Biology subjects

Maklakov, A. A.

Publications and source records attributed to Maklakov, A. A..

18 recordsLinked to original sources

bioRxiv2026

Germline removal reprograms somatic genome maintenance towards faster, energy-efficient, high-fidelity DNA defence and repair

Germ cells maintain their genomes with greater fidelity than somatic cells, yet how germline status systemically shapes somatic genome protection in vertebrates remains poorly understood. Combining germline ablation with multi-organ transcriptomics in zebrafish (Danio rerio), we dissected germline control of somatic DNA repair and genotoxic stress responses. Using CRISPR/Cas9 mediated knockout of the germline determinant gene dnd-1, we compared germline free (GLF) males and germline carrying (GLC) siblings across five somatic organs at baseline and following sub-lethal {gamma}-irradiation, with sampling at 3 h and 24 h post-irradiation. Germline ablation profoundly reorganised baseline somatic transcription, favouring shorter, exon rich genes with functions in chromatin integrity, cell cycle control, and high-fidelity DNA repair, and attenuating DREAM complex repression of canonical repair targets. After irradiation, GLF fish mounted a faster response that rapidly engaged homologous recombination, checkpoint control, and proteostasis, whereas GLC fish remained biased toward biosynthetic and translational programmes. Hedgehog signalling acted as a transient regulatory node coordinating the strain-specific DNA damage response, and a repeat-rich region of chromosome 4 emerged as a hotspot of coordinated gene transposable element (TE) activity. GLF soma showed reduced early TE expression after irradiation, with LTR retrotransposons showing the strongest concordance with nearby differentially expressed genes. Our findings identify germline status as a systems level switch that tunes somatic genome maintenance and TE dynamics across multiple organs and provide a molecular framework for understanding how the germline regulates somatic ageing in vertebrates.

genetics↗

bioRxiv2026

Sexual selection purges mutation load, but not overall genetic diversity in populations, decreasing vulnerability to extinction

Theory suggests sexual selection will enhance population viability by purging deleterious alleles. However, direct genomic evidence for this fundamental idea is scarce and contradictory. We combined long-term experimental evolution with whole-genome re-sequencing to directly test how sexual selection affects mutation load, genomic divergence and extinction risk in Tribolium castaneum. After 156 generations, populations evolving under strong sexual selection carried substantially fewer deleterious alleles than populations under weak sexual selection, based on both individual-level estimates of missense and nonsense variants and population-level Rxy analyses, indicating more efficient purging of deleterious alleles. In contrast, nucleotide diversity and runs of homozygosity were similar across treatments, indicating that purging was targeted at deleterious variation, and that reduced mutation load in populations under strong sexual selection was not explained by demographic effects. Importantly, population-level mutation load estimates provided best explained extinction risk under inbreeding, directly linking sexual selection to purging and population viability for the first time. Genome scans of high and low sexual selection populations revealed peaks of divergence, enriched for genes involved in courtship, sex discrimination, and seminal fluid proteins. Our results provide direct genomic evidence that sexual selection can reduce mutation load without eroding standing genetic diversity and thus adaptive potential, while driving adaptive divergence in reproductive traits. This beneficial purging may help explain the widespread prevalence of sexual reproduction in nature despite inherent costs and have important ramifications as to how we manage populations of conservation concern. Significance StatementA long standing and unconfirmed prediction is that sexual selection can improve population health by biasing reproduction away from individuals with high deleterious mutation load. However, direct genomic evidence is lacking, and the indirect data available are scant and contradictory. Now, using whole-genome resequencing of experimental evolved beetle populations, we show that populations evolving under stronger sexual selection carry fewer deleterious mutations and, importantly, are less vulnerable to extinction. Our results provide the first direct genomic support for this long-debated evolutionary process that may help explain the widespread prevalence of sexual reproduction in nature. Our findings also highlight the importance of allowing sexual selection to act in populations of conservation concern.

evolutionary biology↗

bioRxiv2025

Lifespan-extending downregulation of insulin signalling reduces germline mutation load

Reduced insulin/IGF-1 signalling (IIS) robustly extends lifespan and enhances somatic stress resistance across taxa, yet its consequences for germline genome integrity remain unclear. Here we combine multigenerational mutation accumulation with whole-genome sequencing in C. elegans to test whether adulthood-only IIS downregulation can simultaneously promote somatic maintenance and limit germline mutational burden. We reduced IIS by adult-onset daf-2 RNAi in wild-type and heritable RNAi-deficient (hrde-1) backgrounds, allowing either spontaneous or UV-induced germline mutations to accumulate over multiple generations. In wild-type animals, reduced IIS lowered germline single-nucleotide mutation rates by up to [~]50% and prevented the UV-induced elevation in mutation rate, without detectable costs to fecundity or lineage persistence. By contrast, in hrde-1 mutants the same intervention increased both point mutations and transposable-element-driven insertions under UV exposure, accelerating lineage extinction. Thus, the genome-protective effect of reduced IIS critically requires the germline nuclear Argonaute HRDE-1, which mediates small-RNA-guided epigenetic silencing. Functional annotation of germline variants revealed enrichment in pathways linked to development, cellular maintenance and conserved longevity regulators, including IIS and mTOR, and identified high-impact mutations in genes with human orthologs implicated in neurodegeneration and cancer. Our findings show that IIS can coordinate somatic and germline maintenance in concert, rather than in competition, through an HRDE-1-dependent epigenetic pathway. This work positions nutrient-sensing IIS as a central regulator of germline genome stability and suggests that IIS downregulation can reduce germline mutation load while extending lifespan, with broad implications for biogerontology and evolutionary biology.

evolutionary biology↗

bioRxiv2025

Evolutionary trade-offs between intergenerational and transgenerational fitness effects

Intergenerational and transgenerational fitness effects can shape evolutionary processes. Theoretically, however, intergenerational and transgenerational effects can trade-off with each other with profound consequences for evolutionary processes. Here we show that beneficial intergenerational effects that increase offspring fitness can result in detrimental transgenerational effects that decrease great-grand offspring fitness. We combined theoretical modelling and experimental approaches to investigate multigenerational fitness trade-offs induced by larval starvation in Caenorhabditis elegans. We demonstrate that larval starvation triggers a cascading effect: starved individuals suffered marked fitness losses, their direct offspring enjoyed fitness gains in both starvation and ad libitum environments, but great-grand-offspring paid fitness costs. Demographic simulation models revealed that genotypes exploiting this short-term intergenerational advantage outcompete rival genotypes despite the deferred transgenerational debt. Our findings demonstrate that adaptive intergenerational gains can be intrinsically linked to maladaptive transgenerational outcomes, challenging the assumption that transgenerational effects are inherently beneficial and highlighting the role of multigenerational trade-offs in evolution.

evolutionary biology↗

bioRxiv2025

Mutation accumulation underpins evolution of lifespan extension by dietary restriction

Dietary restriction (DR) extends lifespan in animals and plants, but its evolutionary causes are elusive. Adaptive hypotheses posit that DR extends lifespan because organisms reallocate resources from reproduction to survival ( disposable soma) or recycle cellular waste to maximize either their immediate reproduction ( nutrient recycling) or survival ( clean cupboards). We developed an experimental paradigm that tricks Caenorhabditis elegans nematodes into increasing their reproductive effort under DR via food odour, thus allowing us to test these hypotheses. We found that experimentally increased reproduction under DR does not affect immediate or long-term survival benefits compared to DR animals that did not reproduce, thus refuting all three adaptive hypotheses. Our data suggest that a large part of suppressed fertility under DR is a result of organisms refraining from producing offspring in a poor environment. We developed a model based on Hamiltonian forces of selection to show that lifespan extension under DR evolves because DR suppresses fertility, directly increasing selection against mortality in DR environment. Our analytical approach suggests that DR-driven lifespan extension can evolve under a broader range of conditions not previously anticipated, such as a relaxed need for physiological or genetic trade-offs. Instead, we show how reduced survival on plentiful food can evolve via mutation accumulation.

evolutionary biology↗

bioRxiv2023

Early-adulthood intermittent fasting and reduced insulin/IGF-1 signalling additively increase lifespan and slow down reproductive ageing

The developmental theory of ageing proposes that age-specific decline in the force of natural selection results in suboptimal levels of gene expression in adulthood, leading to functional senescence. This theory explicitly predicts that optimising gene expression in adulthood can ameliorate functional senescence and improve fitness. Reduced insulin/IGF-1 signalling (rIIS) extends the reproductive lifespan of Caenorhabditis elegans at the cost of reduced reproduction. Here, we show that adulthood-only rIIS improves late-life reproduction without any detrimental effects on other life-history traits in both benign and stressful conditions. Remarkably, we show that rIIS additively extends late-life reproduction and lifespan when animals are exposed to a fluctuating food environment - intermittent fasting (IF) - resulting in reduced food intake in early adulthood. Full factorial genome-wide RNA-Seq across the life course demonstrated that IF and rIIS modulate the age-specific expression of pro-longevity genes. IF, rIIS and combined IF + rIIS treatment downregulated genes involved in peptide metabolism in early life and differentially regulated immunity genes in later life. Importantly, combined IF + rIIS treatment uniquely regulated a large cluster of genes in mid-life that are associated with immune response. These results suggest that optimising gene expression in adulthood can decelerate reproductive ageing and increase fitness.

molecular biology↗

bioRxiv2023

Sex-specific growth and lifespan effects of germline removal in the dioecious nematode Caenorhabditis remanei

Germline regulates the expression of life-history traits and mediates the trade-off between reproduction and somatic maintenance. However, germline maintenance in itself can be costly, and the costs can vary between the sexes depending on the number of gametes produced across the lifetime. We tested this directly by germline ablation using glp-1 RNAi in a dioecious nematode Caenorhabditis remanei. Germline removal strongly increased heat-shock resistance in both sexes, thus confirming the role of the germline in regulating somatic maintenance. However, germline removal resulted in increased lifespan only in males. High costs of mating strongly reduced lifespan in both sexes and obliterated the survival benefit of germline-less males even though neither sex produced any offspring. Furthermore, germline removal reduced male growth before maturation but not in adulthood, while female growth rate was reduced both before and especially after maturation. Thus, germline removal improves male lifespan without major growth costs, while germline-less females grow slower and do not live longer than reproductively functional counterparts in the absence of environmental stress. Overall, these results suggest that germline maintenance is costlier for males than for females.

evolutionary biology↗

bioRxiv2022

Fasting increases investment in soma upon refeeding at the cost of gamete quality in zebrafish

Fasting increases lifespan in invertebrates, improves biomarkers of health in vertebrates, and is increasingly proposed as a promising route to improve human health. Nevertheless, little is known about how fasted animals use resources upon refeeding, and how such decisions affect putative trade-offs between somatic growth and repair, reproduction, and gamete quality. Such fasting-induced trade-offs are based on strong theoretical foundations and have been recently discovered in invertebrates, but the data on vertebrates is lacking. Here we report that fasted female zebrafish, Danio rerio, increase investment in soma upon refeeding but it comes at a cost of egg quality. Specifically, an increase in fin re-growth was accompanied by a reduction in 24-hours post-fertilization offspring survival. Refed males showed a reduction in sperm velocity and impaired 24-hour post-fertilisation offspring survival. These findings underscore the necessity of considering the impact on eggs and sperm when assessing evolutionary and biomedical implications of lifespan-extending treatments in females and males and call for careful evaluation of the effects of fasting (both during and post) on fertilisation.

evolutionary biology↗

bioRxiv2021

Inbreeding reduces fitness of seed beetles under thermal stress

Human-induced environmental change can influence populations both at the global level through climatic warming and at the local level through habitat fragmentation. As populations become more isolated, they can suffer from high levels of inbreeding which contributes to a reduction in fitness, termed inbreeding depression. However, it is still unclear if this increase in homozygosity also results in a corresponding increase in sensitivity to stressful conditions, which could intensify the already detrimental effects of environmental warming. Here, in a fully factorial design, we assessed the life-long impact of increased mutation load and elevated temperature on key life history traits in the seed beetle, Callosobruchus maculatus. We found that beetles raised at higher temperatures had far reduced fitness and survival than beetles from control temperatures. Importantly, these negative effects were exacerbated in inbred beetles as a result of increased mutation load, with further detrimental effects manifesting on individual hatching probability and lifetime reproductive success. These results reveal the harmful impact that increasing temperature and likelihood of habitat fragmentation due to anthropogenetic changes in environmental conditions could have on populations of organisms worldwide.

evolutionary biology↗

bioRxiv2021

Beneficial cumulative effects of old parental age on offspring fitness

Old parental age is commonly associated with negative effects on offspring life-history traits. Such parental effect senescence is predicted to have a cumulative detrimental effect over successive generations. However, old parents may benefit from producing high-quality offspring when these compete for seasonal resources. Thus, old parents may choose to increase investment in their offspring, thereby producing fewer but larger and more competitive progeny. We show that Caenorhabditis elegans hermaphrodites increase parental investment with advancing age, resulting in fitter offspring who reach their reproductive peak earlier. Remarkably, these effects increased over six successive generations of breeding from old parents and were subsequently reversed following a single generation of breeding from a young parent. These results contradict the theory that old parents transfer a cumulative detrimental "ageing factor" to their offspring. Instead, our findings support the hypothesis that offspring of old parents receive more resources and convert them into increasingly faster life-histories.

evolutionary biology↗

bioRxiv2020

Reduced insulin signalling in adulthood protects soma and germline under mutation accumulation

Adulthood-only downregulation of insulin/IGF-1 signalling (IIS), an evolutionarily conserved pathway regulating resource allocation between somatic maintenance and reproduction, increases lifespan without fecundity cost in the nematode, Caenorhabditis elegans. However, long-term multigenerational effects of reduced IIS remain unexplored and are proposed to carry costs for offspring quality. To test this hypothesis, we ran a mutation accumulation (MA) experiment and downregulated IIS in half of the 400 MA lines by silencing daf-2 gene expression using RNA interference (RNAi) across 40 generations. Contrary to the prediction, adulthood-only daf-2 RNAi reduced extinction of MA lines both under UV-induced and spontaneous mutation accumulation. Fitness of the surviving UV-induced MA lines was higher under daf-2 RNAi. Reduced IIS increased intergenerational F1 offspring fitness under UV stress but had no quantifiable transgenerational effects. Functional hrde-1 was required for the benefits of multigenerational daf-2 RNAi. Overall, we found net benefit to fitness from multigenerational reduction of IIS and the benefits became more apparent under stress. Because reduced daf-2 expression during development carries fitness costs, we suggest that our findings are best explained by the developmental theory of ageing, which maintains that the decline in the force of selection with age results in poorly regulated gene expression in adulthood.

evolutionary biology↗

bioRxiv2020

Transgenerational fitness effects of lifespan extension by dietary restriction in Caenorhabditis elegans

Dietary restriction increases lifespan in a broad variety of organisms and improves health in humans. However, long-term transgenerational consequences of dietary interventions are poorly understood. Here we investigated the effect of dietary restriction by temporary fasting (TF) on mortality risk, age-specific reproduction and fitness across three generations of descendants in C. elegans. We show that while TF robustly reduces mortality risk and improves late-life reproduction in the parental generation (P0), it has a wide range of both positive and deleterious effects on future generations (F1-F3). Remarkably, great-grandparental exposure to TF in early-life reduces fitness and increases mortality risk of F3 descendants to such an extent that TF no longer promotes a lifespan extension. These findings reveal that transgenerational trade-offs accompany the instant benefits of dietary restriction underscoring the need to consider fitness of future generations in pursuit of healthy ageing.

evolutionary biology↗

bioRxiv2020

Variable environments select for short lifespan

The role of environmental variation in the evolution of lifespan is contested. Classic theory predicts that variable environments favour the evolution of long life, but recent theoretical work suggests that environmental variation can instead select for shorter lifespan when the changes are rapid relative to generation time. Here, we used experimental evolution to study how lifespan evolves in response to temperature variation. Genetically diverse populations of the outcrossing nematode Caenorhabditis remanei, were exposed to a novel, stressful temperature for 30 generations, under stable, gradually warming or fluctuating thermal regimes. We found the evolution of shorter lifespan in populations exposed to environments that fluctuated within the individuals lifetime, compared to populations evolving in stable warm temperature. While climate warming is predicted to increase environmental stochasticity, our results show that fast temperature cycles can rapidly select for short lifespan.

evolutionary biology↗

bioRxiv2020

Evolutionary causes of lifespan extension by dietary restriction: linking theory and mechanisms

Dietary restriction (DR), reduced food intake without malnutrition, increases lifespan across a broad range of taxa, but the evolutionary underpinning of this phenomenon is poorly understood. The resource reallocation hypothesis proposes that dietary restricted animals divert resources from reproduction to somatic maintenance to increase survival in times of nutrient scarcity in favour of future reproduction. The "longevity by-product" hypothesis proposes instead that dietary restricted animals increase nutrient recycling via autophagy to maximise immediate reproduction, thereby reducing cellular toxic waste and leading to longer lifespan as an unselected by-product. The "longevity by-product" hypothesis makes a unique prediction that blocking autophagy in DR animals will simultaneously reduce lifespan and reproduction. To test the adaptive value of autophagy under dietary restriction, we inhibited autophagy using bec-1 RNAi knockdown in DR and fully-fed Caenorhabditis elegans nematodes. Our findings confirm that autophagic inhibition results in a significantly shorter lifespan under DR, suggesting that autophagy is important for survival in times of famine. Remarkably, we also show that inhibiting autophagy throughout adult life significantly increases reproduction in both dietary restricted and fully fed worms. Moreover, this did not come at a transgenerational cost to offspring fitness. Our results suggest that autophagy is an energetically costly process that reduces resources available for reproduction, but is necessary for survival during famine, and are thus consistent with the resource reallocation hypothesis.

evolutionary biology↗

bioRxiv2019

Cost-free lifespan extension via optimisation of gene expression in adulthood supports the developmental theory of ageing

Classic theory upholds that energy trade-offs between reproduction and somatic maintenance underpin the evolution of ageing and lifespan. In contrast, the developmental theory of ageing (DTA) suggests that organismal senescence is caused by dysregulated gene expression in adulthood due to decline in selection gradients with age. The DTA predicts that age-specific optimisation of gene expression can improve survival without fitness costs. Here we investigated consequences for survival, reproduction, egg size and fitness of early-life, adulthood and post-reproductive onset of RNAi knockdown of five well-described \"longevity\" genes involved in key biological processes in Caenorhabditis elegans nematodes: nutrient-sensing signalling via insulin/IGF-1 (age-1) and target-of-rapamycin (raga-1) pathways, global protein synthesis (ifg-1), global protein synthesis in somatic cells (ife-2) and mitochondrial respiration (nuo-6). Downregulation of these genes in adulthood and/or during post-reproductive period improves survival, while there was little evidence for a link between impaired reproduction and extended lifespan. Our findings demonstrate that hyper-function of diverse physiological processes after sexual maturation is detrimental for survival. Therefore, optimisation of gene expression in adult organisms can ameliorate ageing and increase fitness.

evolutionary biology↗

bioRxiv2019

Kin selection and sexual conflict: male relatedness and familiarity do not affect female fitness in seed beetles

Theory maintains that kin selection can mediate sexual conflict because within-group male relatedness should reduce male-male competition, thereby reducing collateral harm to females. We tested whether male relatedness and familiarity can lessen female harm in the seed beetle Callosobruchus maculatus. Neither male relatedness nor familiarity influenced female lifetime reproductive success or individual fitness. However, male relatedness, but not familiarity, marginally improved female survival. Because male relatedness improved female survival in late life when C. maculatus females are no longer producing offspring, our results do not provide support for the role of kin selection in mediating sexual conflict. The fact that male relatedness improves the post-reproductive part of female life cycle strongly suggests that the effect is non-adaptive. We discuss adaptive and non-adaptive mechanisms that could result in reduced female harm in this and previous studies and suggest that cognitive error is a likely explanation.

evolutionary biology↗

bioRxiv2019

Environmental variation mediates the evolution of anticipatory parental effects

Theory maintains that when future environment is predictable, parents should adjust the phenotype of their offspring to match the anticipated environment. The plausibility of positive anticipatory parental effects is hotly debated and the experimental evidence for the evolution of such effects is currently lacking. We experimentally investigated the evolution of anticipatory maternal effects in a range of environments that differ drastically in how predictable they are. Populations of the nematode Caenorhabditis remanei, adapted to 20{degrees}C, were exposed to a novel temperature (25{degrees}C) for 30 generations with either positive or zero correlation between parent and offspring environment. We found that populations evolving in novel environments that were predictable across generations evolved a positive anticipatory maternal effect, since they required maternal exposure to 25{degrees}C to achieve maximum reproduction in that temperature. In contrast, populations evolving under zero environmental correlation had lost this anticipatory maternal effect. Similar but weaker patterns were found if instead rate-sensitive population growth was used as a fitness measure. These findings demonstrate that anticipatory parental effects evolve in response to environmental change so that ill-fitting parental effects can be rapidly lost. Evolution of positive anticipatory parental effects can aid population viability in rapidly changing but predictable environments. Impact summaryParents can help their offspring by adjusting offsprings phenotype to match their environment. Such anticipatory parental effects would be beneficial, but only if parents can accurately predict the environment in which their offspring will develop and live. The plausibility of such anticipatory parental effects is hotly debated. The theory is clear that the predictability of the environment should play a defining role. We used an "experimental evolution" approach in a fast reproducing nematode worm Caenorhabditis remanei to tackle this question and follow the evolution of parental effects in different environments in real-time. We found that populations evolving in a novel but predictable environment indeed had anticipatory parental effects that increased fitness of their offspring in that environment. In contrast, when evolving in an unpredictable environment where such parental effects would be disadvantageous, the parental effect was rapidly lost in evolution. Our novel experimental environments were constructed by exposing worms to increased temperature. Anticipatory parental effects play an important role in adaptation to novel environments and will affect the viability of populations under climate heating.

evolutionary biology↗

bioRxiv2018

Reduced insulin/IGF-1 signalling in adult parents increases offspring fitness

Classical theory maintains that ageing evolves via energy trade-offs between reproduction and survival leading to accumulation of unrepaired cellular damage with age. In contrast, the emerging new theory postulates that ageing evolves because of deleterious late-life hyper-function of reproduction-promoting genes leading to excessive biosynthesis in late-life. The hyper-function theory uniquely predicts that optimizing nutrient-sensing molecular signalling in adulthood can simultaneously postpone ageing and increase Darwinian fitness. Here we show that reducing evolutionarily conserved insulin/IGF-1 nutrient-sensing signalling via daf-2 RNA interference (RNAi) fulfils this prediction in Caenorhabditis elegans nematodes. Long-lived daf-2 RNAi parents showed normal fecundity as self-fertilizing hermaphrodites and improved late-life reproduction when mated to males. Remarkably, the offspring of daf-2 RNAi parents had higher Darwinian fitness across three different genotypes. Thus, reduced nutrient-sensing signalling in adulthood improves both parental longevity and offspring fitness supporting the emerging view that sub-optimal gene expression in late-life lies at the heart of ageing. Impact StatementUnderstanding mechanisms underpinning ageing is fundamental to improving quality of life in an increasingly long-lived society. Recent breakthroughs have challenged the long-standing paradigm that the energy trade-off between reproduction and somatic maintenance causes organismal senescence via slow accumulation of unrepaired cellular damage with age. The emerging new theory of ageing provides a conceptually novel framework by proposing that ageing is a direct consequence of physiological processes optimized for early-life function, such as growth and early-life reproduction, that are running too high (i.e. at hyperfunction) in late adulthood. Contrary to the classic view based on damage accumulation, the hyperfunction theory proposes that suboptimal gene expression in late-life causes ageing via excessive biosynthesis. Thus, the hyperfunction theory uniquely predicts that longevity and Darwinian fitness can be simultaneously increased by reducing unnecessarily high levels of nutrient-sensing signalling in adulthood. Here we show that reducing evolutionarily conserved nutrient-sensing signalling pathway fulfils this prediction in Caenorhabditis elegans nematodes. We found that downregulation of the insulin/IGF-1 signalling in adult C. elegans nematodes not only improves longevity but, most intriguingly, increases fitness of the resulting offspring in the next generation. We found support for increase in offspring fitness across different genetic backgrounds. Our findings contradict the theoretical conjecture that energy trade-offs between growth, reproduction and longevity is the universal cause of senescence and provide strong experimental support for the emerging hyperfunction theory of ageing.

genetics↗