothesis, particularly molecular evidence, has remained limited. Here we test one of its predictions, that genes relatively highly expressed in old adults vs. young adults should be under weaker purifying selection than those relatively highly expressed in young adults. To do so, we combine 23 RNA-sequencing and 35 microarray gene expression datasets (including 9 tissues from 5 mammalian species) with protein and regulatory sequence conservation estimates across mammals. We identify age-related decrease in transcriptome conservation (ADICT) in four tissues, brain, liver, lung, and artery, but not in other tissues, most notably muscle and heart. ADICT is driven both by decreased expression of highly conserved genes and up-regulation of poorly conserved genes during ageing, in line with the MA hypothesis. Lowly conserved and up-regulated genes in ADICT-associated tissues have overlapping functional properties, particularly involving apoptosis and inflammation, with no evidence for a history of positive selection. Our results suggest that tissues vary in how evolution has shaped their ageing patterns. We find that in some tissues, genes up-regulated during ageing, possibly in response to accumulating cellular and histological damage, are under weaker purifying selection than other genes. We propose that accumulation of slightly deleterious substitutions in these genes may underlie their suboptimal regulation and activity during ageing, shaping senescent phenotypes such as inflammaging.
... These results are in accordance with theory that predicts an increase of inbreeding depression with age under mutation accumulation (Charlesworth & Hughes, 1996;Keller et al., 2008). Similar results were found in Soay sheep and red deer as well as in a freshwater snail (Wilson et al., 2007;Escobar et al., 2008). Purging effects decrease with age due to the fact that selection against deleterious mutations is less strong in older individuals compared with younger ones. ...
Inbreeding and ageing can affect characteristics of reproductive physiology, influencing an individual’s fecundity, fertility, and thus fitness. The effects of inbreeding and age are expected to depend on several factors such as inbreeding history of a population, lifespan, or environmental influences. Here, we investigated the impact of inbreeding and age on gonadal and sperm traits in males of Pelvicachromis taeniatus, a small West African cichlid featuring an inbreeding mating system. Lab-bred inbred and outbred, young and aged males were compared. Microsatellite heterozygosity was additionally taken into account. While age effects were generally present with aged males having larger testis and longer sperm but less sperm than young ones, inbreeding effects were less strongly pronounced and age specific. Negative inbreeding effects were generally absent in young males suggesting purging of deleterious alleles after continuous inbreeding in the natural P. taeniatus population. In aged males, inbreeding affected testes mass and sperm number. Age-dependent inbreeding effects are consistent with the mutation accumulation model of ageing. Generally, our results suggest that ageing can influence gamete performance and fitness and, thus, has evolutionary consequences.
... This is a strong assumption given that the distribution of, and the link between, mating success and reproductive success may vary with systematic shifts at the individual level (cumulative effects of mating, J.N.A. Hoffer & J.M. Koene, pers. comm.; sex-specific senescence, Escobar et al. 2008), the population demographic level (temporal changes in sex ratios, Forsgren et al. 2004; Baena & Mac ıasOrd o~ nez 2012; Wacker et al. 2014), or the environmental level (e.g. food availability Janicke, David & Chapuis 2015;Morimoto, Pizzari & Wigby 2016;see also Siepielski, DiBattista & Carlson 2009;Evans & Garcia-Gonzalez 2016). ...
(1) Routine assessments of overall sexual selection, including comparisons of its direction and intensity between sexes or species, rely on summary metrics that capture the essence of sexual selection. Nearly all currently employed metrics require population-wide estimates of individual mating success and reproductive success. The resulting sexual selection metrics, however, can heavily and systematically vary with the chosen approaches in terms of sampling, measurement, and analysis.
(2) Our review illustrates this variation using the Bateman gradient, a particularly prominent sexual selection metric. It represents the selection gradient on mating success and – given the latter's pivotal role in defining sexual selection – reflects a trait-independent integrative proxy for the maximum strength of sexual selection. Drawing from a recent meta-analysis, we evaluate potential biases arising from study design, data collection, and parameter estimation, and provide suggestions to mitigate such biases in future studies.
(3) With respect to study design, we argue that currently almost inexistent manipulative studies must complement the dominating correlative studies to inform us about causality in sexual selection. With respect to data collection, we outline how different measures of mating and reproductive success affect the components of sexual (and natural) selection that are reflected in standard summary metrics. With respect to parameter estimation, we show the potential impact of decisions about data inclusion and the chosen quantitative approach on inferences of sexual selection and its sex difference.
(4) We expect this meta-analytical review to aid future studies in providing less biased and more informative estimates of sexual selection.
