Pleiotropy Hypothesis Research Articles

Evidence for the Role of Selection for Reproductively Advantageous Alleles in Human Aging

ABSTRACT The antagonistic pleiotropy hypothesis is one of the leading theories in the evolutionary origin of aging. It states that mutations contributing to aging could be positively selected for if they are advantageous early in life and promote earlier reproduction or more offspring. The evidence supporting the antagonistic pleiotropy hypothesis in humans is mixed and lacks unambiguous genome-wide support. The UK Biobank contains the genotypes and various phenotypes of 500,000 participants, offering an opportunity to test the antagonistic pleiotropy hypothesis in humans. This analysis aimed to use the UK Biobank to determine whether genetic variants influencing reproduction are likely to affect lifespan, whether pleiotropy between reproduction and lifespan are largely antagonistic, and whether pleiotropic mutations promoting reproduction but causing aging are favored by natural selection. In addition, potential molecular mechanisms linking reproduction to aging were investigated. Genetic correlation between 2 phenotypic traits was defined as the proportion of variance that the 2 traits share due to genetic causes and is a measure of the contribution of pleiotropy to the covariation of the traits. Four reproductive traits were focused on negative age at first birth, negative age at first sex, number of children fathers, and age at menopause, with larger values of these traits corresponding to higher reproduction. Two life span traits were examined: father's age at death and mother's age at death. Data were available for a total of 276,406 UK Biobank participants, and 583 genetic variants were reported to be associated with at least 1 reproductive trait. A strong, negative genetic correlation was observed between the 3 reproductive traits and 2 life span traits, supporting the antagonistic pleiotropy hypothesis. Individuals ranked in the top third in polygenic score (PGS) for the 3 reproductive traits had a significantly lower probability of survival to age 76 (SV76) than that of individuals ranked in the bottom third. Compared with randomly selected polymorphisms, those impacting reproduction were 5 times more likely to affect life span and 7.5 times more likely to affect life span antagonistically. Among individuals with the same number of children ever born, SV76 was negatively correlated with the PGS for each of the 4 reproductive traits. In this study, the evidence shows a strong negative genetic correlation between reproduction and parental life span, as well as between parental reproduction and parental life span. This supports the antagonistic pleiotropy hypothesis of aging in humans.

Evidence for the role of selection for reproductively advantageous alleles in human aging

The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here, we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 U.K. Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and life span. Individuals with higher polygenetic scores for reproduction ( PGS R ) have lower survivorships to age 76 ( SV 76 ), and PGS R increased over birth cohorts from 1940 to 1969. Similar trends are seen from individual genetic variants examined. The antagonistically pleiotropic variants are often associated with cis-regulatory effects across multiple tissues or on multiple target genes. These and other findings support the antagonistic pleiotropy hypothesis of aging in humans and point to potential molecular mechanisms of the reproduction–life-span antagonistic pleiotropy.

Divorce is linked with extra‐pair paternity in a monogamous passerine

The question of why socially monogamous females engage in extra‐pair behaviour is long‐standing in evolutionary biology. Due to a lack of empirical support among passerine birds, recent work has moved away from the indirect‐benefits hypothesis to explain extra‐pair mating behaviour by females, instead favouring the hypothesis that this is the result of a pleiotropic effect. That is, a trait under strong positive selection in either or both sexes are genetically linked with another, potentially unrelated, trait. For example, genes beneficial to female fecundity (that promote within‐pair solicitation of mating from a male partner) might also lead to extra‐pair behaviour (by also promoting solicited copulations from extra‐pair males). Here, we test two predictions from this hypothesis: We test the prediction that female divorce, measured as the number of social mates within a given year, is linked with 1) the number of extra‐pair males engaged by the female and 2) the proportion of the female's offspring that are extra‐pair. Our results show that females who divorce their social partner are more likely to produce extra‐pair offspring than those who maintain social monogamy, supporting the pleiotropy hypothesis. However, those females did not also have a higher proportion of extra‐pair offspring. The number of broods initiated was also positively correlated with the number of extra‐pair males that sired a female's offspring, probably through increased opportunity for extra‐pair males to sire offspring over a longer breeding season. Our results support the intrasexual pleiotropy hypothesis as a driver of female extra‐pair behaviour.

Cocktail-party listening and cognitive abilities show strong pleiotropy.

The cocktail-party problem refers to the difficulty listeners face when trying to attend to relevant sounds that are mixed with irrelevant ones. Previous studies have shown that solving these problems relies on perceptual as well as cognitive processes. Previously, we showed that speech-reception thresholds (SRTs) on a cocktail-party listening task were influenced by genetic factors. Here, we estimated the degree to which these genetic factors overlapped with those influencing cognitive abilities. We measured SRTs and hearing thresholds (HTs) in 493 listeners, who ranged in age from 18 to 91 years old. The same individuals completed a cognitive test battery comprising 18 measures of various cognitive domains. Individuals belonged to large extended pedigrees, which allowed us to use variance component models to estimate the narrow-sense heritability of each trait, followed by phenotypic and genetic correlations between pairs of traits. All traits were heritable. The phenotypic and genetic correlations between SRTs and HTs were modest, and only the phenotypic correlation was significant. By contrast, all genetic SRT-cognition correlations were strong and significantly different from 0. For some of these genetic correlations, the hypothesis of complete pleiotropy could not be rejected. Overall, the results suggest that there was substantial genetic overlap between SRTs and a wide range of cognitive abilities, including abilities without a major auditory or verbal component. The findings highlight the important, yet sometimes overlooked, contribution of higher-order processes to solving the cocktail-party problem, raising an important caveat for future studies aiming to identify specific genetic factors that influence cocktail-party listening.

Identification of New Candidate Genes Related to Semen Traits in Duroc Pigs through Weighted Single-Step GWAS.

Semen traits play a key role in the pig industry because boar semen is widely used in purebred and crossbred pigs. The production of high-quality semen is crucial to ensuring a good result in artificial insemination. With the wide application of artificial insemination in the pig industry, more and more attention has been paid to the improvement of semen traits by genetic selection. The purpose of this study was to identify the genetic regions and candidate genes associated with semen traits of Duroc boars. We used weighted single-step GWAS to identify candidate genes associated with sperm motility, sperm progressive motility, sperm abnormality rate and total sperm count in Duroc pigs. In Duroc pigs, the three most important windows for sperm motility-sperm progressive motility, sperm abnormality rate, and total sperm count-explained 12.45%, 9.77%, 15.80%, and 12.15% of the genetic variance, respectively. Some genes that are reported to be associated with spermatogenesis, testicular function and male fertility in mammals have been detected previously. The candidate genes CATSPER1, STRA8, ZSWIM7, TEKT3, UBB, PTBP2, EIF2B2, MLH3, and CCDC70 were associated with semen traits in Duroc pigs. We found a common candidate gene, STRA8, in sperm motility and sperm progressive motility, and common candidate genes ZSWIM7, TEKT3 and UBB in sperm motility and sperm abnormality rate, which confirms the hypothesis of gene pleiotropy. Gene network enrichment analysis showed that STRA8, UBB and CATSPER1 were enriched in the common biological process and participated in male meiosis and spermatogenesis. The SNPs of candidate genes can be given more weight in genome selection to improve the ability of genome prediction. This study provides further insight into the understanding the genetic structure of semen traits in Duroc boars.

Pan-cancer surveys indicate cell cycle-related roles of primate-specific genes in tumors and embryonic cerebrum

BackgroundDespite having been extensively studied, it remains largely unclear why humans bear a particularly high risk of cancer. The antagonistic pleiotropy hypothesis predicts that primate-specific genes (PSGs) tend to promote tumorigenesis, while the molecular atavism hypothesis predicts that PSGs involved in tumors may represent recently derived duplicates of unicellular genes. However, these predictions have not been tested.ResultsBy taking advantage of pan-cancer genomic data, we find the upregulation of PSGs across 13 cancer types, which is facilitated by copy-number gain and promoter hypomethylation. Meta-analyses indicate that upregulated PSGs (uPSGs) tend to promote tumorigenesis and to play cell cycle-related roles. The cell cycle-related uPSGs predominantly represent derived duplicates of unicellular genes. We prioritize 15 uPSGs and perform an in-depth analysis of one unicellular gene-derived duplicate involved in the cell cycle, DDX11. Genome-wide screening data and knockdown experiments demonstrate that DDX11 is broadly essential across cancer cell lines. Importantly, non-neutral amino acid substitution patterns and increased expression indicate that DDX11 has been under positive selection. Finally, we find that cell cycle-related uPSGs are also preferentially upregulated in the highly proliferative embryonic cerebrum.ConclusionsConsistent with the predictions of the atavism and antagonistic pleiotropy hypotheses, primate-specific genes, especially those PSGs derived from cell cycle-related genes that emerged in unicellular ancestors, contribute to the early proliferation of the human cerebrum at the cost of hitchhiking by similarly highly proliferative cancer cells.

Female dewlap ornaments are evolutionarily labile and associated with increased diversification rates in Anolis lizards.

The evolution of costly signalling traits has largely focused on male ornaments. However, our understanding of ornament evolution is necessarily incomplete without investigating the causes and consequences of variation in female ornamentation. Here, we study the Anolis lizard dewlap, a trait extensively studied as a male secondary sexual characteristic but present in females of several species. We characterized female dewlaps for 339 species to test hypotheses about their evolution. Our results did not support the hypothesis that female dewlaps are selected against throughout the anole phylogeny. Rather, we found that female dewlaps were evolutionary labile. We also did not find support for the adaptive hypothesis that interspecific competition drove the evolution of female dewlaps. However, we did find support for the pleiotropy hypothesis as species with larger females and reduced sexual size dimorphism were more likely to possess female dewlaps. Lastly, we found that female dewlap presence influenced diversification rates in anoles, but only secondarily to a hidden state. Our results demonstrate that female ornamentation is widespread in anoles and the traditional hypothesis of divergent selection between the sexes does not fully explain their evolution. Instead, female ornamentation is likely to be subject to complex adaptive and non-adaptive evolutionary forces.

Differential Effects of Fundamental and Longitudinal Life History Trade-Offs on Delay Discounting: An Evolutionary Framework

We synthesized life history theory and the antagonistic pleiotropy hypothesis to form an integrative framework for understanding delay discounting (DD). We distinguished between fundamental and longitudinal life history trade-offs to explain individual and age differences of DD. Fundamental life history trade-offs are characterized by life history strategies (LHS), describing how individuals adjust reproductive timing according to childhood environments, while longitudinal life history trade-offs characterize how individuals make trade-offs between early- vs. late-life reproduction as a function of age. Results of a life-span sample (242 Chinese participants) supported several theoretical predictions: (a) slower LHS predicted lower DD; (b) the relationship between chronological age and DD was U-shaped; (c) the effects of age and LHS were differential. Mechanisms underlying fundamental and longitudinal trade-offs were explored. Regarding fundamental trade-offs, LHS mediated the effects of childhood environment on DD. Regarding longitudinal trade-offs, the U-shaped relationship was more evident between physical age and DD: older adults who were in poorer physical health felt older and exhibited a higher DD. Neither the time perspective nor anticipatory time perception mediated the effect of life history trade-offs. We concluded that DD was a product of two distinct life history trade-offs, reflecting both the trait-like quality and age-related development.

Hormonal modulation of reproduction and fertility signaling in polistine wasps

In social insects, it has been suggested that reproduction and the production of particular fertility-linked cuticular hydrocarbons (CHC) may be under shared juvenile hormone (JH) control, and this could have been key in predisposing such cues to later evolve into full-fledged queen pheromone signals. However, to date, only few studies have experimentally tested this “hormonal pleiotropy” hypothesis. Here, we formally test this hypothesis using data from four species of Polistine wasps, Polistes dominula, Polistes satan, Mischocyttarus metathoracicus, and Mischocyttarus cassununga, and experimental treatments with JH using the JH analogue methoprene and the anti-JH precocene. In line with reproduction being under JH control, our results show that across these four species, precocene significantly decreased ovary development when compared with both the acetone solvent-only control and the methoprene treatment. Consistent with the hormonal pleiotropy hypothesis, these effects on reproduction were further matched by subtle shifts in the CHC profiles, with univariate analyses showing that in P. dominula and P. satan the abundance of particular linear alkanes and mono-methylated alkanes were affected by ovary development and our hormonal treatments. The results indicate that in primitively eusocial wasps, and particularly in Polistes, reproduction and the production of some CHC cues are under joint JH control. We suggest that pleiotropic links between reproduction and the production of such hydrocarbon cues have been key enablers for the origin of true fertility and queen signals in more derived, advanced eusocial insects.

APOE‐ε4 carriers have superior recall on the ‘What was where?’ visual short‐term memory binding test at age 70, despite a detrimental effect of β‐amyloid

AbstractBackgroundWhile APOE‐ε4 carriers are at higher risk of Alzheimer’s disease (AD), there is evidence that APOE‐ε4 may have some beneficial effects across the life‐span, including on cognition. It is unclear how such effects may relate to subtle memory decline during the preclinical phase of AD. Two previous studies reported that APOE‐ε4 carriers recalled object locations more accurately than non‐carriers on the “What was where?” visual short‐term memory binding test (10.1016/j.cortex.2016.12.016; 10.1016/j.neurobiolaging.2018.09.017), but these studies did not account for preclinical AD pathology.MethodThe “What was where?” task (Figure 1) was administered to participants in Insight 46 – a sub‐study of the British 1946 birth cohort – who were all born during the same week (aged 69‐71 at assessment (Table 1)). Outcomes included object identification and a sensitive analogue measure of localisation error (the distance between the location reported by the participant and the true location). Two‐dimensional mixture models (10.31234/osf.io/q57fm) were used to isolate three sources of localisation error: imprecision, guessing, and misbinding (swapping an object’s location with that of a different object). β‐Amyloid status (positive / negative) was determined from 18F‐Florbetapir‐PET. Multivariable regression models were used to investigate differential effects of APOE genotype (ε4‐carrier / non‐carrier) and β‐amyloid status on performance in 398 cognitively‐normal participants, adjusting for confounders including a prospectively‐collected measure of childhood cognitive ability.Result APOE‐ε4 and β‐amyloid had opposing effects on object identification, with APOE‐ε4 predicting better recall and β‐amyloid‐positivity predicting poorer recall. APOE‐ε4 carriers also recalled object locations more precisely, but a subtle detrimental effect of β‐amyloid on localisation was seen only among non‐carriers (Table 2, Figure 2). Childhood cognitive ability also predicted performance over 60 years later (Table 2).ConclusionIn this large population‐based sample of cognitively‐normal ∼70‐year‐olds, a positive association between APOE‐ε4 and short‐term visual memory was observed. For the localization measure, this appeared to be protective against a subtle deficit associated with β‐amyloid pathology. This is consistent with the antagonistic pleiotropy hypothesis – whereby a gene controls both beneficial and detrimental traits – and provides novel evidence that these effects persist into older age, even among individuals who may be in the preclinical stages of AD.

Reproduction and signals regulating worker policing under identical hormonal control in social wasps

In social Hymenoptera, fertility and fertility signalling are often under identical hormonal control, and it has been suggested that such hormonal pleiotropies can help to maintain signal honesty. In the common wasp Vespula vulgaris, for example, fertile queens have much higher juvenile hormone (JH) titers than workers, and JH also controls the production of chemical fertility cues present on the females’ cuticle. To regulate reproductive division of labour, queens use these fertility cues in two distinct ways: as queen pheromones that directly suppress the workers’ reproduction as well as to mark queen eggs and enable the workers to recognize and police eggs laid by other workers. Here, we investigated the hormonal pleiotropy hypothesis by testing if experimental treatment with the JH analogue methoprene could enable the workers to lay eggs that evade policing. In support of this hypothesis, we find that methoprene-treated workers laid more eggs, and that the chemical profiles of their eggs were more queen-like, thereby causing fewer of their eggs to be policed compared to in the control. Overall, our results identify JH as a key regulator of both reproduction and the production of egg marking pheromones that mediate policing behaviour in eusocial wasps.

Genetic Basis of Maize Resistance to Multiple Insect Pests: Integrated Genome-Wide Comparative Mapping and Candidate Gene Prioritization.

Several species of herbivores feed on maize in field and storage setups, making the development of multiple insect resistance a critical breeding target. In this study, an association mapping panel of 341 tropical maize lines was evaluated in three field environments for resistance to fall armyworm (FAW), whilst bulked grains were subjected to a maize weevil (MW) bioassay and genotyped with Diversity Array Technology’s single nucleotide polymorphisms (SNPs) markers. A multi-locus genome-wide association study (GWAS) revealed 62 quantitative trait nucleotides (QTNs) associated with FAW and MW resistance traits on all 10 maize chromosomes, of which, 47 and 31 were discovered at stringent Bonferroni genome-wide significance levels of 0.05 and 0.01, respectively, and located within or close to multiple insect resistance genomic regions (MIRGRs) concerning FAW, SB, and MW. Sixteen QTNs influenced multiple traits, of which, six were associated with resistance to both FAW and MW, suggesting a pleiotropic genetic control. Functional prioritization of candidate genes (CGs) located within 10–30 kb of the QTNs revealed 64 putative GWAS-based CGs (GbCGs) showing evidence of involvement in plant defense mechanisms. Only one GbCG was associated with each of the five of the six combined resistance QTNs, thus reinforcing the pleiotropy hypothesis. In addition, through in silico co-functional network inferences, an additional 107 network-based CGs (NbCGs), biologically connected to the 64 GbCGs, and differentially expressed under biotic or abiotic stress, were revealed within MIRGRs. The provided multiple insect resistance physical map should contribute to the development of combined insect resistance in maize.

The dark side of coloration: Ecogeographical evidence supports Gloger's rule in American marsupials.

Geographical distribution of color phenotypes and associations with ecological predictors remains poorly understood. An important geographic pattern concerning this topic is Gloger's rule, which predicts the increase of pigmentation in endothermic animals from cold and dry to warm and wet environments. Didelphid marsupials exhibit a variety of color patterns, ranging from light and dark uniform to more complex colorations. However, surprisingly little is known about the adaptive significance of dark coloration in this singular group of mammals. Using a phylogenetic comparative approach, we investigated whether coloration in different body regions of didelphids (i.e., dorsum and face) is associated with variables representing heat and humidity of the environment, as predicted by Gloger's rule. We demonstrated that Gloger's rule explains the interspecific color variation in American marsupials, especially when considering the facial region. Thus, dark coloration was more frequent among didelphid species occupying warm and wet environments than cold and dry environments. We also discuss the selective forces that can potentially explain coat color variation in didelphid marsupials, including camouflage, pathogen resistance, and pleiotropy hypotheses.

The role of genetic constraints and social environment in explaining female extra-pair mating.

Why do females of socially monogamous species engage in extra-pair copulations? This long-standing question remains a puzzle, because the benefits of female promiscuous behavior often do not seem to outweigh the costs. Genetic constraint models offer an answer by proposing that female promiscuity emerges through selection favoring alleles that are either beneficial for male reproductive success (intersexual pleiotropy hypothesis) or beneficial for female fecundity (intrasexual pleiotropy hypothesis). A previous quantitative genetic study on captive zebra finches, Taeniopygia guttata, reported support for the first, but not for the second hypothesis. Here, we re-examine both hypotheses based on data from lines selected for high and low male courtship rate. In contrast to previous conclusions, our new analyses clearly reject the hypothesis that male and female promiscuity are genetically homologous traits. We find some support for a positive genetic correlation between female promiscuity and fecundity. This study also shows that the behavioral outcome of extra-pair courtships primarily depends on individual-specific female preferences and not on the "attractiveness" of the social mate. In contrast, patterns of paternity are strongly influenced by the social partner and the pair bond, presumably reflecting variation in copulation behavior, fertility, or sperm competitiveness.

Effect of apolipoprotein E polymorphism on cognition and brain in the Cambridge Centre for Ageing and Neuroscience cohort.

Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the ‘antagonistic pleiotropy’ hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report – https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18–88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.

Defence compounds in pollen: why do they occur and how do they affect the ecology and evolution of bees?

Pollen plays two important roles in angiosperm reproduction, serving as a vehicle for the plant's male gametes, but also, in many species, as a lure for pollen-feeding animals. Despite being an important food source for many pollinators, pollen often contains compounds with known deterrent or toxic properties, as documented in a growing number of studies. Here we review these studies and discuss the role of pollen defensive compounds in the coevolutionary relationship between plants and bees, the preeminent consumers of pollen. Next, we evaluate three hypotheses that may explain the existence of defensive compounds in pollen. The pleiotropy hypothesis, which proposes that defensive compounds in pollen merely reflect physiological spillover from other plant tissues, is contradicted by evidence from several species. Although plants may experience selection to defend pollen against poor-quality pollinators, we also find only partial support for the protection-against-pollen-collection-hypothesis. Finally, pollen defences might protect pollen from colonisation by antagonistic microorganisms (antimicrobial hypothesis), although data to evaluate this idea are scarce. Further research on the effects of pollen defensive compounds on pollinators, pollen thieves, and pollen-colonising microbes will be needed to understand why many plants have chemically defended pollen, and the consequences of those defences for pollen consumers.

The Evolution of Tau Phosphorylation and Interactions.

Tau is a neuronal microtubule-associated protein (MAP) that is involved in the regulation of axonal microtubule assembly. However, as a protein with intrinsically disordered regions (IDRs), tau also interacts with many other partners in addition to microtubules. Phosphorylation at selected sites modulates tau’s various intracellular interactions and regulates the properties of IDRs. In Alzheimer’s disease (AD) and other tauopathies, tau exhibits pathologically increased phosphorylation (hyperphosphorylation) at selected sites and aggregates into neurofibrillary tangles (NFTs). By bioinformatics means, we tested the hypothesis that the sequence of tau has changed during the vertebrate evolution in a way that novel interactions developed and also the phosphorylation pattern was affected, which made tau prone to the development of tauopathies. We report that distinct regions of tau show functional specialization in their molecular interactions. We found that tau’s amino-terminal region, which is involved in biological processes related to “membrane organization” and “regulation of apoptosis,” exhibited a strong evolutionary increase in protein disorder providing the basis for the development of novel interactions. We observed that the predicted phosphorylation sites have changed during evolution in a region-specific manner, and in some cases the overall number of phosphorylation sites increased owing to the formation of clusters of phosphorylatable residues. In contrast, disease-specific hyperphosphorylated sites remained highly conserved. The data indicate that novel, non-microtubule related tau interactions developed during evolution and suggest that the biological processes, which are mediated by these interactions, are of pathological relevance. Furthermore, the data indicate that predicted phosphorylation sites in some regions of tau, including a cluster of phosphorylatable residues in the alternatively spliced exon 2, have changed during evolution. In view of the “antagonistic pleiotropy hypothesis” it may be worth to take disease-associated phosphosites with low evolutionary conservation as relevant biomarkers into consideration.

Pleiotropic Effects of mTOR and Autophagy During Development and Aging.

Autophagy as a ubiquitous catabolic process causes degradation of cytoplasmic components and is generally considered to have beneficial effects on health and lifespan. In contrast, inefficient autophagy has been linked with detrimental effects on the organism and various diseases, such as Parkinson’s disease. Previous research, however, showed that this paradigm is far from being black and white. For instance, it has been reported that increased levels of autophagy during development can be harmful, but become advantageous in the aging cell or organism, causing enhanced healthspan and even longevity. The antagonistic pleiotropy hypothesis postulates that genes, which control various traits in an organism, can be fitness-promoting in early life, but subsequently trigger aging processes later. Autophagy is controlled by the mechanistic target of rapamycin (mTOR), a key player of nutrient sensing and signaling and classic example of a pleiotropic gene. mTOR acts upstream of transcription factors such as FOXO, NRF, and TFEB, controlling protein synthesis, degradation, and cellular growth, thereby regulating fertility as well as aging. Here, we review recent findings about the pleiotropic role of autophagy during development and aging, examine the upstream factors, and contemplate specific mechanisms leading to disease, especially neurodegeneration.

Impact of Spatial Heterogeneity on Drosophila melanogaster Adaptation to Unfavourable Food Media: The Results of an Experimental Evolution Study

The spatiotemporal variability of environmental conditions is assumed to have a strong impact on the course of microevolution processes, including the efficiency of adaptation to unfavourable conditions and the probability of ecological specialization or, conversely, generalization (the acquisition of multipurpose adaptations). The experimentаl research on these effects is still at the initial stage, and the temporal, rather than spatial, heterogeneity of the environment is analyzed in most studies. We performed an evolution experiment that involved the adaptation of Drosophila melanogaster lines to two unfavourable media: a high-salt (S) medium and a starch-based (St) medium of low nutritional value. Some of the experimental lines had access to one of the two unfavourable media only (homogeneous environment), whereas the others had access to both media and could choose between them (heterogeneous environment). The control lines were reared on a normal laboratory medium (N) that provided favourable conditions for the species. The degree of adaptation of lines obtained on the S, St, and N media was assessed after one and a half years of adaptation. The reproduction efficiency (the amount of adult progeny derived from a pair of parents within a specified time interval), adult lifespan, oviposition rate, and ageing-related changes in the former were assessed. Flies reared in a heterogeneous environment were superior to those reared in a homogeneous one with regard to most adaptation parameters on all three media. The results agree with the hypothesis concerning the promotion of generalization and more efficient adaptation to unfavourable conditions upon spatial heterogeneity of the environment. The obtained data do not support the hypothesis of antagonistic pleiotropy, which leads to “evolutionary trade-offs” and a lower competitiveness of generalists than that of specialists under stable conditions.

Apolipoprotein ε4 is associated with better cognitive control allocation in healthy young adults

Many gene variants may impair our health and cognitive abilities at old age, but some of them paradoxically improve the same or similar functions at much younger age (antagonistic pleiotropy hypothesis). Such a diametric pattern may also hold true for the ancestral Apolipoprotein E (APOE) ε4 allele, which increases the risk for Alzheimer's disease and cognitive decline in old age, but may benefit (pre)frontal (executive) functions in young carriers. We therefore investigated potential cognitive benefits of the risk allele on cognitive control capacities and top-down control allocation (“metacontrol”) in n = 190 healthy young adults.On a behavioral level, we found young APOE ε4 carriers to better adapt to different degrees of cognitive control requirements, with superior performance in case of high control demands. On a neurophysiological level, these group differences were reflected by modulations of the N450 component, which were rooted in activation differences of the superior frontal gyrus (SFG, BA8). Taken together, our results suggest that young ε4 carriers are more efficient than non-carriers at allocating cognitive control resources based on the actual task requirements (i.e. metacontrol), as they seem to experience less conflict/exert less effort and recruit fewer additional prefrontal areas when task set complexity increases. We further found that ε2 carriers processed implicit spatial stimulus features to a stronger degree than ε3 and ε4 carriers, but failed to benefit from this, as the additional information likely increased response selection conflicts. This finding should however be treated with ample caution as the group of ε2 carriers was comparatively small.