A large-effect fitness trade-off across environments is explained by a single mutation affecting cold acclimation.

Identifying the genetic basis of local adaptation and fitness trade-offs across environments is a central goal of evolutionary biology. Cold acclimation is an adaptive plastic response for surviving seasonal freezing, and costs of acclimation may be a general mechanism for fitness trade-offs across environments in temperate zone species. Starting with locally adapted ecotypes of Arabidopsis thaliana from Italy and Sweden, we examined the fitness consequences of a naturally occurring functional polymorphism in CBF2. This gene encodes a transcription factor that is a major regulator of cold-acclimated freezing tolerance and resides within a locus responsible for a genetic trade-off for long-term mean fitness. We estimated the consequences of alternate genotypes of CBF2 on 5-y mean fitness and fitness components at the native field sites by comparing near-isogenic lines with alternate genotypes of CBF2 to their genetic background ecotypes. The effects of CBF2 were validated at the nucleotide level using gene-edited lines in the native genetic backgrounds grown in simulated parental environments. The foreign CBF2 genotype in the local genetic background reduced long-term mean fitness in Sweden by more than 10%, primarily via effects on survival. In Italy, fitness was reduced by more than 20%, primarily via effects on fecundity. At both sites, the effects were temporally variable and much stronger in some years. The gene-edited lines confirmed that CBF2 encodes the causal variant underlying this genetic trade-off. Additionally, we demonstrated a substantial fitness cost of cold acclimation, which has broad implications for potential maladaptive responses to climate change.

Contraception ends the genetic maintenance of human same-sex sexual behavior.

Because human same-sex sexual behavior (SSB) is heritable and leads to fewer offspring, it is puzzling why SSB-associated alleles have not been selectively purged. Current evidence supports the antagonistic pleiotropy hypothesis that SSB-associated alleles benefit individuals exclusively performing opposite-sex sexual behavior by increasing their number of sexual partners and consequently their number of offspring. However, by analyzing the UK Biobank, here, we show that having more sexual partners no longer predicts more offspring since the availability of oral contraceptives in the 1960s and that SSB is now genetically negatively correlated with the number of offspring, suggesting a loss of SSB's genetic maintenance in modern societies.

Did the creeping vole sex chromosomes evolve through a cascade of adaptive responses to a selfish x chromosome?

The creeping vole Microtus oregoni exhibits remarkably transformed sex chromosome biology, with complete chromosome drive/drag, X-Y fusions, sex reversed X complements, biased X inactivation, and X chromosome degradation. Beginning with a selfish X chromosome, I propose a series of adaptations leading to this system, each compensating for deleterious consequences of the preceding adaptation: (1) YY embryonic inviability favored evolution of a selfish feminizing X chromosome; (2) the consequent Y chromosome transmission disadvantage favored X-Y fusion ("XP "); (3) Xist-based silencing of Y-derived XP genes favored a second X-Y fusion ("XM "); (4) X chromosome dosage-related costs in XP XM males favored the evolution of XM loss during spermatogenesis; (5) X chromosomal dosage-related costs in XM 0 females favored the evolution of XM drive during oogenesis; and (6) degradation of the non-recombining XP favored the evolution of biased X chromosome inactivation. I discuss recurrent rodent sex chromosome transformation, and selfish genes as a constructive force in evolution.

An antagonistic pleiotropic gene regulates the reproduction and longevity tradeoff.

The antagonistic pleiotropy theory of aging proposes that genes enhancing fitness in early life limit the lifespan, but the molecular evidence remains underexplored. By profiling translatome changes in Caenorhabditis elegans during starvation recovery, we find that an open reading frame (ORF) trl-1 "hidden" within an annotated pseudogene significantly translates upon refeeding. trl-1 mutant animals increase brood sizes but shorten the lifespan and specifically impair germline deficiency­induced longevity. The loss of trl-1 abnormally up-regulates the translation of vitellogenin that produces copious yolk to provision eggs, whereas vitellogenin overexpression is known to reduce the lifespan. We show that the TRL-1 protein undergoes liquid­liquid phase separation (LLPS), through which TRL-1 granules recruit vitellogenin messenger RNA and inhibit its translation. These results indicate that trl-1 functions as an antagonistic pleiotropic gene to regulate the reproduction­longevity tradeoff by optimizing nutrient production for the next generation.

Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans.

Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen. From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4 Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.

Therapeutic Opportunities of Targeting Canonical and Noncanonical PcG/TrxG Functions in Acute Myeloid Leukemia.

Transcriptional deregulation is a key driver of acute myeloid leukemia (AML), a heterogeneous blood cancer with poor survival rates. Polycomb group (PcG) and Trithorax group (TrxG) genes, originally identified in Drosophila melanogaster several decades ago as master regulators of cellular identity and epigenetic memory, not only are important in mammalian development but also play a key role in AML disease biology. In addition to their classical canonical antagonistic transcriptional functions, noncanonical synergistic and nontranscriptional functions of PcG and TrxG are emerging. Here, we review the biochemical properties of major mammalian PcG and TrxG complexes and their roles in AML disease biology, including disease maintenance as well as drug resistance. We summarize current efforts on targeting PcG and TrxG for treatment of AML and propose rational synthetic lethality and drug-induced antagonistic pleiotropy options involving PcG and TrxG as potential new therapeutic avenues for treatment of AML.

The Role of Selection and Migration in the Evolution of (Auto)Immunity Genes.

The genetic architecture of multiple sclerosis is complicated. Additionally, the disease incidence varies per population or per geographical region. A recent study gives convincing explanations about the north-south incidence gradient of multiple sclerosis in Europe, by analyzing ancient and modern human genomes. Interestingly, the evidence shows that multiple sclerosis associated immunogenetic variants underwent positive selection in Asian and European populations. Lifestyle and pathogen infections probably shaped the overall multiple sclerosis risk. These results complete the findings of previous studies that showed that a high percentage of the autoimmunity associated genetic variants are under selection pressure.

Dominance reversals: the resolution of genetic conflict and maintenance of genetic variation.

Beneficial reversals of dominance reduce the costs of genetic trade-offs and can enable selection to maintain genetic variation for fitness. Beneficial dominance reversals are characterized by the beneficial allele for a given context (e.g. habitat, developmental stage, trait or sex) being dominant in that context but recessive where deleterious. This context dependence at least partially mitigates the fitness consequence of heterozygotes carrying one non-beneficial allele for their context and can result in balancing selection that maintains alternative alleles. Dominance reversals are theoretically plausible and are supported by mounting empirical evidence. Here, we highlight the importance of beneficial dominance reversals as a mechanism for the mitigation of genetic conflict and review the theory and empirical evidence for them. We identify some areas in need of further research and development and outline three methods that could facilitate the identification of antagonistic genetic variation (dominance ordination, allele-specific expression and allele-specific ATAC-Seq (assay for transposase-accessible chromatin with sequencing)). There is ample scope for the development of new empirical methods as well as reanalysis of existing data through the lens of dominance reversals. A greater focus on this topic will expand our understanding of the mechanisms that resolve genetic conflict and whether they maintain genetic variation.

Aging at Evolutionary Crossroads: Longitudinal Gene Co-expression Network Analyses of Proximal and Ultimate Causes of Aging in Bats.

How, when, and why do organisms, their tissues, and their cells age remain challenging issues, although researchers have identified multiple mechanistic causes of aging, and three major evolutionary theories have been developed to unravel the ultimate causes of organismal aging. A central hypothesis of these theories is that the strength of natural selection decreases with age. However, empirical evidence on when, why, and how organisms age is phylogenetically limited, especially in natural populations. Here, we developed generic comparisons of gene co-expression networks that quantify and dissect the heterogeneity of gene co-expression in conspecific individuals from different age-classes to provide topological evidence about some mechanical and fundamental causes of organismal aging. We applied this approach to investigate the complexity of some proximal and ultimate causes of aging phenotypes in a natural population of the greater mouse-eared bat Myotis myotis, a remarkably long-lived species given its body size and metabolic rate, with available longitudinal blood transcriptomes. M. myotis gene co-expression networks become increasingly fragmented with age, suggesting an erosion of the strength of natural selection and a general dysregulation of gene co-expression in aging bats. However, selective pressures remain sufficiently strong to allow successive emergence of homogeneous age-specific gene co-expression patterns, for at least 7 years. Thus, older individuals from long-lived species appear to sit at an evolutionary crossroad: as they age, they experience both a decrease in the strength of natural selection and a targeted selection for very specific biological processes, further inviting to refine a central hypothesis in evolutionary aging theories.

Evolvability Costs of Niche Expansion.

What prevents generalists from displacing specialists, despite obvious competitive advantages of utilizing a broad niche? The classic genetic explanation is antagonistic pleiotropy: genes underlying the generalism produce 'jacks-of-all-trades' that are masters of none. However, experiments challenge this assumption that mutations enabling niche expansion must reduce fitness in other environments. Theory suggests an alternative cost of generalism: decreased evolvability, or the reduced capacity to adapt. Generalists using multiple environments experience relaxed selection in any one environment, producing greater relative lag load. Additionally, mutations fixed by generalist lineages early during their evolution that avoid or compensate for antagonistic pleiotropy may limit access to certain future evolutionary trajectories. Hypothesized evolvability costs of generalism warrant further exploration, and we suggest outstanding questions meriting attention.

Resting-state brain signal complexity discriminates young healthy APOE e4 carriers from non-e4 carriers.

It is well established that the e4 allele of the APOE gene is associated with impaired brain functionality and cognitive decline in humans at elder age. However, it is controversial whether and how the APOE e4 allele is associated with superior brain function among young healthy individuals, thus indicates a case of antagonistic pleiotropy of APOE e4 allele. Signal complexity is a critical aspect of brain activity that has been associated with brain function. In this study, the multiscale entropy (MSE) of resting-state EEG signals among a sample of young healthy adults (N = 260) as an indicator of brain signal complexity was investigated. It was of interest whether MSE differs across APOE genotype groups while age and education level were controlled for and whether the APOE genotype effect on MSE interacts with MSE time scale, as well as EEG recording condition. Results of linear mixed models indicate overall larger MSE in APOE e4 carriers. This genotype-dependent difference is larger at high as compared with low time scales. The interaction effect between APOE genotype and recording condition indicates increased between-state MSE change in young healthy APOE e4 carriers as compared with non-carriers. Because higher complexity is commonly taken to be associated with better cognitive functioning, the present results complement previous findings and therefore point to a pleiotropic spectrum of the APOE gene polymorphism.

The Mystery of Cancer Resistance: A Revelation Within Nature.

Cancer, a disease due to uncontrolled cell proliferation is as ancient as multicellular organisms. A 255-million-years-old fossilized forerunner mammal gorgonopsian is probably the oldest evidence of cancer, to date. Cancer seems to have evolved by adapting to the microenvironment occupied by immune sentinel, modulating the cellular behavior from cytotoxic to regulatory, acquiring resistance to chemotherapy and surviving hypoxia. The interaction of genes with environmental carcinogens is central to cancer onset, seen as a spectrum of cancer susceptibility among human population. Cancer occurs in life forms other than human also, although their exposure to environmental carcinogens can be different. Role of genetic etiology in cancer in multiple species can be interesting with regard to not only cancer susceptibility, but also genetic conservation and adaptation in speciation. The widely used model organisms for cancer research are mouse and rat which are short-lived and reproduce rapidly. Research in these cancer prone animal models has been valuable as these have led to cancer therapy. However, another rewarding area of cancer research can be the cancer-resistant animal species. The Peto's paradox and G-value paradox are evident when natural cancer resistance is observed in large mammals, like elephant and whale, small rodents viz. Naked Mole Rat and Blind Mole Rat, and Bat. The cancer resistance remains to be explored in other small or large and long-living animals like giraffe, camel, rhinoceros, water buffalo, Indian bison, Shire horse, polar bear, manatee, elephant seal, walrus, hippopotamus, turtle and tortoise, sloth, and squirrel. Indeed, understanding the molecular mechanisms of avoiding neoplastic transformation across various life forms can be potentially having translational value for human cancer management. Adapted and Modified from (Hanahan and Weinberg 2011).

Weak antagonistic fitness effects can maintain an inversion polymorphism.

The study of chromosomal inversion polymorphisms has received much recent attention, particularly in cases where inversions have drastic effects on phenotypes and fitness (e.g. lethality of homozygotes). Less attention has been paid to the question of the maintenance of inversion polymorphisms that show only weak effects. Here, we study the maintenance of such an inversion polymorphism that links 250 genes on chromosome Tgu11 in the zebra finch (Taeniopygia guttata). Based on data from over 6000 captive birds, we estimated the effects of this inversion on a wide range of fitness-related traits. We found that, compared with the ancestral allele A, the inverted allele D had small additive beneficial effects on male siring success and on female fecundity. These fitness-enhancing effects may explain the initial spread of the derived D allele (allele frequency 53%). However, individuals that were homozygous for D had a slightly lower survival rate, which may explain why the D allele has not spread to fixation. We used individual-based simulations to examine how an inversion polymorphism with such antagonistic fitness effects behaves over time. Our results indicate that polymorphisms become stabilized at an intermediate allele frequency if the inversion links an additively beneficial allele of small effect size to a recessive weakly deleterious mutation, overall resulting in weak net heterosis. Importantly, this conclusion remains valid over a wide range of selection coefficients against the homozygous DD (up to lethality), suggesting that the conditions needed to maintain the polymorphism may frequently be met. However, the simulations also suggest that in our zebra finch populations, the estimated recessive deleterious effect of the D allele (on survival in captivity) is not quite large enough to prevent fixation of the D allele in the long run. Estimates of fitness effects from free-living populations are needed to validate these results.

A sex skew in life-history research: the problem of missing males.

Life-history strategies are diverse. While understanding this diversity is a fundamental aim of evolutionary biology and biodemography, life-history data for some traits-in particular, age-dependent reproductive investment-are biased towards females. While other authors have highlighted this sex skew, the general scale of this bias has not been quantified and its impact on our understanding of evolutionary ecology has not been discussed. This review summarizes why the sexes can evolve different life-history strategies. The scale of the sex skew is then discussed and its magnitude compared between taxonomic groups, laboratory and field studies, and through time. We discuss the consequences of this sex skew for evolutionary and ecological research. In particular, this sex bias means that we cannot test some core evolutionary theory. Additionally, this skew could obscure or drive trends in data and hinder our ability to develop effective conservation strategies. We finally highlight some ways through which this skew could be addressed to help us better understand broad patterns in life-history strategies.

A life-history trade-off gene with antagonistic pleiotropic effects on reproduction and survival in limiting environments.

Although life-history trade-offs are central to life-history evolution, their mechanistic basis is often unclear. Traditionally, trade-offs are understood in terms of competition for limited resources among traits within an organism, which could be mediated by signal transduction pathways at the level of cellular metabolism. Nevertheless, trade-offs are also thought to be produced as a consequence of the performance of one activity generating negative consequences for other traits, or the result of genes or pathways that simultaneously regulate two life-history traits in opposite directions (antagonistic pleiotropy), independent of resource allocation. Yet examples of genes with antagonistic effects on life-history traits are limited. This study provides direct evidence for a gene-RLS1, that is involved in increasing survival in nutrient-limiting environments at a cost to immediate reproduction in the single-celled photosynthetic alga, Chlamydomonas reinhardtii. Specifically, we show that RLS1 mutants are unable to properly suppress their reproduction in phosphate-deprived conditions. Although these mutants have an immediate reproductive advantage relative to the parental strain, their long-term survival is negatively affected. Our data suggest that RLS1 is a bona fide life-history trade-off gene that suppresses immediate reproduction and ensures survival by downregulating photosynthesis in limiting environments, as part of the general acclimation response to nutrient deprivation in photosynthetic organisms.

Genetic trade-offs underlie divergent life history strategies for local adaptation in white clover.

Local adaptation is common in plants, yet characterization of its underlying genetic basis is rare in herbaceous perennials. Moreover, while many plant species exhibit intraspecific chemical defence polymorphisms, their importance for local adaptation remains poorly understood. We examined the genetic architecture of local adaptation in a perennial, obligately-outcrossing herbaceous legume, white clover (Trifolium repens). This widespread species displays a well-studied chemical defence polymorphism for cyanogenesis (HCN release following tissue damage) and has evolved climate-associated cyanogenesis clines throughout its range. Two biparental F2  mapping populations, derived from three parents collected in environments spanning the U.S. latitudinal species range (Duluth, MN, St. Louis, MO and Gainesville, FL), were grown in triplicate for two years in reciprocal common garden experiments in the parental environments (6,012 total plants). Vegetative growth and reproductive fitness traits displayed trade-offs across reciprocal environments, indicating local adaptation. Genetic mapping of fitness traits revealed a genetic architecture characterized by allelic trade-offs between environments, with 100% and 80% of fitness QTL in the two mapping populations showing significant QTL×E interactions, consistent with antagonistic pleiotropy. Across the genome there were three hotspots of QTL colocalization. Unexpectedly, we found little evidence that the cyanogenesis polymorphism contributes to local adaptation. Instead, divergent life history strategies in reciprocal environments were major fitness determinants: selection favoured early investment in flowering at the cost of multiyear survival in the southernmost site versus delayed flowering and multiyear persistence in the northern environments. Our findings demonstrate that multilocus genetic trade-offs contribute to contrasting life history characteristics that allow for local adaptation in this outcrossing herbaceous perennial.

Stress-Induced Phenoptosis: Mechanistic Insights and Evolutionary Implications.

Evolution by natural selection results in biological traits that enable organismic adaptation and survival under various stressful environments. External stresses can be sometimes too severe to overcome, leading to organismic death either because of failure in adapting to such stress, or alternatively, through a regulated form of organismic death (phenoptosis). While regulated cell deaths, including apoptosis, have been extensively studied, little is known about the molecular and cellular mechanisms underlying phenoptosis and its evolutionary significance for multicellular organisms. In this article, we review documented phenomena and mechanistic evidence emerging from studies of stress-induced phenoptosis in the multicellular organism C. elegans and stress-induced deaths at cellular levels in organisms ranging from bacteria to mammals, focusing on abiotic and pathogen stresses. Genes and signaling pathways involved in phenoptosis appear to promote organismic death during severe stress and aging, while conferring fitness and immune defense during mild stress and early life, consistent with their antagonistic pleiotropy actions. As cell apoptosis during development can shape tissues and organs, stress-induced phenoptosis may also contribute to possible benefits at the population level, through mechanisms including kin selection, abortive infection, and soma-to-germline resource allocation. Current models can generate experimentally testable predictions and conceptual frameworks with implications for understanding both stress-induced phenoptosis and natural aging.

A non-coding indel polymorphism in the fruitless gene of Drosophila melanogaster exhibits antagonistically pleiotropic fitness effects.

The amount of genetic variation for fitness within populations tends to exceed that expected under mutation-selection-drift balance. Several mechanisms have been proposed to actively maintain polymorphism and account for this discrepancy, including antagonistic pleiotropy (AP), where allelic variants have opposing effects on different components of fitness. Here, we identify a non-coding indel polymorphism in the fruitless gene of Drosophila melanogaster and measure survival and reproductive components of fitness in males and females of replicate lines carrying each respective allele. Expressing the fruitless region in a hemizygous state reveals a pattern of AP, with one allele generating greater reproductive fitness and the other conferring greater survival to adulthood. Different fitness effects were observed in an alternative genetic background, which may reflect dominance reversal and/or epistasis. Our findings link sequence-level variation at a single locus with complex effects on a range of fitness components, thus helping to explain the maintenance of genetic variation for fitness. Transcription factors, such as fruitless, may be prime candidates for targets of balancing selection since they interact with multiple target loci and their associated phenotypic effects.

Support for the adaptive decoupling hypothesis from whole-transcriptome profiles of a hypermetamorphic and sexually dimorphic insect, Neodiprion lecontei.

Though seemingly bizarre, the dramatic morphological and ecological transformation that occurs when immature life stages metamorphose into reproductive adults is one of the most successful developmental strategies on the planet. The adaptive decoupling hypothesis (ADH) proposes that metamorphosis is an adaptation for breaking developmental links between traits expressed in different life stages, thereby facilitating their independent evolution when exposed to opposing selection pressures. Here, we draw inspiration from the ADH to develop a conceptual framework for understanding changes in gene expression across ontogeny. We hypothesized that patterns of stage-biased and sex-biased gene expression are the product of both decoupling mechanisms and selection history. To test this hypothesis, we characterized transcriptome-wide patterns of gene-expression traits for three ecologically distinct larval stages (all male) and adult males and females of a hypermetamorphic insect (Neodiprion lecontei). We found that stage-biased gene expression was most pronounced between larval and adult males, which is consistent with the ADH. However, even in the absence of a metamorphic transition, considerable stage-biased expression was observed among morphologically and behaviourally distinct larval stages. Stage-biased expression was also observed across ecologically relevant Gene Ontology categories and genes, highlighting the role of ecology in shaping patterns of gene expression. We also found that the magnitude and prevalence of stage-biased expression far exceeded adult sex-biased expression. Overall, our results highlight how the ADH can shed light on transcriptome-wide patterns of gene expression in organisms with complex life cycles. For maximal insight, detailed knowledge of organismal ecology is also essential.

How fitness consequences of early-life conditions vary with age in a long-lived seabird: A Bayesian multivariate analysis of age-specific reproductive values.

Evolutionary theory suggests that individuals can benefit from deferring the fitness cost of developing under poor conditions to later in life. Although empirical evidence for delayed fitness costs of poor developmental conditions is abundant, individuals that die prematurely have not often been incorporated when estimating fitness, such that age-specific fitness costs, and therefore the relative importance of delayed fitness costs are actually unknown. We developed a Bayesian statistical framework to estimate age-specific reproductive values in relation to developmental conditions. We applied it to data obtained from a long-term longitudinal study of common terns Sterna hirundo, using sibling rank to describe variation in developmental conditions. Common terns have a maximum of three chicks, and later hatching chicks acquire less food, grow more slowly and have a lower fledging probability than their earlier hatched siblings. We estimated fitness costs in adulthood to constitute c. 45% and 70% of the total fitness costs of hatching third and second, respectively, compared to hatching first. This was due to third-ranked hatchlings experiencing especially high pre-fledging mortality, while second-ranked hatchlings had lower reproductive success in adulthood. Both groups had slightly lower adult survival. There was, however, no evidence for sibling rank-specific rates of senescence. We additionally found years with low fledgling production to be associated with particularly strong pre-fledging selection on sibling rank, and with increased adult survival to the next breeding season. This suggests that adults reduce parental allocation to reproduction in poor years, which disproportionately impacts low-ranked offspring. Interpreting these results, we suggest that selection at the level of the individual offspring for delaying fitness costs is counteracted by selection for parental reduction in brood size when resources are limiting.