Aposematic coloration offers an opportunity to explore the molecular mechanisms underlying canalization. In this study, the role of epigenetic regulation underlying robustness was explored in the aposematic coloration of the milkweed bug, Oncopeltus fasciatus. Polycomb (Pc) and Enhancer of zeste (E(z)), which encode components of the Polycomb repressive complex 1 (PRC1) and PRC2, respectively, and jing, which encodes a component of the PRC2.2 subcomplex, were knocked down in the fourth instar of O. fasciatus. Knockdown of these genes led to alterations in scutellar morphology and melanization. In particular, when Pc was knocked down, the adults developed a highly melanized abdomen, head and forewings at all temperatures examined. In contrast, the E(z) and jing knockdown led to increased plasticity of the dorsal forewing melanization across different temperatures. Moreover, jing knockdown adults exhibited increased plasticity in the dorsal melanization of the head and the thorax. These observations demonstrate that histone modifiers may play a key role during the process of canalization to confer robustness in the aposematic coloration.

A large body of evidence is documenting the impact of reduced pH on marine species and ecosystems. This information is used to infer the present and future impacts of ocean acidification. However, a vast majority of the studies were performed using constant pH and the high level of pH variability experienced by marine organisms on the coastal zone was often overlooked. Recent studies highlight the key role of this variability in driving biological response to pH as well as species sensitivity to ocean acidification. For example, it was hypothesized that because of local adaptation, the extreme of the present range of pH variability is a good predictor for local biological thresholds. Using a complex experimental design, we investigated what part of the pH variability is driving the biological response of the sea urchin Echinus esculentus larvae. Comparing stable (pH 8.13, 7.82, 7.53) and fluctuating treatments (12 h at pH 8.13 and 12 h at pH 7.53) following natural or inverted diurnal cycles, we were able to show that (i) under constant conditions, low pH deviating from the present range of natural variability had a negative effect on larval growth rate and calcification; (ii) under fluctuating conditions, a desynchronization of the pH variation with the photoperiod led to decreased larval growth rate and calcification; (iii) overall, larval fitness (survival, growth and calcification) was higher under fluctuating conditions as compared to constant. While these data do not support the hypothesis that the minimum pH is the main driver of the biological response, they provide evidence of adaptation to variability in a coastal species with associated a cost of plasticity but not a cost of canalization.

The historical challenges to bridge the gaps between developmental biology and population or statistical genetics under the explanatory dominance of the Modern Evolutionary Synthesis during the 20th century have been thoroughly documented. However, although several attempts to integrate these fields have been made, most have been deemed unsuccessful. As an example of those efforts, in this paper I discuss the work of James Meadows Rendel, a student of J. B. S. Haldane and disciple of Conrad Hal Waddington. I present his largely forgotten or unrecognized, but innovative, ideas about canalization and the role of development in phylogeny as a valuable piece to connect these fields that could still have important ramifications for today\'s evolutionary biology. In fact, it is expected that the legacy of J. M. Rendel will be rediscovered, and more importantly, incorporated and extended by future researchers, in light of the growth of evolutionary developmental biology in the last decades. What is more, this case offers a chance to critically revisit standard historiographies about the dichotomy between developmental and population genetics research frameworks in 20th century biology.

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.

Receptor-mediated signaling plays a central role in tissue regeneration, and it is dysregulated in disease. Here, we build a signaling-response map for a model regenerative human tissue: the airway epithelium. We analyzed the effect of 17 receptor-mediated signaling pathways on organotypic cultures to determine changes in abundance and phenotype of epithelial cell types. This map recapitulates the gamut of known airway epithelial signaling responses to these pathways. It defines convergent states induced by multiple ligands and diverse, ligand-specific responses in basal cell and secretory cell metaplasia. We show that loss of canonical differentiation induced by multiple pathways is associated with cell-cycle arrest, but that arrest is not sufficient to block differentiation. Using the signaling-response map, we show that a TGFB1-mediated response underlies specific aberrant cells found in multiple lung diseases and identify interferon responses in COVID-19 patient samples. Thus, we offer a framework enabling systematic evaluation of tissue signaling responses. A record of this paper\'s transparent peer review process is included in the supplemental information.

The concept of control is central to understanding and applications of biological network models. Some of their key structural features relate to control functions, through gene regulation, signaling, or metabolic mechanisms, and computational models need to encode these. Applications of models often focus on model-based control, such as in biomedicine or metabolic engineering. This paper presents an approach to model-based control that exploits two common features of biological networks, namely their modular structure and canalizing features of their regulatory mechanisms. The paper focuses on intracellular regulatory networks, represented by Boolean network models. A main result of this paper is that control strategies can be identified by focusing on one module at a time. This paper also presents a criterion based on canalizing features of the regulatory rules to identify modules that do not contribute to network control and can be excluded. For even moderately sized networks, finding global control inputs is computationally very challenging. The modular approach presented here leads to a highly efficient approach to solving this problem. This approach is applied to a published Boolean network model of blood cancer large granular lymphocyte (T-LGL) leukemia to identify a minimal control set that achieves a desired control objective.

Dysregulation of fatty acid metabolites can play a crucial role in the progression of complex diseases, such as cardiovascular disease, digestive diseases, and metabolic diseases. Metabolites can have either protective or risk effects on a disease; however, the details of such associations remain contentious. In this study, we demonstrate an integrative PheWAS approach to establish high confidence, causally suggestive of metabolite-disease associations for three fatty acid metabolites, namely, omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, for 1,254 disease endpoints. Metabolite-disease associations were established if there was a concordant direction of effect and significance for metabolite level and genetic risk score for the metabolite. There was enrichment for metabolite associations with diseases of the respiratory system for omega-3 fatty acids, diseases of the circulatory system and endocrine system for omega-6 fatty acids, and diseases of the digestive system for docosahexaenoic acid. Upon performing Mendelian randomization on a subset of the outcomes, we identified 3, 6, and 15 significant diseases associated with omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, respectively. We then demonstrate a class of prevalence-risk relationships indicative of (de)canalization of disease under high and low fatty acid metabolite levels. Finally, we show that the interaction between the metabolites and obesity demonstrates that the degree of protection afforded by fatty acid metabolites is strongly modulated by underlying metabolic health. This study evaluated the disease architectures of three polyunsaturated fatty acids (PUFAs), which were validated by several PheWAS modes of support. Our results not only highlight specific diseases associated with each metabolite but also disease group enrichments. In addition, we demonstrate an integrative PheWAS methodology that can be applied to other components of the human metabolome or other traits of interest. The results of this study can be used as an atlas to cross-compare genetic with non-genetic disease associations for the three PUFAs investigated. The findings can be explored through our R shiny app at https://pufa.biosci.gatech.edu.

Animal personality has been shown to be influenced by both genetic and environmental factors and shaped by natural selection. Currently, little is known about mechanisms influencing the development of personality traits. This study examines the extent to which personality development is genetically influenced and/or environmentally responsive (plastic). We also investigated the role of evolutionary history, assessing whether personality traits could be canalized along a genetic and ecological divergence gradient. We tested the plastic potential of boldness in juveniles of five Icelandic Arctic charr morphs (Salvelinus alpinus), including two pairs of sympatric morphs, displaying various degrees of genetic and ecological divergence from the ancestral anadromous charr, split between treatments mimicking benthic versus pelagic feeding modalities. We show that differences in mean boldness are mostly affected by genetics. While the benthic treatment led to bolder individuals overall, the environmental effect was rather weak, suggesting that boldness lies under strong genetic influence with reduced plastic potential. Finally, we found hints of differences by morphs in boldness canalization through reduced variance and plasticity, and higher consistency in boldness within morphs. These findings provide new insights on how behavioural development may impact adaptive diversification.

An examination of innate behavior and its possible origins suggests parallels with the formation of habitual behavior. Inflexible but adaptive responses-innate reflexive behavior, Pavlovian conditioned responses, and operant habits-may have evolved from variable behavior in phylogeny and ontogeny. This form of \"plasticity-first\" scientific narrative was unpopular post-Darwin but has recently gained credibility in evolutionary biology. The present article seeks to identify originating events and contingencies contributing to such inflexible but adaptive behavior at both phylogenic and ontogenic levels of selection. In ontogeny, the development of inflexible performance (i.e., habit) from variable operant behavior is reminiscent of the genetic accommodation of initially variable phylogenic traits. The effects characteristic of habit (e.g., unresponsiveness to reinforcer devaluation) are explicable as the result of a conflict between behaviors at distinct levels of selection. The present interpretation validates the practice of seeking hard analogies between evolutionary biology and operant behavior. Finding such parallels implies the validity of a claim that organismal behavior, both innate and learned, is a product of selection by consequences. A complete and coherent account of organismal behavior may ultimately focus on functional selective histories in much the same way evolutionary biology does with its subject matter.

Although individual differences in the behavior of animals, sometimes referred to as personality, have recently received considerable attention, the development of such differences remains understudied. We previously found consistent individual differences in behavior in four tests simulating everyday contexts in 74 preweaning age kittens from 16 litters of the domestic cat. To study the development of consistent among-individual differences in four behavioral traits in cats, we followed a subset of these same individuals and repeated the same tests at 6 and 12 months of age. Some individual differences in behavior became increasingly repeatable with age due to a combination of decreased individual-level variance (canalization) and increased among-individual variance; these changes in variance and repeatability continued into adulthood (12 months). We did not observe behavioral syndromes at any age, in contrast to our previous reports in a different population of adult cats. The mechanisms that underlie increased repeatability with age and the possibility of personality structure differing between populations in this species remain to be studied.