Evolutionary genetics of personality in the Trinidadian guppy II: Sexual dimorphism and genotype-by-sex interactions (article)

This is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record. Accompanying data available at: https://doi.org/10.24378/exe.224 via the link in this recordSexual dimorphism in behaviour and personality have been identified in a number of species, but few studies have assessed the extent of shared genetic architecture across the sexes. Under sexually antagonistic selection, mechanisms are expected to evolve that reduce evolutionary conflict, resulting in genotype-by-sex (GxS) interactions. Here, we assess the extent of sexual dimorphism in four risk-taking behaviour traits in the Trinidadian guppy, Poecilia reticulata, and apply a multivariate approach to test for GxS interactions. We also quantify the among-individual and genetic covariances between personality and size and growth which are known a priori to differ between the sexes. We found significant sexual dimorphism in three of the four behaviours, although rmf between sex-specific homologous traits was significantly less than +1 for only one behaviour. Using multivariate models, we then estimated sex-specific genetic (co)variance matrices (Gm and Gf) and tested for asymmetry of the cross-trait cross-sex genetic covariance structure (submatrix B). While Gm and Gf were not significantly different from each other overall, their respective leading eigen vectors were poorly aligned. Statistical support for asymmetry in B was found, but limited to a single trait pair for which the cross-sex covariances differed (i.e. COVA(m,f) ≠ COVA(f,m)). Thus, while single- and multi-trait perspectives evidence some GxS, the overall picture is one of similarity between the sexes in their genetic (co)variance structures. Our results suggest behavioural traits related to risk-taking may lack the sex-specific genetic architecture for further dimorphism to evolve under what is hypothesised to be antagonistic selection

Development of G: A test in an amphibious fish

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.The data used in this manuscript has been achieved in Dryad repository: doi:10.5061/dryad.m56pj5b.Heritable variation in, and genetic correlations among, traits determine the response of multivariate phenotypes to natural selection. However, as traits develop over ontogeny, patterns of genetic (co)variation and integration captured by the G matrix may also change. Despite this, few studies have investigated how genetic parameters underpinning multivariate phenotypes change as animals pass through major life history stages. Here, using a self-fertilizing hermaphroditic fish species, mangrove rivulus (Kryptolebias marmoratus), we test the hypothesis that G changes from hatching through reproductive maturation. We also test Cheverud’s conjecture by asking whether phenotypic patterns provide an acceptable surrogate for patterns of genetic (co)variation within and across ontogenetic stages. For a set of morphological traits linked to locomotor (jumping) performance, we find that the overall level of genetic integration (as measured by the mean-squared correlation across all traits) does not change significantly over ontogeny. However, we also find evidence that some trait-specific genetic variances and pairwise genetic correlations do change. Ontogenetic changes in G indicate the presence of genetic variance for developmental processes themselves, while also suggesting that any genetic constraints on morphological evolution may be age-dependent. Phenotypic correlations closely resembled genetic correlations at each stage in ontogeny. Thus, our results are consistent with the premise that – at least under common environment conditions - phenotypic correlations can be a good substitute for genetic correlations in studies of multivariate developmental evolution

Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)

PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3′5′ adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the Hsp20 by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window

Testing the stability of behavioural coping style across stress contexts in the Trinidadian guppy

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.1. Within-populations, individuals can vary in stress response, a multivariate phenomenon comprising neuroendocrine, physiological and behavioural traits. 2. Verbal models of individual stress ‘coping style’ have proposed that the behavioural component of this variation can be described as a single axis, with each individual’s coping style being consistent across time and stress contexts. 3. Focusing on this behavioural component of stress response, and combining repeated measures of multiple traits with a novel multivariate modelling framework, we test for the existence of coping style variation and assess its stability across contexts in the Trinidadian guppy (Poecilia reticulata). 4. Specifically, we test the following hypotheses: (i) there exists repeatable among-individual behavioural (co)variation (‘personality’) within a mild stress context consistent with a risk-averse—risk-prone continuum of behavioural coping style, (ii) there is population-level plasticity in behaviour as a function of stressor severity, (iii) there is among-individual variation in plasticity (i.e., IxE), and (iv) the presence of IxE reduces cross-context stability of behavioural coping style. 5. We found significant repeatable among-individual behavioural (co)variation in the mild stress context (open field trial), represented as an I matrix. However, I was not readily described by a simple risk-averse—risk-prone continuum as posited by the original coping style model. We also found strong evidence for population-level changes in mean behaviour with increasing stressor severity (simulated avian and piscine predation risks). 6. Single-trait analyses did show the presence of individual-by-environment interactions (IxE), as among-individual cross-context correlations were significantly less than +1. However, multi-trait analysis revealed the consequences of this plasticity variation were minimal. Specifically, we found little evidence for changes in the structure of I between mild and moderate stress contexts overall, and only minor changes between the two moderate contexts (avian versus piscine predator). 7. We show that a multivariate approach to assessing changes in among individual (co)variance across contexts can prevent the over-interpretation of statistically significant, but small, individual-by-environment effects. While behavioural flexibility enables populations (and individuals) to respond rapidly to changes in the environment, multivariate personality structure can be conserved strongly across such contexts.Funding was provided by a grant from the Biotechnology and Biological Sciences Research Council (BBSRC, grant BB/L022656/1). A.J.Y. is supported by a BBSRC David Phillips Fellowship

Genetic variance for behavioural 'predictability' of stress response.

Genetic factors underpinning phenotypic variation are required if natural selection is to result in adaptive evolution. However, evolutionary and behavioural ecologists typically focus on variation among individuals in their average trait values and seek to characterize genetic contributions to this. As a result, less attention has been paid to if and how genes could contribute towards within-individual variance or trait 'predictability'. In fact, phenotypic 'predictability' can vary among individuals, and emerging evidence from livestock genetics suggests this can be due to genetic factors. Here, we test this empirically using repeated measures of a behavioural stress response trait in a pedigreed population of wild-type guppies. We ask (a) whether individuals differ in behavioural predictability and (b) whether this variation is heritable and so evolvable under selection. Using statistical methodology from the field of quantitative genetics, we find support for both hypotheses and also show evidence of a genetic correlation structure between the behavioural trait mean and individual predictability. We show that investigating sources of variability in trait predictability is statistically tractable and can yield useful biological interpretation. We conclude that, if widespread, genetic variance for 'predictability' will have major implications for the evolutionary causes and consequences of phenotypic variation.This work was supported by the Biotechnology and Biological Sciences Research Council (grant BB/L022656/1) and by a BBSRC studentship to PMP

Genetic variance for behavioural ‘predictability’ of the stress response

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordGenetic factors underpinning phenotypic variation are required if natural selection is to result in adaptive evolution. However, evolutionary and behavioural ecologists typically focus on variation among individuals in their average trait values, and seek to characterise genetic contributions to this. As a result, less attention has been paid to if and how genes could contribute towards within-individual variance, or trait “predictability”. In fact, phenotypic ‘predictability’ can vary among individuals, and emerging evidence from livestock genetics suggests this can be due to genetic factors. Here we test this empirically using repeated measures of a behavioural stress response trait in a pedigreed population of wild-type guppies. We ask (1) whether individuals differ in behavioural predictability, and (2) whether this variation is heritable and so evolvable under selection. Using statistical methodology from the field of quantitative genetics, we find support for both hypotheses and also show evidence of a genetic correlation structure between the behavioural trait mean and individual predictability. We show that investigating sources of variability in trait predictability is statistically tractable, and can yield useful biological interpretation. We conclude that, if widespread, genetic variance for ‘predictability’ will have major implications for the evolutionary causes and consequences of phenotypic variation.Biotechnology & Biological Sciences Research Council (BBSRC

Compartmentalized PDE4A5 signaling impairs hippocampal synaptic plasticity and long-term memory

Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling

Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density

Genetic integration of behavioural and endocrine components of the stress response

This is the final version. Available on open access from eLife Sciences Publications via the DOI in this recordData Availability: Data and analysis code have been deposited in Dryad. Datasets Generated: Data from: Genetic integration of behavioural and endocrine components of the stress response: Houslay TM, Earley RL, White SJ, Lammers W, Grimmer AJ, Travers LM, Johnson EL, Young AJ, Wilson AJ, 2021, https://doi.org/10.5061/dryad.z34tmpgcg, Dryad Digital Repository, doi:10.5061/dryad.z34tmpgcgThe vertebrate stress response comprises a suite of behavioural and physiological traits that must be functionally integrated to ensure organisms cope adaptively with acute stressors. Natural selection should favour functional integration, leading to a prediction of genetic integration of these traits. Despite the implications of such genetic integration for our understanding of human and animal health, as well as evolutionary responses to natural and anthropogenic stressors, formal quantitative genetic tests of this prediction are lacking. Here we demonstrate that acute stress response components in Trinidadian guppies are both heritable and integrated on the major axis of genetic covariation. This integration could either facilitate or constrain evolutionary responses to selection, depending upon the alignment of selection with this axis. Such integration also suggests artificial selection on the genetically correlated behavioural responses to stress could offer a viable non-invasive route to the improvement of health and welfare in captive animal populations.Biotechnology and Biological Sciences Research Council (BBSRC