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Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease. [ABSTRACT FROM AUTHOR]

Abstract: A future quantitative genetics theory should link genetic variation to phenotypic variation in a causally cohesive way based on how genes actually work and interact. We provide a theoretical framework for predicting and understanding the manifestation of genetic variation in haploid and diploid regulatory networks with arbitrary feedback structures and intra-locus and inter-locus functional dependencies. Using results from network and graph theory, we define propagation functions describing how genetic variation in a locus is propagated through the network, and show how their derivatives are related to the network’s feedback structure. Similarly, feedback functions describe the effect of genotypic variation of a locus on itself, either directly or mediated by the network. A simple sign rule relates the sign of the derivative of the feedback function of any locus to the feedback loops involving that particular locus. We show that the sign of the phenotypically manifested interaction between alleles at a diploid locus is equal to the sign of the dominant feedback loop involving that particular locus, in accordance with recent results for a single locus system. Our results provide tools by which one can use observable equilibrium concentrations of gene products to disclose structural properties of the network architecture. Our work is a step towards a theory capable of explaining the pleiotropy and epistasis features of genetic variation in complex regulatory networks as functions of regulatory anatomy and functional location of the genetic variation. [Copyright &y& Elsevier]

Functional dependencies between genes are a defining characteristic of gene networks underlying quantitative traits. However, recent studies show that the proportion of the genetic variation that can be attributed to statistical epistasis varies from almost zero to very high. It is thus of fundamental as well as instrumental importance to better understand whether different functional dependency patterns among polymorphic genes give rise to distinct statistical interaction patterns or not. Here we address this issue by combining a quantitative genetic model approach with genotype-phenotype models capable of translating allelic variation and regulatory principles into phenotypic variation at the level of gene expression. We show that gene regulatory networks with and without feedback motifs can exhibit a wide range of possible statistical genetic architectures with regard to both type of effect explaining phenotypic variance and number of apparent loci underlying the observed phenotypic effect. Although all motifs are capable of harboring significant interactions, positive feedback gives rise to higher amounts and more types of statistical epistasis. The results also suggest that the inclusion of statistical interaction terms in genetic models will increase the chance to detect additional QTL as well as functional dependencies between genetic loci over a broad range of regulatory regimes. This article illustrates how statistical genetic methods can fruitfully be combined with nonlinear systems dynamics to elucidate biological issues beyond reach of each methodology in isolation. [ABSTRACT FROM AUTHOR]

Background: While invasive social distancing measures have proven efficient to control the spread of pandemics failing wide-scale deployment of vaccines, they carry vast societal costs. The development of a diagnostic methodology for identifying COVID-19 infection through simple testing was a reality only a few weeks after the novel virus was officially announced. Thus, we were interested in exploring the ability of regular testing of non-symptomatic people to reduce cases and thereby offer a non-pharmaceutical tool for controlling the spread of a pandemic. Methods: We developed a data-driven individual-based epidemiological network model in order to investigate epidemic countermeasures. This models is based on high-resolution demographic data for each municipality in Norway, and each person in the model is subject to Susceptible-Exposed-Infectious-Recovered (SEIR) dynamics. The model was calibrated against hospitalization data in Oslo, Norway, a city with a population of 700k which we have used as the simulations focus. Results: Finding that large households function as hubs for the propagation of COVID-19, we assess the intervention efficiency of targeted pooled household testing (TPHT) repeatedly. For an outbreak with reproductive number R=1.4, we find that weekly TPHT of the 25% largest households brings R below unity. For the case of R=1.2, our results suggest that TPHT with the largest 25% of households every three days in an urban area is as effective as a lockdown in curbing the outbreak. Our investigations of different disease parameters suggest that these results are markedly improved for disease variants that more easily infect young people, and when compliance with self-isolation rules is less than perfect among suspected symptomatic cases. These results are quite robust to changes in the testing frequency, city size, and the household-size distribution. Our results are robust even with only 50% of households willing to participate in TPHT, provided the total number of tests stay unchanged. Conclusions: Pooled and targeted household testing appears to be a powerful non-pharmaceutical alternative to more invasive social-distancing and lock-down measures as a localized early response to contain epidemic outbreaks. [ABSTRACT FROM AUTHOR]

We scale the population of the baseline Oslo model ( = 1) to generate larger ( > 1) or smaller networks with household, school, daycare, workplace and nursing home size-distributions unchanged. B Effect of TPHT in response to a sudden rise in cases (reaching 1000 symptomatic individuals), assuming general infectivity parameters similar to those of Oslo in late May 2020 but with 75% increased infectivity of random contacts giving R = 1.2. F Response of weekly TPHT to changes in distribution of household size, relative to the baseline Oslo model ( = 0). [Extracted from the article]

• Model personalisation requires more than anatomical personalisation. • Model uncertainty and sensitivity are important considerations for clinical interpretation. • Model verification and validation are critical for trust underpinning clinical decision support. • The cardiovascular digital twin will support diagnosis and prognosis by responding continuously to increasing volumes of information collected as the individual goes about their daily life. The aim of this position paper is to provide a brief overview of the current status of cardiovascular modelling and of the processes required and some of the challenges to be addressed to see wider exploitation in both personal health management and clinical practice. In most branches of engineering the concept of the digital twin, informed by extensive and continuous monitoring and coupled with robust data assimilation and simulation techniques, is gaining traction: the Gartner Group listed it as one of the top ten digital trends in 2018. The cardiovascular modelling community is starting to develop a much more systematic approach to the combination of physics, mathematics, control theory, artificial intelligence, machine learning, computer science and advanced engineering methodology, as well as working more closely with the clinical community to better understand and exploit physiological measurements, and indeed to develop jointly better measurement protocols informed by model-based understanding. Developments in physiological modelling, model personalisation, model outcome uncertainty, and the role of models in clinical decision support are addressed and 'where-next' steps and challenges discussed. [ABSTRACT FROM AUTHOR]

The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid β that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain's interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure-mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space. The space was divided into sheets (i.e., space between two parallel membranes) and tunnels (where three or more membranes meet). Simulation results indicate that even for larger extracellular volume fractions than what is reported for sleep and for geometries with a high tunnel volume fraction, the permeability was too low to allow for any substantial bulk flow at physiological hydrostatic pressure gradients. For two different geometries with the same extracellular volume fraction the geometry with the most tunnel volume had 36% higher permeability, but the bulk flow was still insignificant. These simulation results suggest that even large molecule solutes would be more easily cleared from the brain interstitium by diffusion than by bulk flow. Thus, diffusion within the interstitial space combined with advection along vessels is likely to substitute for the lymphatic drainage system in other organs. [ABSTRACT FROM AUTHOR]

A major rationale for the advocacy of epigenetically mediated adaptive responses is that they facilitate faster adaptation to environmental challenges. This motivated us to develop a theoretical- experimental framework for disclosing the presence of such adaptation- speeding mechanisms in an experimental evolution setting circumventing the need for pursuing costly mutation-accumulation experiments. To this end, we exposed clonal populations of budding yeast to a whole range of stressors. By growth phenotyping, we found that almost complete adaptation to arsenic emerged after a few mitotic cell divisions without involving any phenotypic plasticity. Causative mutations were identified by deep sequencing of the arsenic-adapted populations and reconstructed for validation. Mutation effects on growth phenotypes, and the associated mutational target sizes were quantified and embedded in datadriven individual-based evolutionary population models. We found that the experimentally observed homogeneity of adaptation speed and heterogeneity of molecular solutions could only be accounted for if the mutation rate had been near estimates of the basal mutation rate. The ultrafast adaptation could be fully explained by extensive positive pleiotropy such that all beneficial mutations dramatically enhanced multiple fitness components in concert. As our approach can be exploited across a range of model organisms exposed to a variety of environmental challenges, it may be used for determining the importance of epigenetic adaptation- speeding mechanisms in general. [ABSTRACT FROM AUTHOR]

The mouse is an important model for theoretical-experimental cardiac research, and biophysically based whole organ models of the mouse heart are now within reach. However, the passive material properties of mouse myocardium have not been much studied. We present an experimental setup and associated computational pipeline to quantify these stiffness properties. A mouse heart was excised and the left ventricle experimentally inflated from 0 to 1.44 kPa in eleven steps, and the resulting deformation was estimated by echocardiography and speckle tracking. An in silico counterpart to this experiment was built using finite element methods and data on ventricular tissue microstructure from diffusion tensor MRI. This model assumed a hyperelastic, transversely isotropic material law to describe the force-deformation relationship, and was simulated for many parameter scenarios, covering the relevant range of parameter space. To identify well-fitting parameter scenarios, we compared experimental and simulated outcomes across the whole range of pressures, based partly on gross phenotypes (volume, elastic energy, and short- and long-axis diameter), and partly on node positions in the geometrical mesh. This identified a narrow region of experimentally compatible values of the material parameters. Estimation turned out to be more precise when based on changes in gross phenotypes, compared to the prevailing practice of using displacements of the material points. We conclude that the presented experimental setup and computational pipeline is a viable method that deserves wider application. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics related to the integration of evolutionary biology and physiological science including the comparisons of chromatin marking and small RNA profiles in populations at initial stages of evolutionary divergence, Modern Synthesis, and the history and philosophy of the relevant concepts of the gene and their interpretations of the consequences.

Here we discuss life-history evolution from the perspective of adaptive phenotypic plasticity, with a focus on polyphenisms for somatic maintenance and survival. Polyphenisms are adaptive discrete alternative phenotypes that develop in response to changes in the environment. We suggest that dauer larval diapause and its associated adult phenotypes in the nematode (Caenorhabditis elegans), reproductive dormancy in the fruit fly (Drosophila melanogaster) and other insects, and the worker castes of the honey bee (Apis mellifera) are examples of what may be viewed as the polyphenic regulation of somatic maintenance and survival. In these and other cases, the same genotype can--depending upon its environment--express either of two alternative sets of life-history phenotypes that differ markedly with respect to somatic maintenance, survival ability, and thus life span. This plastic modulation of somatic maintenance and survival has traditionally been underappreciated by researchers working on aging and life history. We review the current evidence for such adaptive life-history switches and their molecular regulation and suggest that they are caused by temporally and/or spatially varying, stressful environments that impose diversifying selection, thereby favoring the evolution of plasticity of somatic maintenance and survival under strong regulatory control. By considering somatic maintenance and survivorship from the perspective of adaptive life-history switches, we may gain novel insights into the mechanisms and evolution of aging. [ABSTRACT FROM AUTHOR]

The genotype-phenotype map (GP map) concept applies to any time point in the ontogeny of a living system. It is the outcome of very complex dynamics that include environmental effects, and bridging the genotype-phenotype gap is synonymous with understanding these dynamics. The context for this understanding is physiology, and the disciplinary goals of physiology do indeed demand the physiological community to seek this understanding. We claim that this task is beyond reach without use of mathematical models that bind together genetic and phenotypic data in a causally cohesive way. We provide illustrations of such causally cohesive genotype-phenotype models where the phenotypes span from gene expression profiles to development of whole organs. Bridging the genotype-phenotype gap also demands that large-scale biological ('omics') data and associated bioinformatics resources be more effectively integrated with computational physiology than is currently the case. A third major element is the need for developing a phenomics technology way beyond current state of the art, and we advocate the establishment of a Human Phenome Programme solidly grounded on biophysically based mathematical descriptions of human physiology. [ABSTRACT FROM AUTHOR]

. Purpose: Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure of unknown aetiology. Patients with IIH usually suffer from headache and visual disturbances. High intracranial pressure despite normal ventricle size and negative MRI indicate perturbed water flux across cellular membranes, which is provided by the brain water channel aquaporin-4 (AQP4). IIH could be associated with malfunctioning intracerebral water homeostasis and cerebrospinal fluid (CSF) reabsorption based on functional or regulatory alterations of AQP4. Methods: Clinical data, blood and CSF samples were collected from 28 patients with IIH. Clinical characteristics were assessed, and a genetic association study was performed by sequencing the AQP4 gene on chromosome 18. Genetic data were compared with 52 healthy controls and matched by age, sex and ethnicity. Chi-square test and linear discriminant analysis (LDA) were used in the search of a genotype-phenotype association. Results: While the majority of patients responded to medical treatment, four required shunt application. All, except one, had a good visual outcome. The 24 AQP4 gene SNPs showed no association with IIH. Full cross-validation of the LDA modelling resulted in only 55.1% correct classification of the cases and controls, with a corresponding estimated p-value 0.37. Conclusions: Our genetic case-control study did not indicate an association between AQP4 gene variants and IIH. However, the theory of an etiopathogenic link between IIH and AQP4 is tempting, and discussed in this article. Association studies with large sample size are difficult to perform owing is the rarity of the condition. [ABSTRACT FROM AUTHOR]

Abstract: Dynamic models of biological systems often possess complex and multivariate mappings between input parameters and output state variables, posing challenges for comprehensive sensitivity analysis across the biologically relevant parameter space. In particular, more efficient and robust ways to obtain a solid understanding of how the sensitivity to each parameter depends on the values of the other parameters are sorely needed. We report a new methodology for global sensitivity analysis based on Hierarchical Cluster-based Partial Least Squares Regression (HC-PLSR)-based approximations (metamodelling) of the input–output mappings of dynamic models, which we expect to be generic, efficient and robust, even for systems with highly nonlinear input–output relationships. The two-step HC-PLSR metamodelling automatically separates the observations (here corresponding to different combinations of input parameter values) into groups based on the dynamic model behaviour, then analyses each group separately with Partial Least Squares Regression (PLSR). This produces one global regression model comprising all observations, as well as regional regression models within each group, where the regression coefficients can be used as sensitivity measures. Thereby a more accurate description of complex interactions between inputs to the dynamic model can be revealed through analysis of how a certain level of one input parameter affects the model sensitivity to other inputs. We illustrate the usefulness of the HC-PLSR approach on a dynamic model of a mouse heart muscle cell, and demonstrate how it reveals interaction patterns of probable biological significance not easily identifiable by a global regression-based sensitivity analysis alone. Applied for sensitivity analysis of a complex, high-dimensional dynamic model of the mouse heart muscle cell, several interactions between input parameters were identified by the two-step HC-PLSR analysis that could not be detected in the single-step global analysis. Hence, our approach has the potential to reveal new biological insight through the identification of complex parameter interaction patterns. The HC-PLSR metamodel complexity can be adjusted according to the nonlinear complexity of the input–output mapping of the analysed dynamic model through adjustment of the number of regional regression models included. This facilitates sensitivity analysis of dynamic models of varying complexities. [Copyright &y& Elsevier]

We estimated additive genetic variation and heritability of survival after Gyrodactylus salaris infection from survival records in a pedigreed family material of wild Atlantic salmon (Salmo salar) in a controlled challenge test. We used a statistical model that distinguishes between survival time for the fish that died and the ability to survive the entire test as two separate traits. Eleven of the 49 full-sib families suffered 100% mortality, 15 families had between 10% and 25% survival, and the four least affected families had survival rates between 36% and 48%. Estimated heritability of survival on the liability scale was 0.32 ± 0.10. Time until death for fish that died during the test and the ability to survive the entire test were not expressions of the same genetic trait. Simply selecting survivors as parents for the next generation is expected to more than double the overall survival rate in only one generation, given similar exposure to the parasite. Improving the genetic capacity to survive the infection will probably not eradicate the parasite, but when used as a disease control measure, such improvement may contain the infection at a level where the parasite ceases to be a major problem. [ABSTRACT FROM AUTHOR]

The Pacific chinook salmon occurs as both white- and red-fleshed populations, with the flesh color type (red or white) seemingly under strong genetic influence. Previously published data on crosses between red- and white-fleshed individuals cannot he reconciled with a simple Mendelian two-locus, two-allele model, pointing to either a more complex inheritance pattern or the existence of gene interactions. Here we show that a standard single-locus, three-allele model can fully explain these data. Moreover, by implementing the single-locus model at the parameter level of a previously developed mathematical model describing carotenoid dynamics in salmon, we show that variation at a single gene involved in the muscle uptake of carotenoids is able to explain the available data. This illustrates how such a combined approach can generate biological understanding that would not he possible in a classical population genetic explanatory structure. An additional asset of this approach is that by allowing parameters to become phenotypes obeying a given genetic model, biological interpretations of mechanisms involved at a resolution level far beyond what is built into the original dynamic model are made possible. These insights can in turn he exploited in experimental studies as well as in construction of more detailed models. [ABSTRACT FROM AUTHOR]

Pigmented flesh, a trait uniquely present in four of the 10 genera of salmonid fishes, is caused by the ubiquitous capacity of these genera for accumulating dietary carotenoids in muscle tissue. Here we combine life history reasoning with current knowledge of carotenoid metabolism to suggest a possible evolutionary scenario accounting for the emergence and maintenance of this phenotype. We claim that a basal carotenoid metabolism and a hormonally controlled targeted degradation of muscle tissue during maturation were established before the anadromous life style and that these proximal features were concomitantly exploited by natural selection in an ancestral anadromous and nest-making salmonid. Three different selection regimes are suggested to account for available empirical data concerning emergence, as well as maintenance, of the flesh pigmentation trait: a primary one driven by the need for enhanced somatic maintenance accompanying nest making under starving conditions, a secondary one driven by sexual selection, and a tertiary one driven by exposure to a meager carotenoid diet in nonanadromous freshwater populations. Finally, an experimental research program thought to be instrumental for fully resolving this evolutionary puzzle is suggested. [ABSTRACT FROM AUTHOR]

Candidate single-nucleotide polymorphisms (SNPs) were analyzed for associations to an unselected whole genome pool of tumor mRNA transcripts in 50 unrelated patients with breast cancer. SNPs were selected from 203 candidate genes of the reactive oxygen species pathway. We describe a general statistical framework for the simultaneous analysis of gene expression data and SNP genotype data measured for the same cohort, which revealed significant associations between subsets of SNPs and transcripts, shedding light on the underlying biology. We identified SNPs in EGF. IL1A, MAPK8, XPC, SOD2, and ALOX12 that are associated with the expression patterns of a significant number of transcripts, indicating the presence of regulatory SNPs in these genes. SNPs were found to act in trans in a total of 115 genes. SNPs in 43 of these 115 genes were found to act both in cis and in trans. Finally, subsets of SNPs that share significantly many common associations with a set of transcripts (biclusters) were identified. The subsets of transcripts that are significantly associated with the same set of SNPs or to a single SNP were shown to be functionally coherent in Gene Ontology and pathway analyses and coexpressed in other independent data sets, suggesting that many of the observed associations are within the same functional pathways. To our knowledge, this article is the first study to correlate SNP genotype data in the germ line with somatic gene expression data in breast tumors. It provides the statistical framework for further genotype expression correlation studies in cancer data sets. [ABSTRACT FROM AUTHOR]

A striking example of plasticity in life span is seen in social insects such as ants and bees, where different castes may display distinct ageing patterns. In particular, the honeybee offers an intriguing illustration of environmental control on ageing rate. Honeybee workers display a temporal division of labour where young bees (or ‘hive bees’) perform tasks within the brood nest, and older bees forage for nectar, pollen propolis and water. When bees switch from the hive bee to the forager stage, their cellular defence machinery is down-regulated by a dramatic reduction in the number of functioning haemocytes (immunocytes). This study documents that the yolk precursor vitellogenin is likely to be involved in a regulatory pathway that controls the observed decline in somatic maintenance function of honeybee foragers. An association between the glyco-lipoprotein vitellogenin and immune function has not previously been reported for any organism. Honeybee workers are functionally sterile, and via the expression of juvenile hormone, a key gonotrophic hormone in adult insects, their vitellogenin levels are influenced by social interactions with other bees. Our results therefore suggest that in terms of maintenance of the cellular immune system, senescence of the honeybee worker is under social control. [Copyright &y& Elsevier]

Vitellogenin is a female-specific glucolipoprotein yolk precursor produced by all oviparous animals. Vitellogenin expression is under hormonal control, and the protein is generally synthesized directly before yolk deposition. In the honeybee (Apis mellifera), viteliogenin is not only synthesized by the reproductive queen, but also by the functionally sterile workers. In summer, the worker population consists of a hive bee group performing a multitude of tasks including nursing inside the nest, and a forager group specialized in collecting nectar, pollen, water, and propolis. VitelIogenin is synthesized in large quantities by hive bees. When hive bees develop into foragers, their juvenile hormone titers increase, and this causes cessation of their vitellogenin production. This inverse relationship between vitellogenin synthesis and juvenile hormone is opposite to the norm in insects, and the underlying proximate processes and life-history reasons are still not understood. Here we document an alternative use of vitellogenin by showing that it is a source for the proteinaceous royal jelly that is produced by the hive bees. Hive bees use the jelly to feed larvae, queen, workers, and drones. This finding suggests that the evolution of a brood-rearing worker class and a specialized forager class in an advanced eusocial insect society has been directed by an alternative utilization of yolk protein. [ABSTRACT FROM AUTHOR]

In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment., (© 2024. The Author(s).)

The past decade has seen a dramatic rise in consumer technologies able to monitor a variety of cardiovascular parameters. Such devices initially recorded markers of exercise, but now include physiological and health-care focused measurements. The public are keen to adopt these devices in the belief that they are useful to identify and monitor cardiovascular disease. Clinicians are therefore often presented with health app data accompanied by a diverse range of concerns and queries. Herein, we assess whether these devices are accurate, their outputs validated, and whether they are suitable for professionals to make management decisions. We review underpinning methods and technologies and explore the evidence supporting the use of these devices as diagnostic and monitoring tools in hypertension, arrhythmia, heart failure, coronary artery disease, pulmonary hypertension, and valvular heart disease. Used correctly, they might improve health care and support research., Competing Interests: Declaration of interests EAA is an advisor to Apple and has received funding from Apple, Google, and Samsung. AL receives research support from Apple. PDM has received speaker's honoraria from Abbot. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

With limited availability of vaccines, an efficient use of the limited supply of vaccines in order to achieve herd immunity will be an important tool to combat the wide-spread prevalence of COVID-19. Here, we compare a selection of strategies for vaccine distribution, including a novel targeted vaccination approach (EHR) that provides a noticeable increase in vaccine impact on disease spread compared to age-prioritized and random selection vaccination schemes. Using high-fidelity individual-based computer simulations with Oslo, Norway as an example, we find that for a community reproductive number in a setting where the base pre-vaccination reproduction number R = 2.1 without population immunity, the EHR method reaches herd immunity at 48% of the population vaccinated with 90% efficiency, whereas the common age-prioritized approach needs 89%, and a population-wide random selection approach requires 61%. We find that age-based strategies have a substantially weaker impact on epidemic spread and struggle to achieve herd immunity under the majority of conditions. Furthermore, the vaccination of minors is essential to achieving herd immunity, even for ideal vaccines providing 100% protection., Competing Interests: The authors have declared that no competing interests exist.

Each animal in the Darwinian theater is exposed to a number of abiotic and biotic risk factors causing mortality. Several of these risk factors are intimately associated with the act of energy acquisition as such and with the amount of reserve the organism has available from this acquisition for overcoming temporary distress. Because a considerable fraction of an individual's lifetime energy acquisition is spent on somatic maintenance, there is a close link between energy expenditure on somatic maintenance and mortality risk. Here, we show, by simple life-history theory reasoning backed up by empirical cohort survivorship data, how reduction of mortality risk might be achieved by restraining allocation to somatic maintenance, which enhances lifetime fitness but results in aging. Our results predict the ubiquitous presence of senescent individuals in a highly diverse group of natural animal populations, which may display constant, increasing, or decreasing mortality with age. This suggests that allocation to somatic maintenance is primarily tuned to expected life span by stabilizing selection and is not necessarily traded against reproductive effort or other traits. Due to this ubiquitous strategy of modulating the somatic maintenance budget so as to increase fitness under natural conditions, it follows that individuals kept in protected environments with very low environmental mortality risk will have their expected life span primarily defined by somatic damage accumulation mechanisms laid down by natural selection in the wild., Competing Interests: The authors declare no competing interest.

The whole-genome duplication 80 million years ago of the common ancestor of salmonids (salmonid-specific fourth vertebrate whole-genome duplication, Ss4R) provides unique opportunities to learn about the evolutionary fate of a duplicated vertebrate genome in 70 extant lineages. Here we present a high-quality genome assembly for Atlantic salmon (Salmo salar), and show that large genomic reorganizations, coinciding with bursts of transposon-mediated repeat expansions, were crucial for the post-Ss4R rediploidization process. Comparisons of duplicate gene expression patterns across a wide range of tissues with orthologous genes from a pre-Ss4R outgroup unexpectedly demonstrate far more instances of neofunctionalization than subfunctionalization. Surprisingly, we find that genes that were retained as duplicates after the teleost-specific whole-genome duplication 320 million years ago were not more likely to be retained after the Ss4R, and that the duplicate retention was not influenced to a great extent by the nature of the predicted protein interactions of the gene products. Finally, we demonstrate that the Atlantic salmon assembly can serve as a reference sequence for the study of other salmonids for a range of purposes.

Exposing natural selection driving phenotypic and genotypic adaptive differentiation is an extraordinary challenge. Given that an organism's life stages are exposed to the same environmental variations, we reasoned that fitness components, such as the lag, rate, and efficiency of growth, directly reflecting performance in these life stages, should often be selected in concert. We therefore conjectured that correlations between fitness components over natural isolates, in a particular environmental context, would constitute a robust signal of recent selection. Critically, this test for selection requires fitness components to be determined by different genetic loci. To explore our conjecture, we exhaustively evaluated the lag, rate, and efficiency of asexual population growth of natural isolates of the model yeast Saccharomyces cerevisiae in a large variety of nitrogen-limited environments. Overall, fitness components were well correlated under nitrogen restriction. Yeast isolates were further crossed in all pairwise combinations and coinheritance of each fitness component and genetic markers were traced. Trait variations tended to map to quantitative trait loci (QTL) that were private to a single fitness component. We further traced QTLs down to single-nucleotide resolution and uncovered loss-of-function mutations in RIM15, PUT4, DAL1, and DAL4 as the genetic basis for nitrogen source use variations. Effects of SNPs were unique for a single fitness component, strongly arguing against pleiotropy between lag, rate, and efficiency of reproduction under nitrogen restriction. The strong correlations between life stage performances that cannot be explained by pleiotropy compellingly support adaptive differentiation of yeast nitrogen source use and suggest a generic approach for detecting selection., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A fundamental question in biology is whether variation in organisms primarily emerges as a function of adaptation or as a function of neutral genetic drift. Trait variation in the model organism baker's yeast follows population bottlenecks rather than environmental boundaries suggesting that it primarily results from genetic drift. Based on the yeast life history, we hypothesized that population-specific loss-of-function mutations emerging in genes recently released from selection is the predominant cause of trait variation within the species. As retention of one functional copy of a gene in diploid yeasts is typically sufficient to maintain completely unperturbed performance, we also conjectured that a crossing of natural yeasts from populations with different loss-of-function mutations would provide a further efficient test bed for this hypothesis. Charting the first species-wide map of trait inheritance in a eukaryotic organism, we found trait heredity to be strongly biased toward diploid hybrid performance exactly mimicking the performance of the best of the parents, as expected given a complete dominance of functional over nonfunctional alleles. Best parent heterosis, partial dominance, and negative nonadditivity were all rare phenomena. Nonadditive inheritance was observed primarily in crosses involving at least one very poor performing parent, most frequently of the West African population, and when molecularly dissected, loss-of-function alleles were identified as the underlying cause. These findings provide support for that population-specific loss-of-function mutations do have a strong impact on genotype-phenotype maps and underscores the role of neutral genetic drift as a driver for trait variation within species.

Little is known about the physiological roles of aquaporin-4 (AQP4) in the central nervous system. AQP4 water channels are concentrated in endfeet membranes of astrocytes but also localize to the fine astrocytic processes that abut central synapses. Based on its pattern of expression, we predicted that AQP4 could be involved in controlling water fluxes and changes in extracellular space (ECS) volume that are associated with activation of excitatory pathways. Here, we show that deletion of Aqp4 accentuated the shrinkage of the ECS that occurred in the mouse hippocampal CA1 region during activation of Schaffer collateral/commissural fibers. This effect was found in the stratum radiatum (where perisynaptic astrocytic processes abound) but not in the pyramidal cell layer (where astrocytic processes constitute but a minor volume fraction). For both genotypes the ECS shrinkage was most pronounced in the pyramidal cell layer. Our data attribute a physiological role to AQP4 and indicate that this water channel regulates extracellular volume dynamics in the mammalian brain., (Copyright © 2012 Wiley Periodicals, Inc.)

Exposed to a sufficiently high extracellular potassium concentration ([K( + )]₀), the neuron can fire spontaneous discharges or even become inactivated due to membrane depolarisation ('depolarisation block'). Since these phenomena likely are related to the maintenance and propagation of seizure discharges, it is of considerable importance to understand the conditions under which excess [K( + )]₀ causes them. To address the putative effect of glial buffering on neuronal activity under elevated [K( + )](o) conditions, we combined a recently developed dynamical model of glial membrane ion and water transport with a Hodgkin-Huxley type neuron model. In this interconnected glia-neuron model we investigated the effects of natural heterogeneity or pathological changes in glial membrane transporter density by considering a large set of models with different, yet empirically plausible, sets of model parameters. We observed both the high [K( + )]₀-induced duration of spontaneous neuronal firing and the prevalence of depolarisation block to increase when reducing the magnitudes of the glial transport mechanisms. Further, in some parameter regions an oscillatory bursting spiking pattern due to the dynamical coupling of neurons and glia was observed. Bifurcation analyses of the neuron model and of a simplified version of the neuron-glia model revealed further insights about the underlying mechanism behind these phenomena. The above insights emphasise the importance of combining neuron models with detailed astroglial models when addressing phenomena suspected to be influenced by the astroglia-neuron interaction. To facilitate the use of our neuron-glia model, a CellML version of it is made publicly available.

Understanding the causal chain from genotypic to phenotypic variation is a tremendous challenge with huge implications for personalized medicine. Here we argue that linking computational physiology to genetic concepts, methodology, and data provides a new framework for this endeavor. We exemplify this causally cohesive genotype-phenotype (cGP) modeling approach using a detailed mathematical model of a heart cell. In silico genetic variation is mapped to parametric variation, which propagates through the physiological model to generate multivariate phenotypes for the action potential and calcium transient under regular pacing, and ion currents under voltage clamping. The resulting genotype-to-phenotype map is characterized using standard quantitative genetic methods and novel applications of high-dimensional data analysis. These analyses reveal many well-known genetic phenomena like intralocus dominance, interlocus epistasis, and varying degrees of phenotypic correlation. In particular, we observe penetrance features such as the masking/release of genetic variation, so that without any change in the regulatory anatomy of the model, traits may appear monogenic, oligogenic, or polygenic depending on which genotypic variation is actually present in the data. The results suggest that a cGP modeling approach may pave the way for a computational physiological genomics capable of generating biological insight about the genotype-phenotype relation in ways that statistical-genetic approaches cannot.

Background: The Atlantic salmon genome is in the process of returning to a diploid state after undergoing a whole genome duplication (WGD) event between 25 and100 million years ago. Existing data on the proportion of paralogous sequence variants (PSVs), multisite variants (MSVs) and other types of complex sequence variation suggest that the rediplodization phase is far from over. The aims of this study were to construct a high density linkage map for Atlantic salmon, to characterize the extent of rediploidization and to improve our understanding of genetic differences between sexes in this species., Results: A linkage map for Atlantic salmon comprising 29 chromosomes and 5650 single nucleotide polymorphisms (SNPs) was constructed using genotyping data from 3297 fish belonging to 143 families. Of these, 2696 SNPs were generated from ESTs or other gene associated sequences. Homeologous chromosomal regions were identified through the mapping of duplicated SNPs and through the investigation of syntenic relationships between Atlantic salmon and the reference genome sequence of the threespine stickleback (Gasterosteus aculeatus). The sex-specific linkage maps spanned a total of 2402.3 cM in females and 1746.2 cM in males, highlighting a difference in sex specific recombination rate (1.38:1) which is much lower than previously reported in Atlantic salmon. The sexes, however, displayed striking differences in the distribution of recombination sites within linkage groups, with males showing recombination strongly localized to telomeres., Conclusion: The map presented here represents a valuable resource for addressing important questions of interest to evolution (the process of re-diploidization), aquaculture and salmonid life history biology and not least as a resource to aid the assembly of the forthcoming Atlantic salmon reference genome sequence.

Atlantic cod (Gadus morhua) is a large, cold-adapted teleost that sustains long-standing commercial fisheries and incipient aquaculture. Here we present the genome sequence of Atlantic cod, showing evidence for complex thermal adaptations in its haemoglobin gene cluster and an unusual immune architecture compared to other sequenced vertebrates. The genome assembly was obtained exclusively by 454 sequencing of shotgun and paired-end libraries, and automated annotation identified 22,154 genes. The major histocompatibility complex (MHC) II is a conserved feature of the adaptive immune system of jawed vertebrates, but we show that Atlantic cod has lost the genes for MHC II, CD4 and invariant chain (Ii) that are essential for the function of this pathway. Nevertheless, Atlantic cod is not exceptionally susceptible to disease under natural conditions. We find a highly expanded number of MHC I genes and a unique composition of its Toll-like receptor (TLR) families. This indicates how the Atlantic cod immune system has evolved compensatory mechanisms in both adaptive and innate immunity in the absence of MHC II. These observations affect fundamental assumptions about the evolution of the adaptive immune system and its components in vertebrates.

European funding under framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for nearly 2 years. The VPH network of excellence (NoE) is helping in the development of common standards, open-source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also helping to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by framework 6 strategy for a European physiome (STEP) project in 2006. It is now time to assess the accomplishments of the last 2 years and update the STEP vision for the VPH. We consider the biomedical science, healthcare and information and communications technology challenges facing the project and we propose the VPH Institute as a means of sustaining the vision of VPH beyond the time frame of the NoE.