Phenotypic integration refers to the study of complex patterns of covariation among functionally related traits in a given organism. It has been investigated throughout the 20th century, but has only recently risen to the forefront of evolutionary ecological research. In this essay, I identify the reasons for this late flourishing of studies on integration, and discuss some of the major areas of current endeavour: the interplay of adaptation and constraints, the genetic and molecular bases of integration, (...) the role of phenotypic plasticity, macroevolutionary studies of integration, and statistical and conceptual issues in the study of the evolution of complex phenotypes. I then conclude with a brief discussion of what I see as the major future directions of research on phenotypic integration and how they relate to our more general quest for the understanding of phenotypic evolution within the neo-Darwinian framework. I suggest that studying integration provides a particularly stimulating and truly interdisciplinary convergence of researchers from fields as disparate as molecular genetics, developmental biology, evolutionary ecology, palaeontology and even philosophy of science. (shrink)

A new voice in the nature-nurture debate can be heard at the interface between evolution and development. Phenotypic integration is a major growth area in research.

How to use a model organism to study phenotypic integration and constraints on evolution.

Psychiatry has witnessed a new wave of approaches to clinical phenotyping and the study of psychopathology, including the National Institute of Mental Health’s Research Domain Criteria, clinical staging, network approaches, the Hierarchical Taxonomy of Psychopathology, and the general psychopathology factor, as well as a revival of interest in phenomenological psychopathology. The question naturally emerges as to what the relationship between these new approaches is – are they mutually exclusive, competing approaches, or can they be integrated in some way and used (...) to enrich each other? In this opinion piece, we propose a possible integration between clinical staging and phenomenological psychopathology. Domains identified in phenomenological psychopathology, such as selfhood, embodiment, affectivity, etc., can be overlaid on clinical stages in order to enrich and deepen the phenotypes captured in clinical staging (‘high resolution’ clinical phenotypes). This approach may be useful both ideographically and nomothetically, in that it could complement diagnosis, enrich clinical formulation, and inform treatment of individual patients, as well as help guide aetiological, prediction, and treatment research. The overlaying of phenomenological domains on clinical stages may require that these domains are reformulated in dimensional rather than categorial terms. This integrative project requires assessment tools, some of which are already available, that are sensitive and thorough enough to pick up on the range of relevant psychopathology. The proposed approach offers opportunities for mutual enrichment: clinical staging may be enriched by introducing greater depth to phenotypes; phenomenological psychopathology may be enriched by introducing stages of severity and disorder progression to phenomenological analysis. (shrink)

Is integrative biology a good idea, or even possible? There has been much interest lately in the unifica- tion of biology and the integration of traditionally separate disciplines such as molecular and develop- mental biology on one hand, and ecology and evolutionary biology on the other. In this paper I ask if and under what circumstances such integration of efforts actually makes sense. I develop by example an analogy with Aristotle’s famous four “causes” that one can investigate concerning (...) any object or phenomenon: material (what something is made of), formal (what distinguishes that particular object from others), efficient (how was the object made) and final (why was the object made). The example is provided by ongoing research on different aspects of flowering time in the model system Arabidop- sis, a small weed belonging to the mustard family. I show that understanding how flowering time is controlled is an epistemologically different sort of question from why and how it evolved, and that the two research agendas can be pursued largely independently of each other. Toward the end, I propose that the real goal of integrative biology is to understand the boundary layers between levels of biologi- cal analysis, something to which modern philosophy of science can contribute significantly. (shrink)

Phenotypic Evolution explicitly recognizes organisms as complex genetic-epigenetic systems developing in response to changing internal and external environments. As a key to a better understanding of how phenotypes evolve, the authors have developed a framework that centers on the concept of the Developmental Reaction Norm. This encompasses their views: (1) that organisms are better considered as integrated units than as disconnected parts (allometry and phenotypic integration); (2) that an understanding of ontogeny is vital for evaluating evolution of (...) adult forms (ontogenetic trajectories, epigenetics, and constraints); and (3) that environmental heterogeneity is ubiquitous and must be acknowledged for its pervasive role in phenotypic expression. (shrink)

Predicting the phenotype of an organism from its genotype is a central question in genetics. Most importantly, we would like to find out if the perturbation of a single gene may be the cause of a disease. However, our current ability to predict the phenotypic effects of perturbations of individual genes is limited. Network models of genes are one tool for tackling this problem. In a recent study, (Lee et al.) it has been shown that network models covering the (...) majority of genes of an organism can be used for accurately predicting phenotypic effects of gene perturbations in multicellular organisms. BioEssays 30:707–710, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Phenotypic plasticity integrates the insights of ecological genetics, developmental biology, and evolutionary theory. Plasticity research asks foundational questions about how living organisms are capable of variation in their genetic makeup and in their responses to environmental factors. For instance, how do novel adaptive phenotypes originate? How do organisms detect and respond to stressful environments? What is the balance between genetic or natural constraints (such as gravity) and natural selection? The author begins by defining phenotypic plasticity and detailing its (...) history, including important experiments and methods of statistical and graphical analysis. He then provides extended examples of the molecular basis of plasticity, the plasticity of development, the ecology of plastic responses, and the role of costs and constraints in the evolution of plasticity. A brief epilogue looks at how plasticity studies shed light on the nature/nurture debate in the popular media. (shrink)

In a now classic paper published in 1991, Alberch introduced the concept of genotype–phenotype (G!P) mapping to provide a framework for a more sophisticated discussion of the integration between genetics and developmental biology that was then available. The advent of evo-devo first and of the genomic era later would seem to have superseded talk of transitions in phenotypic space and the like, central to Alberch’s approach. On the contrary, this paper shows that recent empirical and theoretical advances have (...) only sharpened the need for a different conceptual treat- ment of how phenotypes are produced. Old-fashioned metaphors like genetic blueprint and genetic programme are not only woefully inadequate but positively misleading about the nature of G!P, and are being replaced by an algorithmic approach emerging from the study of a variety of actual G!P maps. These include RNA folding, protein function and the study of evolvable soft- ware. Some generalities are emerging from these disparate fields of analysis, and I suggest that the concept of ‘developmental encoding’ (as opposed to the classical one of genetic encoding) provides a promising computational–theoretical underpinning to coherently integrate ideas on evolvability, modularity and robustness and foster a fruitful framing of the G!P mapping problem. (shrink)

Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the (...) progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. (shrink)

Mathematical modeling can ground communication and reciprocal enrichment among fields of knowledge whose domains are very different. We propose a new mathematical model applicable in biology, specified into ecology and evolutionary biology, and in cultural transmission studies, considered as a branch of economics. Main inspiration for the model are some biological concepts we call “eco-phenotypic” such as development, plasticity, reaction norm, phenotypic heritability, epigenetics, and niche construction. “Physiology” is a core concept we introduce and translate differently in the (...) biological and cultural domains. The model is ecological in that it aims at describing and studying organisms and populations that perform living, intended as a thermodynamic, matter-energy process concerning resources gathering, usage, and depletion in a spatiotemporal context with given characteristics, as well as with multiplication and space occupation. The model also supports evolution, intended as a dynamics including cumulative change in the features of unique organisms that are connected into breeding populations. The model is then applicable to the economics of cultural transmission in which individuals form their attitudes and patterns of behavior under a complex system of influences derived from their “cultural parents”, other members of the society, and the environment. On the side of biology, an innovative goal is to integrate in a single model all the eco-phenotypic concepts as well as both evolution and ecology. On the side of cultural transmission, eco-phenotypic modeling seems more appropriate in capturing some aspects of cultural systems which are modeled away in the earlier framework based on Mendelian population genetics. (shrink)

The integration of digital phenotyping in psychiatry promises unprecedented insights into mental health, particularly in college settings where mental well-being is a growing concern. The COVID-19...

Evolutionary biology is paying increasing attention to the mechanisms that enable phenotypic plasticity, evolvability, and extra‐genetic inheritance. Yet, there is a concern that these phenomena remain insufficiently integrated within evolutionary theory. Understanding their evolutionary implications would require focusing on phenotypes and their variation, but this does not always fit well with the prevalent genetic representation of evolution that screens off developmental mechanisms. Here, we instead use development as a starting point, and represent it in a way that allows genetic, (...) environmental and epigenetic sources of phenotypic variation to be independent. We show why this representation helps to understand the evolutionary consequences of both genetic and non‐genetic phenotype determinants, and discuss how this approach can instigate future areas of empirical and theoretical research. (shrink)

Autism Spectrum Disorder (ASD) is extremely heterogeneous clinically and genetically. There is a pressing need for a better understanding of the heterogeneity of ASD based on scientifically rigorous approaches centered on systematic evaluation of the clinical and research utility of both phenotype and genotype markers. This paper presents a holistic PheWAS-inspired method to identify meaningful associations between ASD phenotypes and genotypes. We generate two types of phenotype-phenotype (p-p) graphs: a direct graph that utilizes only phenotype data, and an indirect graph (...) that incorporates genotype as well as phenotype data. We introduce a novel methodology for fusing the direct and indirect p-p networks in which the genotype data is incorporated into the phenotype data in varying degrees. The hypothesis is that the heterogeneity of ASD can be distinguished by clustering the p-p graph. The obtained graphs are clustered using network-oriented clustering techniques, and results are evaluated. The most promising clusterings are subsequently analyzed for biological and domain-based relevance. Clusters obtained delineated different aspects of ASD, including differentiating ASD-specific symptoms, cognitive, adaptive, language and communication functions, and behavioral problems. Some of the important genes associated with the clusters have previous known associations to ASD. We found that clusters based on integrated genetic and phenotype data were more effective at identifying relevant genes than clusters constructed from phenotype information alone. These genes included five with suggestive evidence of ASD association and one known to be a strong candidate. (shrink)

A new method of observation is currently emerging in psychiatry, based on data collection and behavioral profiling of smartphone users. Numerical phenotyping is a paradigmatic example. This behavioral investigation method uses computerized measurement tools in order to collect characteristics of different psychiatric disorders. First, it is necessary to contextualize the emergence of these new methods and to question their promises and expectations. The international mental health research framework invites us to reflect on methodological issues and to draw conclusions from certain (...) impasses related to the clinical complexity of this field. From this contextualization, the investigation method relating to digital phenotyping can be questioned in order to identify some of its potentials. These new methods are also an opportunity to test psychoanalysis. It is then necessary to identify the elements of fruitful analysis that clinical experience and research in psychoanalysis have been able to deploy regarding the challenges of digital technology. An analysis of this theme's litterature shows that psychoanalysis facilitates a reflection on the psychological effects related to digital methods. It also shows how it can profit from the research potential offered by new technical tools, considering the progress that has been made over the past fifty years. This cross-fertilization of the potential and limitations of digital methods in mental health intervention in the context of theoretical issues at the international level invites us to take a resolutely non-reductionist position. In the field of research, psychoanalysis offers a specific perspective that can well be articulated to an epistemology of networks. Rather than aiming at a numerical phenotyping of patients according to the geneticists' model, the case formulation method appears to be a serious prerequisite to give a limited and specific place to the integration of smartphones in clinical investigation. (shrink)

In addition to obviating the use of synthetic agrochemicals and emphasizing farming in accordance with agro-ecological guidelines, organic farming acknowledges the integrity of plants as an essential element of its natural approaches to crop production. For cultivated plants, integrity refers to their inherent nature, wholeness, completeness, species-specific characteristics, and their being in balance with their (organically farmed) environment, while accomplishing their “natural aim.” We argue that this integrity of plants has ethical value, distinguishing integrity of life, plant-typic integrity, genotypic integrity, (...) and phenotypic integrity. We have developed qualitative criteria to ethically evaluate existing practices and have applied these criteria to assess whether current plant breeding and propagation techniques violate the integrity of crop plants. This process has resulted in a design of a holistic, scientific approach of organic plant breeding and seed production. Our evaluation has met considerable criticism from mainstream (crop) scientists. We respond to the following questions: (1). Can ethics be incorporated into objective crop sciences? (2). What is the nature of the intrinsic value of plants in organic farming? We argue that criteria to take integrity into account can only be assessed from a holistic perspective and we show that a holistic approach is needed to design such ethical notions in a consistent way. The ethical notions have been further elaborated by formulating human responsibility and respect towards crop plants. Responsibility and respect can only be shown by providing crop plants the right to be nurtured and to express natural behavior at all levels of integrity. (shrink)

A fundamental question in biology is whether phenotypes can be predicted by ecological or genomic rules. At least five cases of convergent evolution of the crab‐like body plan (with a wide and flattened shape, and a bent abdomen) are known in decapod crustaceans, and have, for over 140 years, been known as “carcinization.” The repeated loss of this body plan has been identified as “decarcinization.” In reviewing the field, we offer phylogenetic strategies to include poorly known groups, and direct evidence (...) from fossils, that will resolve the history of crab evolution and the degree of phenotypic variation within crabs. Proposed ecological advantages of the crab body are summarized into a hypothesis of phenotypic integration suggesting correlated evolution of the carapace shape and abdomen. Our premise provides fertile ground for future studies of the genomic and developmental basis, and the predictability, of the crab‐like body form. (shrink)

In “Racial Integration and the Problem of Relational Devaluation,” I argue that blacks should reject racial integration on self-protective and solidarity grounds. Integration will intensify the self-worth harms of stigmatization and phenotypic devaluation by leading blacks to more fully internalize their devaluation, and while the integrating process itself might reduce the former, it may well leave in place the latter. In this paper, I reply to the challenges to these arguments presented by Sharon Stanley, Andrew Valls, (...) Elvira Basevich, Michael Merry, and Ronald Sundstrom. (shrink)

This article argues that blacks should reject integration on self-protective and solidarity grounds. It distinguishes two aspects of black devaluation: a ‘stigmatization’ aspect that has to do with the fact that blacks are subject to various forms of discrimination, and an aesthetic aspect (‘phenotypic devaluation’) that concerns the aesthetic devaluation of characteristically black phenotypic traits. It identifies four self-worth harms that integration may inflict, and suggests that these may outweigh the benefits of integration. Further, it (...) argues that, while the integrating process may reduce stigmatization, there is less reason to think that it can do the same for phenotypic devaluation. (shrink)

D. C. Matthew argues that although integration offers blacks social and economic benefits, it also creates the conditions for phenotypic devaluation that leads to harm against black self-worth and servile behavior. Therefore, he advises against integration because the resulting self-worth harms outweigh the benefits of integration. I argue that Matthew’s cost-benefit calculation against integration lacks the requisite evidence, and amounts to a luxury belief that will result in more harm. Moreover, his interpretation of behavior — (...) which he construes as being indicative of a lack of self-worth — is unfounded. Further, his cost-benefit calculation results in socially reactionary sexual policing and ideological purity tests. (shrink)

The expression of epithelial cell adhesion and cytoskeletal genes is orchestrated by an apparently unique set of rules. No tissue‐specific transactivator proteins have been found to drive them; only ubiquitous factors are utilized. In non‐epithelial cells, they are actively repressed. Moreover, it was recently found that a single protein (adenovirus E1a) coordinately represses non‐epithelial genes while inducing epithelial genes. A simple model is offered to explain how epithelial gene expression is coordinated. Under this model, the epithelial cell gene expression program (...) is a transcriptional ‘default’; that is, it occurs in the absence of tissue‐specific transactivation. Conversion to this default requires only that mesenchymal transactivators are not expressed, or that central ‘integrator’ proteins are inactive. In their absence, mesenchymal gene expression cannot occur. Moreover, because the repressors cease to be expressed, the epithelial genes are induced. Oncogenes generally cause the breakdown of the epithelial phenotype ‐ generating carcinomas ‐ so genes such as E1a that cause epithelial conversion may prove useful for both understanding and controlling cancer. (shrink)

Cancer is a singular cellular state, the emergence of which destabilises the homeostasis reached through the evolution to multicellularity. We present the idea that the onset of the cellular disobedience to the metazoan functional and structural architecture, known as the cancer phenotype, is triggered by changes in the cell's external environment that occur with ageing: what ensues is a breach of the social contract of multicellular life characteristic of metazoans. By integrating old ideas with new evidence, we propose that with (...) ageing the environmental information that maintains a multicellular organisation is eroded, rewiring internal processes of the cell, and resulting in an internal shift towards an ancestral condition resulting in the pseudo‐multicellular cancer phenotype. Once that phenotype emerges, a new local social contract is built, different from the homeostatic one, leading to tumour formation and the foundation of a novel local ecosystem. (shrink)

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic (...) epithelial cells that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC, T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms. (shrink)

The question of whether the modern evolutionary synthesis requires an extension has recently become a topic of discussion, and a source of controversy. We suggest that this debate is, for the most part, not about the modern synthesis at all. Rather, it is about the extent to which genetic mechanisms can be regarded as the primary determinants of phenotypic characters. The modern synthesis has been associated with the idea that phenotypes are the result of gene products, while supporters of (...) the extended synthesis have suggested that environmental factors, along with processes such as epigenetic inheritance, and niche construction play an important role in character formation. We argue that the methodology of the modern evolutionary synthesis has been enormously successful, but does not provide an accurate characterization of the origin of phenotypes. For its part, the extended synthesis has yet to be transformed into a testable theory, and accordingly, has yielded few results. We conclude by suggesting that the origin of phenotypes can only be understood by integrating findings from all levels of the organismal hierarchy. In most cases, parts and processes from a single level fail to accurately explain the presence of a given phenotypic trait. The debate between the proponents of the modern and extended syntheses is somewhat reminiscent of the duck-rabbit illusion. The two sides are probably talking about the same thing, but from different perspectives. If not, then we argue that the challenge is to do an experiment that rules out the alternative view. (shrink)

I could summarise Being There unkindly, but not too inaccurately, as “Language of thought: bad. Everything else: good”. For the book is a fast and approving tour of a menagerie of alternatives to the classic computational theory of the mind. Some of the usual suspects appear— neural nets, connectionism—but they are not interrogated as deeply as the new members of the gang. For example, Clark walks us through some interesting new ideas in neuroscience. But none of the gang are pressed (...) very hard. Clark sketches a lot of interesting ideas but “sketches” is the right word. This is a book for the already sympathetic. For none of the examples are developed in the detail that would be required to convince a sceptic. A second issue concerns integration. Clark develops a number of themes as the book unwinds, but by the conclusion I was still uncertain about the extent to which the ideas in Being There are intended to be a package deal. (shrink)

Genomic function is dictated by a combination of DNA sequence and the molecular mechanisms controlling access to genetic information. Access to DNA can be determined by the interpretation of covalent modifications that influence the packaging of DNA into chromatin, including DNA methylation and histone modifications. These modifications are believed to be forms of “epigenetic codes” that exist in discernable combinations that reflect cellular phenotype. Although DNA methylation is known to play important roles in gene regulation and genomic function, its contribution (...) to the encoding of epigenetic information is just beginning to emerge. Here we discuss paradigms associated with the various components of DNA methylation/demethylation and recent advances in the understanding of its dynamic regulation in the genome, integrating these mechanisms into a framework to explain how DNA methylation could contribute to epigenetic codes. (shrink)

Embryonic development and ontogeny occupy whatis often depicted as the black box betweengenes – the genotype – and the features(structures, functions, behaviors) of organisms– the phenotype; the phenotype is not merelya one-to-one readout of the genotype. Thegenes home, context, and locus of operation isthe cell. Initially, in ontogeny, that cell isthe single-celled zygote. As developmentensues, multicellular assemblages of like cells(modules) progressively organized as germlayers, embryonic fields, anlage,condensations, or blastemata, enable genes toplay their roles in development and evolution.As modules, condensations are (...) fundamentaldevelopmental and selectable units ofmorphology (morphogenetic units) that mediateinteractions between genotype and phenotype viaevolutionary developmental mechanisms. In ahierarchy of emergent processes, gene networksand gene cascades (genetic modules) link thegenotype with morphogenetic units such ascondensations, while epigenetic processes suchas embryonic inductions, tissue interactionsand functional integration, link morphogeneticunits to the phenotype. To support theseconclusions I distinguish units of heredityfrom units of transmission and discussepigenetic inheritance by tracing the historyof relationship between embryology andevolution, especially the role(s) assigned tocells or to cellular components in generatingtheories of morphological change in evolution.The concept of cells as modular morphogeneticunits is modeled and illustrated using themammalian dentary bone. (shrink)

The Planteome project provides a suite of reference and species-specific ontologies for plants and annotations to genes and phenotypes. Ontologies serve as common standards for semantic integration of a large and growing corpus of plant genomics, phenomics and genetics data. The reference ontologies include the Plant Ontology, Plant Trait Ontology, and the Plant Experimental Conditions Ontology developed by the Planteome project, along with the Gene Ontology, Chemical Entities of Biological Interest, Phenotype and Attribute Ontology, and others. The project also (...) provides access to species-specific Crop Ontologies developed by various plant breeding and research communities from around the world. We provide integrated data on plant traits, phenotypes, and gene function and expression from 95 plant taxa, annotated with reference ontology terms. (shrink)

Recent research highlights that inflammatory signaling pathways such as pattern recognition receptor (PRR) signaling and inflammatory cytokine signaling play an important role in both on‐demand hematopoiesis as well as steady‐state hematopoiesis. Knockout studies have demonstrated the necessity of several distinct pathways in these processes, but often lack information about the contribution of specific cell types to the phenotypes in question. Transplantation studies have increased the resolution to the level of specific cell types by testing the necessity of inflammatory pathways specifically (...) in donor hematopoietic stem and progenitor cells (HSPCs) or in recipient niche cells. Here, we argue that for an integrated understanding of how these processes occur in vivo and to inform the development of therapies that modulate hematopoietic responses, we need studies that knockout inflammatory signaling receptors in a cell‐specific manner and compare the phenotypes caused by knockout in individual niche cells versus HSPCs. (shrink)

The literature on the evolution of religion has been divided by a fundamental debate between adaptation theories, which explain religious traits as products of selection for religion, and byproduct theories, which explain religious traits as products of selection for other, non-religious functions. Recently, however, a new position has emerged in this debate, as an influential new theory based on cultural selection claims to integrate adaptation theories with byproduct theories, yielding a single, unified account. I argue that the proponents of this (...) view do not say enough about how integration is actually supposed to work, from a logical point of view. Basic questions arise from the assumptions required for unifying these apparently conflicting approaches, which the authors of the account do not address. In response to these questions, I provide a model of the religious phenotype, the Goldberg Exaptation Model, which shows that adaptation and byproduct theories are consistent, and explains how they are positively related, over and above mere consistency. On this view, the religious phenotype is best understood on analogy with a Rube Goldberg device: it is assembled by selection for religion, but using parts designed by selection for other, non-religious functions. (shrink)

We characterize a type of functional explanation that addresses why a homologous trait originating deep in the evolutionary history of a group remains widespread and largely unchanged across the group’s lineages. We argue that biologists regularly provide this type of explanation when they attribute conserved functions to phenotypic and genetic traits. The concept of conserved function applies broadly to many biological domains, and we illustrate its importance using examples of molecular sequence alignments at the intersection of evolution and cell (...) biology. We use these examples to show how the study of conserved functions can integrate knowledge of a trait’s causal effects on fitness and its history of natural selection without invoking adaptation. We also show how conserved function provides a novel basis for addressing objections against evolutionary functions raised by Robert Cummins. (shrink)

The logic of genetic discovery has changed little over time, but the focus of biology is shifting from simple genotype–phenotype relationships to complex metabolic, physiological, developmental, and behavioral traits. In light of this, the traditional reductionist view of individual genes as privileged difference‐making causes of phenotypes is re‐examined. The scope and nature of genetic effects in complex regulatory systems, in which dynamics are driven by regulatory feedback and hierarchical interactions across levels of organization are considered. This review argues that it (...) is appropriate to treat genes as specific actual difference‐makers for the molecular regulation of gene expression. However, they are often neither stable, proportional, nor specific as causes of the overall dynamic behavior of regulatory networks. Dynamical models, properly formulated and validated, provide the tools to probe cause‐and‐effect relationships in complex biological systems, allowing to go beyond the limitations of genetic reductionism to gain an integrative understanding of the causal processes underlying complex phenotypes. (shrink)

The Continuous Parameter Estimation Model is applied to develop individual genomic-level heritabilities for the latent hierarchical structure and developmental dynamics of Life History (LH) strategy LH strategies relate to the allocations of bioenergetic resources into different domains of fitness. LH has moderate to high population-level heritability in humans, both at the level of the high-order Super-K Factor and the lower-order factors, the K-Factor, Covitality Factor, and General Factor of Personality (GFP). Several important questions remain unexplored. We developed measures of genome-level (...) heritabilities employing an American sample of 316 monozygotic (MZ) and 274 dizygotic (DZ) twin dyads and a Swedish sample of 863 MZ and 475 DZ twin dyads. This novel heritability index measures individual genetic transmissibility, therefore opening new avenues for analyzing complex interactions among heritable traits inaccessible to standard structural equations methods. For these samples: (1) moderate to high heritability of factor loadings of Super-K on its lower-order factors is demonstrated, evidencing biological preparedness, genetic accommodation, and the gene-culture coevolution of biased epigenetic rules of development; (2) moderate to high heritability of the magnitudes of the effect of the higher-order factors upon their loadings on their constituent factors, evidencing genetic constraints upon phenotypic plasticity; and (3) that heritability of the LH factors, of factor loadings, and of the magnitudes of the correlations among factors are weaker among those with slower LH speeds, demonstrating that inter-individual variation in transmissibility is a function of individual socioecological selection pressures. (shrink)

The N‐terminal domain of histone H4 has been implicated in various nuclear functions, including gene silencing and activation and replication‐linked chromatin assembly. Many of these have been identified by using H4 mutants in the yeast S. cerevisiae. In a recent paper, Megee et al.(1) use this approach to show that mutants in which all four N‐terminal H4 lysines are substituted with glutamines accumulate increased levels of DNA damage. A single lysine, but not an arginine, anywhere in the N‐terminal domain suppresses (...) this phenotype. It is suggested that histone H4 plays a role in maintaining genome integrity through the cell cycle, possibly by a mechanism involving lysine acetylation. (shrink)

Early in the 20th century, Charles Manning Child attributed organismal gradients in metabolism to interactions among groups of cells. Metabolic gradients are now firmly grounded in redox chemistry, yet modern work on metabolic signaling has consistently focused on the cellular level. Multicellular redox regulation, however, may occur when redox state is determined by the behavior of a group of cells. For instance, typically an abundance of substrate will shift the redox state of mitochondria in the direction of reduction, leading to (...) increased reactive oxygen species (ROS). These ROS, in turn, may modify the conformation and activity of proteins involved in signaling pathways, resulting in phenotypic changes. In contrast, if substrate triggers the contractions of a muscular structure comprising mitochondrion‐rich cells, the resulting metabolic demand may shift the redox state in the direction of oxidation, with a corresponding decrease of ROS and different phenotypic effects. Indeed, colonial hydroids exemplify this process. Parallel examples may occur whenever mitochondria are concentrated in cells of structures that can respond to environmental perturbations with increased metabolic demand. In these circumstances, predicting the direction of metabolic signaling may require an understanding of events at the organismal level. BioEssays 28:72–77, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Computational drug repositioning has been proven as a promising and efficient strategy for discovering new uses from existing drugs. To achieve this goal, a number of computational methods have been proposed, which are based on different data sources of drugs and diseases. These methods approach the problem using either machine learning- or network-based models with an assumption that similar drugs can be used for similar diseases to identify new indications of drugs. Therefore, similarities between drugs and between diseases are usually (...) used as inputs. In addition, known drug-disease associations are also needed for the methods as prior information. It should be noted that those associations are still not well established due to the fact that many of marketed drugs have been withdrawn and this could affect the outcome of the methods. In this study, we propose a novel method named RLSDR to find new uses of drugs. More specifically, it relies on a semi-supervised learning model, Regularized Least Square, thus it does not require definition of non-drug-disease associations as previously proposed machine learning-based methods. In addition, the similarity between drugs measured by chemical structures of drug compounds and the similarity between diseases which share phenotypes can be represented in a form of either similarity network or similarity matrix as inputs of the method. Moreover, instead of using a gold-standard set of known drug-disease associations, we construct an artificial set of the associations based on known disease-gene and drug-target associations. Experiment results demonstrate that RLSDR achieves better prediction performance on the artificial set of drug-disease associations than that on the gold-standard ones in terms of area under the Receiver Operating Characteristic curve. In addition, it outperforms two representative network-based methods irrespective of the prior information of drug-disease associations. Novel indications for a number of drugs are also identified and validated by evidences from a different data resource. (shrink)

Acute starvation can have long-term consequences that are mediated through epigenetic change. Some of these changes are affected by the activity of AMP-activated protein kinase, a master regulator of cellular energy homeostasis. In Caenorhabditis elegans, the absence of AMPK during a period of starvation in an early larval stage results in developmental defects following their recovery on food, while many of them become sterile. Moreover, the loss of AMPK during this quiescent period results in transgenerational phenotypes that can become progressively (...) worse with each successive generation. Our recent data describe a chromatin-based mechanism of how AMPK mediates adjustment to acute starvation in the germ cells, however, the heritable aspect of this AMPK mutant phenotype remains unresolved. Here, we explore how AMPK might affect this process and speculate how the initial transcription that occurs in the germ cells may adversely affect subsequent germline gene expression and/or genomic integrity. AMPK protects germ cell integrity during acute starvation by blocking inappropriate transcription. How these aberrant transcripts cause transgenerational defects is unclear. AMPK likely regulates germline integrity at multiple levels through several targets. The authors speculate here how AMPK disruption during starvation could result in the observed defects seen at each generation. (shrink)

Despite recent progress in the identification of genes that regulate longevity, aging remains a mysterious process. One influential hypothesis is the idea that the potential for cell division and replacement are important factors in aging. In this work, we review and discuss this perspective in the context of interventions in mammals that appear to accelerate or retard aging. Rather than focus on molecular mechanisms, we interpret results from an integrative biology perspective of how gene products affect cellular functions, which in (...) turn impact on tissues and organisms. We review evidence suggesting that mutations that give rise to features resembling premature aging tend to be associated with cellular phenotypes such as increased apoptosis or premature replicative senescence. In contrast, many interventions in mice that extend lifespan and might delay aging, including caloric restriction, tend to either hinder apoptosis or result in smaller animals and thus may be the product of fewer cell divisions. Therefore, it appears plausible that changes in the number of times that cells, and particularly stem cells, divide during an organism's lifespan influence longevity and aging. We discuss possible mechanisms related to this hypothesis and propose experimental paradigms. BioEssays 30:567–578, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

This response shows how the socio-relational framework of expressive behaviors may be used to understand and predict social psychological processes, beyond sex differences in the expression of emotion. I use this opportunity to elaborate on several key concepts on the epigenesis of evolved social behaviors that were not fully addressed in the target article. These are: evidence of a natural history of masculine and feminine specialization (sect. R1); phenotypic plasticity and range of reactivity of social behaviors (sect. R2); exploitive (...) and protective functions of social behaviors (sect. R3); and the role of cognition in some affective responses (sect. R4). I conclude by highlighting (in sect. R5) future directions for psychological research from a socio-relational basis. (shrink)

An increasing number of biologists are expressing discontent with the prevailing theory of neo-Darwinism. In particular, the tendency of neo-Darwinians to adopt genetic determinism and atomistic notions of both genes and organisms is seen as grossly unfair to the body of developmental theory. One faction of dissenteers, the Process Structuralists, take their inspiration from the rational morphologists who preceded Darwin. These neo-rationalists argue that a mature biology must possess universal laws and that these generative laws should be sought within organismal (...) development. Such a rational biology will only be possible once the neo-Darwinian paradigm, with its reliance on inherently stochastic processes, is overthrown.To facilitate this revolution, process structuralism launches a broad attack on the theoritical adequacy of its opponent. It is charged that neo-Darwinism is untestable and therefore its hypotheses are nothing more than adaptive stories. Further, the lamentable tendencies toward genetic determinism and atomism by modern biologists is seen as the inescapable consequences of adopting the neo-Darwinian outlook. (shrink)

Evolutionary systems biology (ESB) is a rapidly growing integrative approach that has the core aim of generating mechanistic and evolutionary understanding of genotype‐phenotype relationships at multiple levels. ESB's more specific objectives include extending knowledge gained from model organisms to non‐model organisms, predicting the effects of mutations, and defining the core network structures and dynamics that have evolved to cause particular intracellular and intercellular responses. By combining mathematical, molecular, and cellular approaches to evolution, ESB adds new insights and methods to the (...) modern evolutionary synthesis, and offers ways in which to enhance its explanatory and predictive capacities. This combination of prediction and explanation marks ESB out as a research manifesto that goes further than its two contributing fields. Here, we summarize ESB via an analysis of characteristic research examples and exploratory questions, while also making a case for why these integrative efforts are worth pursuing. (shrink)

Understanding how traits are integrated at the organismal level remains a fundamental problem at the interface of developmental and evolutionary biology. Hormones, regulatory signaling molecules that coordinate multiple developmental and physiological processes, are major determinants underlying phenotypic integration. The probably best example for this is the lipid-like juvenile hormone (JH) in insects. Here we review the manifold effects of JH, the most versatile animal hormone, with an emphasis on the fruit fly Drosophila melanogaster, an organism amenable to both (...) genetics and endocrinology. JH affects a remarkable number of processes and traits in Drosophila development and life history, including metamorphosis, behavior, reproduction, diapause, stress resistance and aging. While many molecular details underlying JH signaling remain unknown, we argue that studying “hormonal pleiotropy” offers intriguing insights into phenotypic integration and the mechanisms underlying life history evolution. In particular, we illustrate the role of JH as a key mediator of life history trade-offs. BioEssays 27:999–1010, 2005. © 2005 Wiley Periodicals, Inc. (shrink)