Gene regulatory networks generating the phenomena of additivity, dominance and epistasis

We show how the phenomena of genetic dominance, overdominance, additivity, and epistasis are generic features of simple diploid gene regulatory networks. These regulatory network models are together sufficiently complex to catch most of the suggested molecular mechanisms responsible for generating dominant mutations. These include reduced gene dosage, expression or protein activity (haploinsufficiency), increased gene dosage, ectopic or temporarily altered mRNA expression, increased or constitutive protein activity, and dominant negative effects. As classical genetics regards the phenomenon of dominance to be generated by intralocus interactions, we have studied two one-locus models, one with a negative autoregulatory feedback loop, and one with a positive autoregulatory feedback loop. To include the phenomena of epistasis and downstream regulatory effects, a model of a three-locus signal transduction network is also analyzed. It is found that genetic dominance as well as overdominance may be an intra- as well as interlocus interaction phenomenon. In the latter case the dominance phenomenon is intimately connected to either feedback-mediated epistasis or downstream-mediated epistasis. It appears that in the intra- as well as the interlocus case there is considerable room for additive gene action, which may explain to some degree the predictive power of quantitative genetic theory, with its emphasis on this type of gene action. Furthermore, the results illuminate and reconcile the prevailing explanations of heterosis, and they support the old conjecture that the phenomenon of dominance may have an evolutionary explanation related to life history strategy.     

Dominance–diversity relationships in ant communities differ with invasion

The relationship between levels of dominance and species richness is highly contentious, especially in ant communities. The dominance‐impoverishment rule states that high levels of dominance only occur in species‐poor communities, but there appear to be many cases of high levels of dominance in highly diverse communities. The extent to which dominant species limit local richness through competitive exclusion remains unclear, but such exclusion appears more apparent for non‐native rather than native dominant species. Here we perform the first global analysis of the relationship between behavioral dominance and species richness. We used data from 1,293 local assemblages of ground‐dwelling ants distributed across five continents to document the generality of the dominance‐impoverishment rule, and to identify the biotic and abiotic conditions under which it does and does not apply. We found that the behavioral dominance–diversity relationship varies greatly, and depends on whether dominant species are native or non‐native, whether dominance is considered as occurrence or relative abundance, and on variation in mean annual temperature. There were declines in diversity with increasing dominance in invaded communities, but diversity increased with increasing dominance in native communities. These patterns occur along the global temperature gradient. However, positive and negative relationships are strongest in the hottest sites. We also found that climate regulates the degree of behavioral dominance, but differently from how it shapes species richness. Our findings imply that, despite strong competitive interactions among ants, competitive exclusion is not a major driver of local richness in native ant communities. Although the dominance‐impoverishment rule applies to invaded communities, we propose an alternative dominance‐diversification rule for native communities.     

A 7000‐year history of changing plant trait composition in an Amazonian landscape; the role of humans and climate

Tropical forests are shifting in species and trait composition, but the main underlying causes remain unclear because of the short temporal scales of most studies. Here, we develop a novel approach by linking functional trait data with 7000 years of forest dynamics from a fossil pollen record of Lake Sauce in the Peruvian Amazon. We evaluate how climate and human disturbances affect community trait composition. We found weak relationships between environmental conditions and traits at the taxon level, but strong effects for community‐mean traits. Overall, community‐mean traits were more responsive to human disturbances than to climate change; human‐induced erosion increased the dominance of dense‐wooded, non‐zoochorous species with compound leaves, and human‐induced fire increased the dominance of tall, zoochorous taxa with large seeds and simple leaves. This information can help to enhance our understanding of forest responses to past environmental changes, and improve predictions of future changes in tropical forest composition.     

Different mechanisms drive the maintenance of polymorphism at loci subject to strong versus weak fluctuating selection

The long‐running debate about the role of selection in maintaining genetic variation has been given new impetus by the discovery of hundreds of seasonally oscillating polymorphisms in wild Drosophila, possibly stabilized by an alternating summer‐winter selection regime. Historically, there has been skepticism about the potential of temporal variation to balance polymorphism, because selection must be strong to have a meaningful stabilizing effect—unless dominance also varies over time (“reversal of dominance”). Here, we develop a simplified model of seasonally variable selection that simultaneously incorporates four different stabilizing mechanisms, including two genetic mechanisms (“cumulative overdominance” and reversal of dominance), as well as ecological “storage” (“protection from selection” and boom‐bust demography). We use our model to compare the stabilizing effects of these mechanisms. Although reversal of dominance has by far the greatest stabilizing effect, we argue that the three other mechanisms could also stabilize polymorphism under plausible conditions, particularly when all three are present. With many loci subject to diminishing returns epistasis, reversal of dominance stabilizes many alleles of small effect. This makes the combination of the other three mechanisms, which are incapable of stabilizing small effect alleles, a better candidate for stabilizing the detectable frequency oscillations of large effect alleles.     

Antagonistic pleiotropy in species with separate sexes,and the maintenance of genetic variation in life‐history traits and fitness

Antagonistic pleiotropy (AP)—where alleles of a gene increase some components of fitness at a cost to others—can generate balancing selection, and contribute to the maintenance of genetic variation in fitness traits, such as survival, fecundity, fertility, and mate competition. Previous theory suggests that AP is unlikely to maintain variation unless antagonistic selection is strong, or AP alleles exhibit pronounced differences in genetic dominance between the affected traits. We show that conditions for balancing selection under AP expand under the likely scenario that the strength of selection on each fitness component differs between the sexes. Our model also predicts that the vast majority of balanced polymorphisms have sexually antagonistic effects on total fitness, despite the absence of sexual antagonism for individual fitness components. We conclude that AP polymorphisms are less difficult to maintain than predicted by prior theory, even under our conservative assumption that selection on components of fitness is universally sexually concordant. We discuss implications for the maintenance of genetic variation, and for inferences of sexual antagonism that are based on sex‐specific phenotypic selection estimates—many of which are based on single fitness components.     

Age and sex affect quantitative genetic parameters for dominance rank and aggression in free‐living greylag geese

Knowledge of the genetic and environmental influences on a character is pivotal for understanding evolutionary changes in quantitative traits in natural populations. Dominance and aggression are ubiquitous traits that are selectively advantageous in many animal societies and have the potential to impact the evolutionary trajectory of animal populations. Here we provide age‐ and sex‐specific estimates of additive genetic and environmental components of variance for dominance rank and aggression rate in a free‐living, human‐habituated bird population subject to natural selection. We use a long‐term data set on individually marked greylag geese (Anser anser) and show that phenotypic variation in dominance‐related behaviours contains significant additive genetic variance, parental effects and permanent environment effects. The relative importance of these variance components varied between age and sex classes, whereby the most pronounced differences concerned nongenetic components. In particular, parental effects were larger in juveniles of both sexes than in adults. In paired adults, the partner's identity had a larger influence on male dominance rank and aggression rate than in females. In sex‐ and age‐specific estimates, heritabilities did not differ significantly between age and sex classes. Adult dominance rank was only weakly genetically correlated between the sexes, leading to considerably higher heritabilities in sex‐specific estimates than across sexes. We discuss these patterns in relation to selection acting on dominance rank and aggression in different life history stages and sexes and suggest that different adaptive optima could be a mechanism for maintaining genetic variation in dominance‐related traits in free‐living animal populations.     

Testing for beneficial reversal of dominance during salinity shifts in the invasive copepod Eurytemora affinis,and implications for the maintenance of genetic variation

Maintenance of genetic variation at loci under selection has profound implications for adaptation under environmental change. In temporally and spatially varying habitats, non‐neutral polymorphism could be maintained by heterozygote advantage across environments (marginal overdominance), which could be greatly increased by beneficial reversal of dominance across conditions. We tested for reversal of dominance and marginal overdominance in salinity tolerance in the saltwater‐to‐freshwater invading copepod Eurytemora affinis. We compared survival of F1 offspring generated by crossing saline and freshwater inbred lines (between‐salinity F1 crosses) relative to within‐salinity F1 crosses, across three salinities. We found evidence for both beneficial reversal of dominance and marginal overdominance in salinity tolerance. In support of reversal of dominance, survival of between‐salinity F1 crosses was not different from that of freshwater F1 crosses under freshwater conditions and saltwater F1 crosses under saltwater conditions. In support of marginal overdominance, between‐salinity F1 crosses exhibited significantly higher survival across salinities relative to both freshwater and saltwater F1 crosses. Our study provides a rare empirical example of complete beneficial reversal of dominance associated with environmental change. This mechanism might be crucial for maintaining genetic variation in salinity tolerance in E. affinis populations, allowing rapid adaptation to salinity changes during habitat invasions.     

Competition for resources mediated by intrinsic social dominance in sympatric finches

Gouldian Erythrura gouldiae and Long‐tailed Finches Poephila acuticauda are morphologically and ecologically similar sympatric species, for which social dominance relationships are likely to determine access to critical limiting resources. Building on previous research showing that Long‐tailed Finches dominate competition for nest‐sites, I staged dyadic contests for food between the two species in captivity in order to test social dominance dynamics under controlled conditions. Long‐tailed Finches were likely to dominate interactions with Gouldian Finches and expressed higher levels of aggression while competing for access to food. These results suggest a stable dominance relationship between the two species which could be affecting Gouldian Finches' access to food resources in the wild, potentially constraining their ability to recover from recent population declines.     

Evolution of stickleback feeding behaviour: genetics of population divergence at different ontogenetic stages

The evolutionary significance of individual consistency in a given behaviour – called animal personality – has been subject to a lot of recent research. However, the genetic underpinnings of population divergence in mean personality have rarely been studied, especially across different ontogenetic stages. Previous work has shown that marine vs. pond populations of nine‐spined sticklebacks (Pungitius pungitius) have undergone adaptive divergence in a series of fitness‐related traits, including behaviour. One particular behavioural trait important in this system is feeding activity: giant pond sticklebacks are more active feeders than their normal sized marine conspecifics. In a common garden experiment, we raised individuals from pure and hybrid F₁‐generation crosses of a highly divergent marine – pond population pair to see if (i) feeding activity and/or its ontogenetic change was consistent between individuals, and if (ii) population divergence at different ontogenetic stages could be explained by additive genetic, nonadditive genetic or maternal effects. We found that feeding activity decreased with age, but that these changes were consistently different among both individuals and crosses. The among cross patterns were consistent with a nonadditive genetic scenario: in the early period pond sticklebacks expressed dominance for high feeding activity, while in the late period marine sticklebacks expressed dominance for low feeding activity. We conclude that nine‐spined sticklebacks exhibit different feeding personalities, and that the population divergence in feeding personality is explainable by age‐dependent expression of genetic dominance.     

Mapping DNA damage‐dependent genetic interactions in yeast via party mating and barcode fusion genetics

Condition‐dependent genetic interactions can reveal functional relationships between genes that are not evident under standard culture conditions. State‐of‐the‐art yeast genetic interaction mapping, which relies on robotic manipulation of arrays of double‐mutant strains, does not scale readily to multi‐condition studies. Here, we describe barcode fusion genetics to map genetic interactions (BFG‐GI), by which double‐mutant strains generated via en masse “party” mating can also be monitored en masse for growth to detect genetic interactions. By using site‐specific recombination to fuse two DNA barcodes, each representing a specific gene deletion, BFG‐GI enables multiplexed quantitative tracking of double mutants via next‐generation sequencing. We applied BFG‐GI to a matrix of DNA repair genes under nine different conditions, including methyl methanesulfonate (MMS), 4‐nitroquinoline 1‐oxide (4NQO), bleomycin, zeocin, and three other DNA‐damaging environments. BFG‐GI recapitulated known genetic interactions and yielded new condition‐dependent genetic interactions. We validated and further explored a subnetwork of condition‐dependent genetic interactions involving MAG1, SLX4, and genes encoding the Shu complex, and inferred that loss of the Shu complex leads to an increase in the activation of the checkpoint protein kinase Rad53.     

Nonlinear developmental processes as sources of dominance

Phenotypes are the products of developmental processes whose dynamics are controlled by genes. In many developmental processes there is a nonlinear relationship between genetic variation and phenotypic variation. These nonlinear relationships can result in the emergence of dominance among alleles that control the developmental process. We explore the properties of dominance relationships in a simple developmental system consisting of a diffusion-gradient-threshold mechanism commonly deployed in pattern formation. We show that a single nonlinear process (diffusion) within this integrated mechanism leads to the emergence of dominance in all components of the mechanism. Unlike the situation in metabolic pathways, where new mutations are most likely to be recessive, the structure of the nonlinearities in this developmental mechanism is such that in certain circumstances new mutations are equally likely to be dominant or recessive. Although the dominance we observe in this system is the result of a physiological process, we also find that dominance can evolve by microevolutionary mechanisms and thus are able to reconcile the opposing views of Fisher and Wright on dominance.     

Network‐based global inference of human disease genes

Deciphering the genetic basis of human diseases is an important goal of biomedical research. On the basis of the assumption that phenotypically similar diseases are caused by functionally related genes, we propose a computational framework that integrates human protein–protein interactions, disease phenotype similarities, and known gene–phenotype associations to capture the complex relationships between phenotypes and genotypes. We develop a tool named CIPHER to predict and prioritize disease genes, and we show that the global concordance between the human protein network and the phenotype network reliably predicts disease genes. Our method is applicable to genetically uncharacterized phenotypes, effective in the genome‐wide scan of disease genes, and also extendable to explore gene cooperativity in complex diseases. The predicted genetic landscape of over 1000 human phenotypes, which reveals the global modular organization of phenotype–genotype relationships. The genome‐wide prioritization of candidate genes for over 5000 human phenotypes, including those with under‐characterized disease loci or even those lacking known association, is publicly released to facilitate future discovery of disease genes.     

Elevation,Topography, and Edge Effects Drive Functional Composition of Woody Plant Species in Tropical Montane Forests

Tropical montane forests comprise heterogeneous environments along natural gradients of topography and elevation. Human‐induced edge effects further increase the environmental heterogeneity in these forests. The simultaneous effects of natural and human‐induced gradients on the functional diversity of plant leaf traits are poorly understood. In a tropical montane forest in Bolivia, we studied environmental gradients associated with elevation (from 1900 m to 2500 m asl), topography (ridge and gorge), and edge effects (forest edge vs. forest interior), and their relationship with leaf traits and resource‐use strategies. First, we investigated associations of environmental conditions (soil properties and microclimate) with six leaf traits, measured on 119 woody plant species. Second, we evaluated changes in functional composition with community‐weighted means and functional structure with multidimensional functional diversity indices (FRic, FEve and FDiv). We found significant associations between leaf traits and soil properties in accordance with the trade‐off between acquisition and conservation of resources. Functional composition of leaf traits shifted from the dominance of acquisitive species in habitats at low altitudes, gorges, and forest interior to the dominance of conservative species in habitats at high altitudes, ridges, and forest edges. Functional structure was only weakly associated with the environmental gradients. Natural and human‐induced environmental gradients, especially soil properties, are important for driving leaf traits and resource‐use strategies of woody plants. Nevertheless, weak associations between functional structure and environmental gradients suggest a high redundancy of functional leaf traits in this tropical montane forest.     

Haploinsufficiency predictions without study bias

Any given human individual carries multiple genetic variants that disrupt protein-coding genes, through structural variation, as well as nucleotide variants and indels. Predicting the phenotypic consequences of a gene disruption remains a significant challenge. Current approaches employ information from a range of biological networks to predict which human genes are haploinsufficient (meaning two copies are required for normal function) or essential (meaning at least one copy is required for viability). Using recently available study gene sets, we show that these approaches are strongly biased towards providing accurate predictions for well-studied genes. By contrast, we derive a haploinsufficiency score from a combination of unbiased large-scale high-throughput datasets, including gene co-expression and genetic variation in over 6000 human exomes. Our approach provides a haploinsufficiency prediction for over twice as many genes currently unassociated with papers listed in Pubmed as three commonly-used approaches, and outperforms these approaches for predicting haploinsufficiency for less-studied genes. We also show that fine-tuning the predictor on a set of well-studied ‘gold standard’ haploinsufficient genes does not improve the prediction for less-studied genes. This new score can readily be used to prioritize gene disruptions resulting from any genetic variant, including copy number variants, indels and single-nucleotide variants.     

Altered longevity‐assurance activity of p53:p44 in the mouse causes memory loss,neurodegeneration and premature death

The longevity‐assurance activity of the tumor suppressor p53 depends on the levels of Δ40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44^+/+) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin‐like growth factor 1 receptor (IGF‐1R) signaling and altered metabolism of the microtubule‐binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a ‘humanized’ form of the amyloid precursor protein (APP), p44^+/+ animals developed a selective degeneration of memory‐forming and ‐retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis‐ and autophagy‐like cell deaths. These results indicate that altered longevity‐assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF‐1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP_695/swe mice, a model of Alzheimer’s disease.     

Protein deprivation facilitates the independent evolution of behavior and morphology

Ecological conditions such as nutrition can change genetic covariances between traits and accelerate or slow down trait evolution. As adaptive trait correlations can become maladaptive following rapid environmental change, poor or stressful environments are expected to weaken genetic covariances, thereby increasing the opportunity for independent evolution of traits. Here, we demonstrate the differences in genetic covariance among multiple behavioral and morphological traits (exploration, aggression, and body weight) between southern field crickets (Gryllus bimaculatus) raised in favorable (free‐choice) versus stressful (protein‐deprived) nutritional environments. We also quantify the extent to which differences in genetic covariance structures contribute to the potential for the independent evolution of these traits. We demonstrate that protein‐deprived environments tend to increase the potential for traits to evolve independently, which is caused by genetic covariances that are significantly weaker for crickets raised on protein‐deprived versus free‐choice diets. The weakening effects of stressful environments on genetic covariances tended to be stronger in males than in females. The weakening of the genetic covariance between traits under stressful nutritional environments was expected to facilitate the opportunity for adaptive evolution across generations. Therefore, the multivariate gene‐by‐environment interactions revealed here may facilitate behavioral and morphological adaptations to rapid environmental change.     

A Young Manakin Knows His Place: Evidence for an Age‐Graded Dominance Hierarchy Among Long‐Tailed Manakins

In lek‐breeding systems where many males gather at display sites, males benefit from the establishment of dominance hierarchies to reduce intrasexual aggression and the associated risk of injuries. Long‐tailed manakins (Chiroxiphia linearis) exhibit an exploded lek‐breeding system wherein the two top‐ranking males at each display site team up to perform elaborate coordinated courtship displays for females. Young males undergo delayed plumage maturation whereby they acquire distinct pre‐definitive plumage patterns each year until they attain definitive plumage in their fifth year. This unique characteristic is thought to have evolved as a status‐signalling mechanism to aid in the establishment of an age‐graded dominance hierarchy in which older males are dominant to younger males. Previous research has shown evidence for such a dominance hierarchy among alpha and beta males; however, the presence of this hierarchy among males of other age classes has never been quantified. In this study, we investigated the presence of an age‐graded dominance hierarchy by determining whether older males direct more aggressive behaviours towards younger males. We also investigated whether status signalling is less clear within age classes than between age classes, by determining whether males within the same age class exhibit more aggression towards each other. We found that older males performed aggressive behaviours towards younger males much more frequently than younger males performed aggressive behaviours towards older males. We also found that some aggressive interactions occurred between males within the same age class more frequently than between males from different age classes. Our study provides some evidence for an age‐graded dominance hierarchy among male long‐tailed manakins of all age classes and also provides some support for the status‐signalling hypothesis. However, further research is needed to conclusively establish the presence of a linear dominance hierarchy among younger male manakins. This research may help us better understand the evolution of complex hierarchical systems in animals.     

Scaling issues of neutral theory reveal violations of ecological equivalence for dominant Amazonian tree species

Neutral models are often used as null models, testing the relative importance of niche versus neutral processes in shaping diversity. Most versions, however, focus only on regional scale predictions and neglect local level contributions. Recently, a new formulation of spatial neutral theory was published showing an incompatibility between regional and local scale fits where especially the number of rare species was dramatically under‐predicted. Using a forward in time semi‐spatially explicit neutral model and a unique large‐scale Amazonian tree inventory data set, we show that neutral theory not only underestimates the number of rare species but also fails in predicting the excessive dominance of species on both regional and local levels. We show that although there are clear relationships between species composition, spatial and environmental distances, there is also a clear differentiation between species able to attain dominance with and without restriction to specific habitats. We conclude therefore that the apparent dominance of these species is real, and that their excessive abundance can be attributed to fitness differences in different ways, a clear violation of the ecological equivalence assumption of neutral theory.     

The decline in fitness with inbreeding: evidence for negative dominance‐by‐dominance epistasis in Drosophila melanogaster

Genetic interactions can play an important role in the evolution of reproductive strategies. In particular, negative dominance‐by‐dominance epistasis for fitness can theoretically favour sex and recombination. This form of epistasis can be detected statistically because it generates nonlinearity in the relationship between fitness and inbreeding coefficient. Measures of fitness in progressively inbred lines tend to show limited evidence for epistasis. However, tests of this kind can be biased against detecting an accelerating decline due to line losses at higher inbreeding levels. We tested for dominance‐by‐dominance epistasis in Drosophila melanogaster by examining viability at five inbreeding levels that were generated simultaneously, avoiding the bias against detecting nonlinearity that has affected previous studies. We find an accelerating rate of fitness decline with inbreeding, indicating that dominance‐by‐dominance epistasis is negative on average, which should favour sex and recombination.     

Color phenotypes are under similar genetic control in two distantly related species of Timema stick insect

Ecology and genetics are both of general interest to evolutionary biologists as they can influence the phenotypic and genetic response to selection. The stick insects Timema podura and Timema cristinae exhibit a green/melanistic body color polymorphism that is subject to different ecologically based selective regimes in the two species. Here, we describe aspects of the genetics of this color polymorphism in T. podura, and compare this to previous results in T. cristinae. We first show that similar color phenotypes of the two species cluster in phenotypic space. We then use genome‐wide association mapping to show that in both species, color is controlled by few loci, dominance relationships between color alleles are the same, and SNPs associated with color phenotypes colocalize to the same linkage group. Regions within this linkage group that harbor genetic variants associated with color exhibit elevated linkage disequilibrium relative to genome wide expectations, but more strongly so in T. cristinae. We use these results to discuss predictions regarding how the genetics of color could influence levels of phenotypic and genetic variation that segregate within and between populations of T. podura and T. cristinae, drawing parallels with other organisms.