Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

Mammalian body temperature oscillates with the time of the day and is altered in diverse pathological conditions. We recently identified a body temperature‐sensitive thermometer‐like kinase, which alters SR protein phosphorylation and thereby globally controls alternative splicing (AS). AS can generate unproductive variants which are recognized and degraded by diverse mRNA decay pathways—including nonsense‐mediated decay (NMD). Here we show extensive coupling of body temperature‐controlled AS to mRNA decay, leading to global control of temperature‐dependent gene expression (GE). Temperature‐controlled, decay‐inducing splicing events are evolutionarily conserved and pervasively found within RNA‐binding proteins, including most SR proteins. AS‐coupled poison exon inclusion is essential for rhythmic GE of SR proteins and has a global role in establishing temperature‐dependent rhythmic GE profiles, both in mammals under circadian body temperature cycles and in plants in response to ambient temperature changes. Together, these data identify body temperature‐driven AS‐coupled mRNA decay as an evolutionary ancient, core clock‐independent mechanism to generate rhythmic GE.     

High genetic and epigenetic variation of transposable elements: Potential drivers to rapid adaptive evolution for the noxious invasive weed Mikania micrantha

Why invasive species can rapidly adapt to novel environments is a puzzling question known as the genetic paradox of invasive species. This paradox is explainable in terms of transposable elements (TEs) activity, which are theorized to be powerful mutational forces to create genetic variation. Mikania micrantha, a noxious invasive weed, in this sense provides an excellent opportunity to test the explanation. The genetic and epigenetic variation of 21 invasive populations of M. micrantha in southern China have been examined by using transposon display (TD) and transposon methylation display (TMD) techniques to survey 12 TE superfamilies. Our results showed that M. micrantha populations maintained an almost equally high level of TE‐based genetic and epigenetic variation and they have been differentiated into subpopulations genetically and epigenetically. A similar positive spatial genetic and epigenetic structure pattern was observed within 300 m. Six and seven TE superfamilies presented significant genetic and epigenetic isolation by distance (IBD) pattern. In total, 59 genetic and 86 epigenetic adaptive TE loci were identified. Of them, 51 genetic and 44 epigenetic loci were found to correlate with 25 environmental variables (including precipitation, temperature, vegetation coverage, and soil metals). Twenty‐five transposon‐inserted genes were sequenced and homology‐based annotated, which are found to be involved in a variety of molecular and cellular functions. Our research consolidates the importance of TE‐associated genetic and epigenetic variation in the rapid adaptation and invasion of M. micrantha.     

Population differences in Chinook salmon (Oncorhynchus tshawytscha) DNA methylation: Genetic drift and environmental factors

Local adaptation and phenotypic differences among populations have been reported in many species, though most studies focus on either neutral or adaptive genetic differentiation. With the discovery of DNA methylation, questions have arisen about its contribution to individual variation in and among natural populations. Previous studies have identified differences in methylation among populations of organisms, although most to date have been in plants and model animal species. Here we obtained eyed eggs from eight populations of Chinook salmon (Oncorhynchus tshawytscha) and assayed DNA methylation at 23 genes involved in development, immune function, stress response, and metabolism using a gene‐targeted PCR‐based assay for next‐generation sequencing. Evidence for population differences in methylation was found at eight out of 23 gene loci after controlling for developmental timing in each individual. However, we found no correlation between freshwater environmental parameters and methylation variation among populations at those eight genes. A weak correlation was identified between pairwise DNA methylation dissimilarity among populations and pairwise F _ST based on 15 microsatellite loci, indicating weak effects of genetic drift or geographic distance on methylation. The weak correlation was primarily driven by two genes, GTIIBS and Nkef. However, single‐gene Mantel tests comparing methylation and pairwise F _ST were not significant after Bonferroni correction. Thus, population differences in DNA methylation are more likely related to unmeasured oceanic environmental conditions, local adaptation, and/or genetic drift. DNA methylation is an additional mechanism that contributes to among population variation, with potential influences on organism phenotype, adaptive potential, and population resilience.     

Evidence for a synergistic effect of post‐translational modifications and genomic composition of eEF‐1α on the adaptation of Phytophthora infestans

Genetic variation plays a fundamental role in pathogen''s adaptation to environmental stresses. Pathogens with low genetic variation tend to survive and proliferate more poorly due to their lack of genotypic/phenotypic polymorphisms in responding to fluctuating environments. Evolutionary theory hypothesizes that the adaptive disadvantage of genes with low genomic variation can be compensated for structural diversity of proteins through post‐translation modification (PTM) but this theory is rarely tested experimentally and its implication to sustainable disease management is hardly discussed. In this study, we analyzed nucleotide characteristics of eukaryotic translation elongation factor‐1α (eEF‐lα) gene from 165 Phytophthora infestans isolates and the physical and chemical properties of its derived proteins. We found a low sequence variation of eEF‐lα protein, possibly attributable to purifying selection and a lack of intra‐genic recombination rather than reduced mutation. In the only two isoforms detected by the study, the major one accounted for >95% of the pathogen collection and displayed a significantly higher fitness than the minor one. High lysine representation enhances the opportunity of the eEF‐1α protein to be methylated and the absence of disulfide bonds is consistent with the structural prediction showing that many disordered regions are existed in the protein. Methylation, structural disordering, and possibly other PTMs ensure the ability of the protein to modify its functions during biological, cellular and biochemical processes, and compensate for its adaptive disadvantage caused by sequence conservation. Our results indicate that PTMs may function synergistically with nucleotide codes to regulate the adaptive landscape of eEF‐1α, possibly as well as other housekeeping genes, in P. infestans. Compensatory evolution between pre‐ and post‐translational phase in eEF‐1α could enable pathogens quickly adapting to disease management strategies while efficiently maintaining critical roles of the protein playing in biological, cellular, and biochemical activities. Implications of these results to sustainable plant disease management are discussed.     

Gillespie eco‐evolutionary models (GEMs) reveal the role of heritable trait variation in eco‐evolutionary dynamics

Heritable trait variation is a central and necessary ingredient of evolution. Trait variation also directly affects ecological processes, generating a clear link between evolutionary and ecological dynamics. Despite the changes in variation that occur through selection, drift, mutation, and recombination, current eco‐evolutionary models usually fail to track how variation changes through time. Moreover, eco‐evolutionary models assume fitness functions for each trait and each ecological context, which often do not have empirical validation. We introduce a new type of model, Gillespie eco‐evolutionary models (GEMs), that resolves these concerns by tracking distributions of traits through time as eco‐evolutionary dynamics progress. This is done by allowing change to be driven by the direct fitness consequences of model parameters within the context of the underlying ecological model, without having to assume a particular fitness function. GEMs work by adding a trait distribution component to the standard Gillespie algorithm – an approach that models stochastic systems in nature that are typically approximated through ordinary differential equations. We illustrate GEMs with the Rosenzweig–MacArthur consumer–resource model. We show not only how heritable trait variation fuels trait evolution and influences eco‐evolutionary dynamics, but also how the erosion of variation through time may hinder eco‐evolutionary dynamics in the long run. GEMs can be developed for any parameter in any ordinary differential equation model and, furthermore, can enable modeling of multiple interacting traits at the same time. We expect GEMs will open the door to a new direction in eco‐evolutionary and evolutionary modeling by removing long‐standing modeling barriers, simplifying the link between traits, fitness, and dynamics, and expanding eco‐evolutionary treatment of a greater diversity of ecological interactions. These factors make GEMs much more than a modeling advance, but an important conceptual advance that bridges ecology and evolution through the central concept of heritable trait variation.     

Genetic signature of human longevity in PKC and NF‐κB signaling

Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer''s disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3‐stage study to identify functional longevity‐associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity‐associated genes in the nPKC and NF‐κB signaling pathways by gene‐based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non‐coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF‐κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF‐κB signaling pathways in exceptional longevity may include humans.     

Consequences of genetic linkage for the maintenance of sexually antagonistic polymorphism in hermaphrodites

When selection differs between males and females, pleiotropic effects among genes expressed by both sexes can result in sexually antagonistic selection (SA), where beneficial alleles for one sex are deleterious for the other. For hermaphrodites, alleles with opposing fitness effects through each sex function represent analogous genetic constraints on fitness. Recent theory based on single‐locus models predicts that the maintenance of SA genetic variation should be greatly reduced in partially selfing populations. However, selfing also reduces the effective rate of recombination, which should facilitate selection on linked allelic combinations and expand opportunities for balancing selection in a multilocus context. Here, I develop a two‐locus model of SA selection for simultaneous hermaphrodites, and explore the joint influence of linkage, self‐fertilization, and dominance on the maintainance of SA polymorphism. I find that the effective reduction in recombination caused by selfing significantly expands the parameter space where SA polymorphism can be maintained relative to single‐locus models. In particular, linkage facilitates the invasion of male‐beneficial alleles, partially compensating for the “female‐bias” in the net direction of selection created by selfing. I discuss the implications of accounting for linkage among SA loci for the maintenance of SA genetic variation and mixed mating systems in hermaphrodites.     

Genetic quality and sexual selection: an integrated framework for good genes and compatible genes

Why are females so choosy when it comes to mating? This question has puzzled and marveled evolutionary and behavioral ecologists for decades. In mating systems in which males provide direct benefits to the female or her offspring, such as food or shelter, the answer seems straightforward — females should prefer to mate with males that are able to provide more resources. The answer is less clear in other mating systems in which males provide no resources (other than sperm) to females. Theoretical models that account for the evolution of mate choice in such nonresource-based mating systems require that females obtain a genetic benefit through increased offspring fitness from their choice. Empirical studies of nonresource-based mating systems that are characterized by strong female choice for males with elaborate sexual traits (like the large tail of peacocks) suggest that additive genetic benefits can explain only a small percentage of the variation in fitness. Other research on genetic benefits has examined nonadditive effects as another source of genetic variation in fitness and a potential benefit to female mate choice. In this paper, we review the sexual selection literature on genetic quality to address five objectives. First, we attempt to provide an integrated framework for discussing genetic quality. We propose that the term ‘good gene’ be used exclusively to refer to additive genetic variation in fitness, ‘compatible gene’ be used to refer to nonadditive genetic variation in fitness, and ‘genetic quality’ be defined as the sum of the two effects. Second, we review empirical approaches used to calculate the effect size of genetic quality and discuss these approaches in the context of measuring benefits from good genes, compatible genes and both types of genes. Third, we discuss biological mechanisms for acquiring and promoting offspring genetic quality and categorize these into three stages during breeding: (i) precopulatory (mate choice); (ii) postcopulatory, prefertilization (sperm utilization); and (iii) postcopulatory, postfertilization (differential investment). Fourth, we present a verbal model of the effect of good genes sexual selection and compatible genes sexual selection on population genetic variation in fitness, and discuss the potential trade-offs that might exist between mate choice for good genes and mate choice for compatible genes. Fifth, we discuss some future directions for research on genetic quality and sexual selection.     

Sequence analysis of tyrosine recombinases allows annotation of mobile genetic elements in prokaryotic genomes

Mobile genetic elements (MGEs) sequester and mobilize antibiotic resistance genes across bacterial genomes. Efficient and reliable identification of such elements is necessary to follow resistance spreading. However, automated tools for MGE identification are missing. Tyrosine recombinase (YR) proteins drive MGE mobilization and could provide markers for MGE detection, but they constitute a diverse family also involved in housekeeping functions. Here, we conducted a comprehensive survey of YRs from bacterial, archaeal, and phage genomes and developed a sequence‐based classification system that dissects the characteristics of MGE‐borne YRs. We revealed that MGE‐related YRs evolved from non‐mobile YRs by acquisition of a regulatory arm‐binding domain that is essential for their mobility function. Based on these results, we further identified numerous unknown MGEs. This work provides a resource for comparative analysis and functional annotation of YRs and aids the development of computational tools for MGE annotation. Additionally, we reveal how YRs adapted to drive gene transfer across species and provide a tool to better characterize antibiotic resistance dissemination.     

Overview of the molecular determinants contributing to the expression of Psoriasis and Psoriatic Arthritis phenotypes

Psoriasis and psoriatic arthritis are multifactorial chronic disorders whose etiopathogenesis essentially derives from the alteration of several signalling pathways and the co‐occurrence of genetic, epigenetic and non‐genetic susceptibility factors that altogether affect the functional and structural property of the skin. Although shared and differential susceptibility genes and molecular pathways are known to contribute to the onset of pathological phenotypes, further research is needed to dissect the molecular causes of psoriatic disease and its progression towards Psoriatic Arthritis. This review will therefore be addressed to explore differences and similarities in the etiopathogenesis and progression of both disorders, with a particular focus on genes involved in the maintenance of the skin structure and integrity (keratins and collagens), modulation of patterns of recognition (through Toll‐like receptors and dectin‐1) and immuno‐inflammatory response (by NLRP3‐dependent inflammasome) to microbial pathogens. In addition, special emphasis will be given to the contribution of epigenetic elements (methylation pattern, non‐coding RNAs, chromatin modifiers and 3D genome organization) to the etiopathogenesis and progression of psoriasis and psoriatic arthritis. The evidence discussed in this review highlights how the knowledge of patients'' clinical and (epi)genomic make‐up could be helpful for improving the available therapeutic strategies for psoriasis and psoriatic arthritis treatment.     

The evolution of genetic canalization under fluctuating selection

Abstract.— If the direction of selection changes from generation to generation, the ability to respond to selection is maladaptive: the response to selection in one generation leads to reduced fitness in the next. Because the response is determined by the amount of genetic variance expressed at the phenotypic level, rapidly fluctuating selection should favor modifier genes that reduce the phenotypic effect of alleles segregating at structural loci underlying the trait. Such reduction in phenotypic expression of genetic variation has been named "genetic canalization." I support this argument with a series of two- and multilocus models with alternating linear selection and Gaussian selection with fluctuating optimum. A canalizing modifier gene affects the fitness of its carriers in three ways: (1) it reduces the phenotypic consequences of genetic response to previous selection; (2) it reduces the genetic response to selection, which is manifested as linkage disequilibrium between the modifier and structural loci; and (3) it reduces the phenotypic variance. The first two effects reduce fitness under directional selection sustained for several generations, but improve fitness when the direction of selection has just been reversed. The net effect tends to favor a canalizing modifier under rapidly fluctuating selection regimes (period of eight generations or less). The third effect improves fitness of the modifier allele if the fitness function is convex and reduces it if the function is concave. Under fluctuating Gaussian selection, the population is more likely to experience the concave portion of the fitness function when selection is stronger. Therefore, only weak to moderately strong fluctuating Gaussian selection favors genetic canalization. This paper considerably broadens the conditions that favor genetic canalization, which so far has only been postulated to evolve under long-term stabilizing selection.     

The effect of epistasis on sexually antagonistic genetic variation

There is increasing evidence of segregating sexually antagonistic (SA) genetic variation for fitness in laboratory and wild populations, yet the conditions for the maintenance of such variation can be restrictive. Epistatic interactions between genes can contribute to the maintenance of genetic variance in fitness and we suggest that epistasis between SA genes should be pervasive. Here, we explore its effect on SA genetic variation in fitness using a two locus model with negative epistasis. Our results demonstrate that epistasis often increases the parameter space showing polymorphism for SA loci. This is because selection in one locus is affected by allele frequencies at the other, which can act to balance net selection in males and females. Increased linkage between SA loci had more marginal effects. We also show that under some conditions, large portions of the parameter space evolve to a state where male benefit alleles are fixed at one locus and female benefit alleles at the other. This novel effect of epistasis on SA loci, which we term the ‘equity effect’, may have important effects on population differentiation and may contribute to speciation. More generally, these results support the suggestion that epistasis contributes to population divergence.     

Higher duplicability of less important genes in yeast genomes

Gene duplication plays an important role in evolution because it is the primary source of new genes. Many recent studies showed that gene duplicability varies considerably among genes. Several considerations led us to hypothesize that less important genes have higher rates of successful duplications, where gene importance is measured by the fitness reduction caused by the deletion of the gene. Here, we test this hypothesis by comparing the importance of two groups of singleton genes in the yeast Saccharomyces cerevisiae (Sce). Group S genes did not duplicate in four other yeast species examined, whereas group D experienced duplication in these species. Consistent with our hypothesis, we found group D genes to be less important than group S genes. Specifically, 17% of group D genes are essential in Sce, compared to 28% for group S. Furthermore, deleting a group D gene in Sce reduces the fitness by 24% on average, compared to 38% for group S. Our subsequent analysis showed that less important genes have more cis-regulatory motifs, which could lead to a higher chance of subfunctionalization of duplicate genes and result in an enhanced rate of gene retention. Less important genes may also have weaker dosage imbalance effects and cause fewer genetic perturbations when duplicated. Regardless of the cause, our observation indicates that the previous finding of a less severe fitness consequence of deleting a duplicate gene than deleting a singleton gene is at least in part due to the fact that duplicate genes are intrinsically less important than singleton genes and suggests that the contribution of duplicate genes to genetic robustness has been overestimated.     

Color vision and niche partitioning in a diverse neotropical primate community in lowland Amazonian Ecuador

A recent focus in community ecology has been on how within‐species variability shapes interspecific niche partitioning. Primate color vision offers a rich system in which to explore this issue. Most neotropical primates exhibit intraspecific variation in color vision due to allelic variation at the middle‐to‐long‐wavelength opsin gene on the X chromosome. Studies of opsin polymorphisms have typically sampled primates from different sites, limiting the ability to relate this genetic diversity to niche partitioning. We surveyed genetic variation in color vision of five primate species, belonging to all three families of the primate infraorder Platyrrhini, found in the Yasuní Biosphere Reserve in Ecuador. The frugivorous spider monkeys and woolly monkeys (Ateles belzebuth and Lagothrix lagotricha poeppigii, family Atelidae) each had two opsin alleles, and more than 75% of individuals carried the longest‐wavelength (553–556 nm) allele. Among the other species, Saimiri sciureus macrodon (family Cebidae) and Pithecia aequatorialis (family Pitheciidae) had three alleles, while Plecturocebus discolor (family Pitheciidae) had four alleles—the largest number yet identified in a wild population of titi monkeys. For all three non‐atelid species, the middle‐wavelength (545 nm) allele was the most common. Overall, we identified genetic evidence of fourteen different visual phenotypes—seven types of dichromats and seven trichromats—among the five sympatric taxa. The differences we found suggest that interspecific competition among primates may influence intraspecific frequencies of opsin alleles. The diversity we describe invites detailed study of foraging behavior of different vision phenotypes to learn how they may contribute to niche partitioning.     

Molecular spandrels: tests of adaptation at the genetic level

Although much progress has been made in identifying the genes (and, in rare cases, mutations) that contribute to phenotypic variation, less is known about the effects that these genes have on fitness. Nonetheless, genes are commonly labelled as 'adaptive' if an allele has been shown to affect a phenotype with known or suspected functional importance or if patterns of nucleotide variation at the locus are consistent with positive selection. In these cases, the 'adaptive' designation may be premature and may lead to incorrect conclusions about the relationships between gene function and fitness. Experiments to test targets and agents of natural selection within a genomic context are necessary for identifying the adaptive consequences of individual alleles.     

Rapid loss of MHC class II variation in a bottlenecked population is explained by drift and loss of copy number variation

Population bottlenecks may reduce genetic variation and potentially increase the risk of extinction. Here, we present the first study to use historic samples to analyse loss of variation at the major histocompatibility complex (MHC), which plays a central role in vertebrate disease resistance. Balancing selection acts on the MHC and could moderate the loss of variation expected from drift; however, in a Wisconsin population of greater prairie-chickens (Tympanuchus cupido), the number of MHC class II B alleles per individual declined by 44% following a population bottleneck, compared to a loss of only 8% at microsatellites. Simulations indicate that drift likely reduced MHC variation at the population level, as well as within individuals by reducing the number of gene copies per individual or by fixing the same alleles across multiple loci. These multiple effects of genetic drift on MHC variation could have important implications for immunity and fitness.     

A comprehensive strategy enabling high-resolution functional analysis of the yeast genome

Functional genomic studies in Saccharomyces cerevisiae have contributed enormously to our understanding of cellular processes. Their full potential, however, has been hampered by the limited availability of reagents to systematically study essential genes and the inability to quantify the small effects of most gene deletions on growth. Here we describe the construction of a library of hypomorphic alleles of essential genes and a high-throughput growth competition assay to measure fitness with unprecedented sensitivity. These tools dramatically increase the breadth and precision with which quantitative genetic analysis can be performed in yeast. We illustrate the value of these approaches by using genetic interactions to reveal new relationships between chromatin-modifying factors and to create a functional map of the proteasome. Finally, by measuring the fitness of strains in the yeast deletion library, we addressed an enigma regarding the apparent prevalence of gene dispensability and found that most genes do contribute to growth.