The widespread distribution of fibroblasts underlines their central role in mammalian physiology, development and ageing. The existence of developmentally regulated and site‐specific phenotypic variation in fibroblasts is well documented. Recent evidence has revealed heterogeneity within the fibroblast population of a given tissue at a specified development stage. The relative proportion and tissue distribution of distinct fibroblast subsets must have important consequences in the control of connective tissue and adjacent epithelial functions in health and disease.

BackgroundFried physical frailty, with mobility frailty and non-motor frailty phenotypes, is a heterogeneous syndrome. The coexistence of the two phenotypes and cognitive impairment is referred to as cognitive frailty. It remains unknown whether frailty phenotype has a different association with hearing loss and tinnitus.MethodsOf the 5,328 community-dwelling older adults, 429 participants aged ≥58 years were enrolled in the study. The participants were divided into robust, mobility, and non-mobility frailty, mobility and non-mobility CF, and cognitive decline [subdivided into mild cognitive impairment (...) and pre-MCI] groups. The severity and presentations of HL and/or tinnitus were used as dependent variables in the multivariate logistic or nominal regression analyses with forward elimination adjusted for frailty phenotype stratifications and other covariates.ResultsPatients with physical frailty or who are robust were found to have lower probability of developing severe HL and tinnitus, and presented HL and/or tinnitus than those with only cognitive decline, or CF. Patients with RCF and non-mobility RCF had higher probability with less HL and tinnitus, and the presentation of HL and/or tinnitus than those with PRCF and mobility RCF. Other confounders, age, cognitive and social function, cardiovascular disease, depression, and body mass index, independently mediated the severity of HL and tinnitus, and presented HL and/or tinnitus.ConclusionFrailty phenotypes have divergent association with HL and tinnitus. Further research is required to understand the differential mechanisms and the personalized intervention of HL and tinnitus.Clinical Trial RegistrationClinicalTrials.gov identifier, NCT2017K020. (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)

This chapter contains section titled: Introduction: What is Phenotypic Plasticity? Developmental Conversion and Developmental Sensitivity: Two Forms of Phenotypic Plasticity Environmental Heterogeneity, Cues, and Plasticity Phenotypic Plasticity and Developmental Buffering The Future of Phenotypic Plasticity Research Acknowledgments References Further Reading.

Bacterial populations are heterogeneous, which in many cases can provide a selective advantage during changes in environmental conditions. In some instances, heterogeneity exists at the genetic level, in which significant allelic variation occurs within a population seeded by a single cell. In other cases, heterogeneity exists due to phenotypic differences within a clonal, genetically identical population. A variety of mechanisms can drive this latter strategy. Stochastic fluctuations can drive differential gene expression, but heterogeneity in gene expression (...) can also be driven by environmental changes sensed by individual cells residing in distinct locales. Utilizing multiple single cell approaches, workers have started to uncover the extent of heterogeneity within bacterial populations. This review will first describe several examples of phenotypic and genetic heterogeneity, and then discuss many single cell approaches that have recently been applied to define heterogeneity within bacterial populations. (shrink)

Here, we propose that the heterogeneity of mutational types in populations underpins alternative pathways of evolutionary adaptation. Point mutations, deletions, insertions, transpositions and duplications cause different biological effects and provide distinct adaptive possibilities. Experimental evidence for this notion comes from the mutational origins of adaptive radiations in large, clonal bacterial populations. Independent sympatric lineages with different phenotypes arise from distinct genetic events including gene duplication, different insertion sequence movements and several independent point mutations. The breadth of the mutational spectrum (...) in the ancestral population should be viewed as a form of bet‐hedging, reducing the risk of evolutionary dead ends and complementing the phenotypic and epigenetic heterogeneities that improve the survival capabilities of a population. Different mutational events arise from distinct cellular processes and are subject to separate environmental impacts, so the availability of any particular type of mutation may constrain or promote adaptive pathways in populations. (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)

Diseases causing inherited retinal degeneration in humans, such as retinitis pigmentosa and macular dystrophy, are genetically heterogeneous and clinically diverse. More than 40 genes causing retinal degeneration have been mapped to specific chromosomal sites; of these, at least 10 have been cloned and characterized. Mutations in two proteins, rhodopsin and peripherin/RDS, account for approximately 35% of all cases of autosomal dominant retinitis pigmentosa and a lesser fraction of other retinal conditions. This target article reviews the genes and mutations causing retinal (...) degeneration and proposes mechanisms whereby specific mutations lead to particular clinical consequences, that is, the relationship between genotype and phenotype. Retinitis pigmentosa and macular dystrophy are genetically heterogeneous diseases that cause retinal degeneration in humans and often result in severe visual impairment or blindness. Although many of the genes causing these diseases have not been identified, three photoreceptor-specific proteins have been implicated: rhodopsin, peripherin/RDS, and the P-subunit of rod phosphodiesterase. Mutations in the genes for these three proteins can cause either dominant retinitis pigmentosa, recessive retinitis pigmentosa, dominant congenital stationary night blindness, or dominant macular degeneration. Why this multiplicity of clinical phenotypes? Our target article summarizes the genetic and biochemical background to this question and proposes a number of possible explanations. Discussion focuses mainly on 73 distinct disease-causing mutations of rhodopsin. We feel that rhodopsin and other photoreceptor proteins can serve as model systems for unraveling the connection between genotype and phenotype, not only for inherited retinal diseases but for other degenerative disorders as well. (shrink)

Patients with insomnia complain of problems with sleep onset or sleep maintenance or early morning awakenings, or a combination of these, despite adequate opportunity and circumstances for sleep. In addition, to fulfill the diagnostic criteria for insomnia the complaints need to be associated with negative daytime consequences. For chronic insomnia, the symptoms are required to be present at least 3 days per week for a duration of at least 3 months. Lastly, for insomnia to be defined as a disorder, the (...) sleep complaints and daytime symptoms should not be better explained by another sleep disorder. This criterion represents a diagnostic challenge, since patients suffering from other sleep disorders often complain of insomnia symptoms. For instance, insomnia symptoms are common in e.g., obstructive sleep apnea and circadian rhythm sleep-wake disorders. It may sometimes be difficult to disentangle whether the patient suffers from insomnia disorder or whether the insomnia symptoms are purely due to another sleep disorder. Furthermore, insomnia disorder may be comorbid with other sleep disorders in some patients, e.g., comorbid insomnia and sleep apnea. In addition, insomnia disorder is often comorbid with psychological or somatic disorders and diseases. Thus, a thorough assessment is necessary for correct diagnostics. For chronic insomnia disorder, treatment-of-choice is cognitive behavioral therapy, and such treatment is also effective when the insomnia disorder appears comorbid with other diagnoses. Furthermore, studies suggest that insomnia is a heterogenic disorder with many different phenotypes or subtypes. Different insomnia subtypes may respond differently to treatment, but more research on this issue is warranted. Also, the role of comorbidity on treatment outcome is understudied. This review is part of a Research Topic on insomnia launched by Frontiers and focuses on diagnostic and treatment challenges of the disorder. The review aims to stimulate to more research into the bidirectional associations and interactions between insomnia disorder and other sleep, psychological, and somatic disorders/diseases. (shrink)

Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. An (...) improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter-individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine. Epigenetic and transcriptional variability mediate phenotypic plasticity, enabling adaptation to changing environments. In this review, we describe the sources of inter- and intra-individual variability and discuss epigenetic regulators of gene expression variability, including DNA methylation and chromatin structure. Understanding these molecular mechanisms will improve therapeutic approaches and personalized medicine. (shrink)

Large scale DNA-mutation screening in patients with hereditary retinal diseases greatly enhances our knowledge about retinal function and diseases. Scientists, clinicians, patients, and families involved with retinal disorders may directly benefit from these developments. However, certain aspects of this expanding knowledge, such as the correlation between genotype and phenotype, may be much more complicated than we expect at present.

How we ought to diagnose, categorise and respond to spectrum disabilities such as autism and Attention Deficit/Hyperactivity Disorder (ADHD) is a topic of lively debate. The heterogeneity associated with ADHD and autism is described as falling on various continua of behavioural, neural, and genetic difference. These continua are varyingly described either as extending into the general population, or as being continua within a given disorder demarcation. Moreover, the interrelationships of these continua are likewise often vague and subject to diverse (...) interpretations. -/- In this paper, I explore geneticists' and self-advocates’ perspectives concerning autism and ADHD as continua. These diagnoses are overwhelmingly analysed as falling on a continuum or continua of underlying traits, which supports the notion of “the neurodiversity spectrum”, i.e., a broader swath of human neural and behavioural diversity on which some concentrations of different functioning are diagnosed. I offer a taxonomy of conceptions of the genetic, phenotypic, and endophenotypic dimensionality within and beyond these diagnostic categories, and suggest that the spectrum of neurodiversity is characteristically endophenotypic. (shrink)

Endothelial cells line the inside of all blood vessels, forming a structurally and functionally heterogenous population of cells. Their complexity and diversity has long been recognized, yet very little is known about the molecules and regulatory mechanisms that mediate the heterogeneity of different endothelial cell populations. The constitutive organ‐ and microenvironment‐specific phenotype of endothelial cells controls internal body compartmentation, regulating the trafficking of circulating cells to distinct vascular beds. In contrast, surface molecules associated with the activated cytokine‐inducible endothelial phenotype (...) play a critical role in pathological conditions including inflammation, tumor angiogenesis, and wound healing. Differentiation of the endothelial cell phenotypes appears to follow similar mechanisms to the differentiation of hematopoietic cells, with the exception that endothelial cells maintain transdifferentiating competence. The present review offers a scheme of endothelial cell differentially expressed endothelial cell molecules as targets for directed therapeutic intervention. (shrink)

Stochastic gene expression plays a leading developmental role through its contribution to cell differentiation. It is also proposed to promote phenotypic diversification in malignant cells. However, it remains unclear if these two forms of cellular bet‐hedging are identical or rather display distinct features. Here we argue that bet‐hedging phenomena in cancer cells are more similar to those occurring in unicellular organisms than to those of normal metazoan cells. We further propose that the atavistic bet‐hedging strategies in cancer originate from (...) a hijacking of the normal developmental bet‐hedging of metazoans. Finally, we discuss the constraints that may shape the atavistic bet‐hedging strategies of cancer cells. (shrink)

A wide range of ecological and evolutionary models predict variety in phenotype or behavior when a population is at equilibrium. This heterogeneity can be realized in different ways. For example, it can be realized through a complex population of individuals exhibiting different simple behaviors, or through a simple population of individuals exhibiting complex, varying behaviors. In some theoretical frameworks these different realizations are treated as equivalent, but natural selection distinguishes between these two alternatives in subtle ways. By investigating an (...) increasingly complex series of models, from a simple fluctuating selection model up to a finite population hawk/dove game, we explore the selective pressures which discriminate between pure strategists, mixed at the population level, and individual mixed strategists. Our analysis reveals some important limitations to the “ESS” framework often employed to investigate the evolution of complex behavior. (shrink)

Alterations in the expression of certain genes or in their products can render benign tumor cells metastatic. Experimentally this has been quickly performed by transferring dominantly acting oncogenes such as c‐H‐rasEJ into susceptible cells, but in vivo such a rapid qualitative change in a dominantly acting oncogene occurs only rarely, and progression to highly metastatic phenotypes is thought to occur through a slow stepwise process. Such slow changes can be reversible and need not involve known dominantly acting oncogenes, consistent with (...) clinical observations. An important element of the natural progression of tumors to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity and to evolve into heterogeneous phenotypes, a process that appears to involve mainly quantitative changes in gene expression but which can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene. It is proposed that the highly malignant cells that have slowly evolved in vivo with only a few qualitative gene changes have undergone extensive cycles of diversification and accumulation of quantitative changes in the expression of genes that encode products that are related to malignancy and metastasis. Thus, highly malignant cellular phenotypes can arise quickly through specific qualitative changes in critical controlling genes or more slowly by less critical qualitative genetic changes, coupled with cellular diversification and accumulation of quantitative changes in gene expression. (shrink)

Bacteria have developed an impressive ability to survive and propagate in highly diverse and changing environments by evolving phenotypic heterogeneity. Phenotypic heterogeneity ensures that a subpopulation is well prepared for environmental changes. The expression bet hedging is commonly (but often incorrectly) used by molecular biologists to describe any observed phenotypic heterogeneity. In evolutionary biology, however, bet hedging denotes a risk‐spreading strategy displayed by isogenic populations that evolved in unpredictably changing environments. Opposed to other survival (...) strategies, bet hedging evolves because the selection environment changes and favours different phenotypes at different times. Consequently, in bet hedging populations all phenotypes perform differently well at any time, depending on the selection pressures present. Moreover, bet hedging is the only strategy in which temporal variance of offspring numbers per individual is minimized. Our paper aims to provide a guide for the correct use of the term bet hedging in molecular biology. (shrink)

Advances in the empirical sectors of biology are beginning to reveal evolvability as a major evolutionary process. Yet evolvability’s theoretical role is still intensely debated. Since its inception nearly thirty years ago, the evolvability research front has put a strong emphasis on the non-genetic mechanisms that influence the short-term evolvability of individuals within populations by causing phenotypic heterogeneity, such as developmental trait plasticity, phenotypic plasticity, modularity, the G-P map, robustness, and/or epigenetic variation. However, genetic evolvability mechanisms such (...) as mutation or recombination have a deeper history in evolutionary thought that is often overlooked by those in the evolvability research front, with recent evidence suggesting that species switch to genetic evolvability mechanisms when short-term evolvability strategies fail to relieve selective pressures. For this reason, a causal distinction must be made between genetic evolvability and the more recently emphasized non-genetic (or evo-devo) evolvability to allow for its maturation as a central explanatory concept. I conclude by arguing that the anachronisms of the scientific process are the main culprit behind recent divisions in biology and likely beyond. To streamline theoretical progress, we need to build a new science with new underlying philosophies like restricted pluralism. (shrink)

Phenotypic plasticity is a crucial feature of aggressive cancer, providing the means for cancer progression. Stochastic changes in tumor cell transcriptional programs increase the chances of survival under any condition. I hypothesize that unstable chromatin permits stochastic transitions between transcriptional programs in aggressive cancers and supports non‐genetic heterogeneity of tumor cells as a basis for their adaptability. I present a mechanistic model for unstable chromatin which includes destabilized nucleosomes, mobile chromatin fibers and random enhancer‐promoter contacts, resulting in stochastic (...) transcription. I suggest potential markers for “unsettled” chromatin in tumors associated with poor prognosis. Although many of the characteristics of unstable chromatin have been described, they were mostly used to explain changes in the transcription of individual genes. I discuss approaches to evaluate the role of unstable chromatin in non‐genetic tumor cell heterogeneity and suggest using the degree of chromatin instability and transcriptional noise in tumor cells to predict cancer aggressiveness. (shrink)

Grammatical markers are not uniformly impaired across speakers of different languages, even when speakers share a diagnosis and the marker in question is grammaticalized in a similar way in these languages. The aim of this work is to demarcate, from a cross-linguistic perspective, the linguistic phenotype of three genetically heterogeneous developmental disorders: specific language impairment, Down syndrome, and autism spectrum disorder. After a systematic review of linguistic profiles targeting mainly English-, Greek-, Catalan-, and Spanish-speaking populations with developmental disorders (n = (...) 880), shared loci of impairment are identified and certain domains of grammar are shown to be more vulnerable than others. The distribution of impaired loci is captured by the Locus Preservation Hypothesis which suggests that specific parts of the language faculty are immune to impairment across developmental disorders. Through the Locus Preservation Hypothesis, a classical chicken and egg question can be addressed: Do poor conceptual resources and memory limitations result in an atypical grammar or does a grammatical breakdown lead to conceptual and memory limitations? Overall, certain morphological markers reveal themselves as highly susceptible to impairment, while syntactic operations are preserved, granting support to the first scenario. The origin of resilient syntax is explained from a phylogenetic perspective in connection to the “syntax-before-phonology” hypothesis. (shrink)

Heterogeneity within MDD has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary (...) IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A ([11C]WAY-100635), as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets. (shrink)

Gene expression activity is heterogeneous in a population of isogenic cells. Identifying the molecular basis of this variability will improve our understanding of phenomena like tumor resistance to drugs, virus infection, or cell fate choice. The complexity of the molecular steps and machines involved in transcription and translation could introduce sources of randomness at many levels, but a common constraint to most of these processes is its energy dependence. In eukaryotic cells, most of this energy is provided by mitochondria. A (...) clonal population of cells may show a large variability in the number and functionality of mitochondria. Here, we discuss how differences in the mitochondrial content of each cell contribute to heterogeneity in gene products. Changes in the amount of mitochondria can also entail drastic alterations of a cell's gene expression program, which ultimately leads to phenotypic diversity. (shrink)

Since the 1970s, the origin of cancer is being explored from the point of view of the Somatic Mutation Theory (SMT), focusing on genetic mutations and clonal expansion of somatic cells. As cancer research expanded in several directions, the dominant focus on cells remained steady, but the classes of genes and the kinds of extra-genetic factors that were shown to have causal relevance in the onset of cancer multiplied. The wild heterogeneity of cancer-related mutations and phenotypes, along with the (...) increasing complication of models, led to an oscillation between the hectic search of 'the' few key factors that cause cancer and the discouragement in face of a seeming 'endless complexity'. To tame this complexity, cancer research started to avail itself of the tools that were being developed by Systems Biology. At the same time, anti-reductionist voices began claiming that cancer research was stuck in a sterile research paradigm. This alternative discourse even gave birth to an alternative theory: the Tissue Organization Field Theory (TOFT). A deeper philosophical analysis shows the serious limits of both reductionist and anti-reductionist positions and of their polarization. This book demonstrates that a radical philosophical reflection is necessary to drive cancer research out of its impasses. At the very least, this will be a reflection on the assumptions of different kinds of cancer research, on the implications of what cancer research has been discovering over 40 years and more, on a view of scientific practice that is most able to make sense of the cognitive and social conflicts that are seen in the scientific community (and in its results), and, finally, on the nature of living entities with which we entertain this fascinating epistemological dance that we call scientific research. The proposed Dynamic and Relational View of carcinogenesis is a starting point in all these directions. (shrink)

No two individuals with the autism diagnosis are ever the same—yet many practitioners and parents can recognize signs of ASD very rapidly with the naked eye. What, then, is this phenotype of autism that shows itself across such distinct clinical presentations and heterogeneous developments? The “signs” seem notoriously slippery and resistant to the behavioral threshold categories that make up current assessment tools. Part of the problem is that cognitive and behavioral “abilities” typically are theorized as high-level disembodied and modular functions—that (...) are assessed discretely (impaired, normal, enhanced) to define a spectral syndrome. Even as biology reminds us that organic developing bodies are not made up of independent switches, we remain often seduced by the simplicity of mechanistic and cognitive models. Developmental disorders such as autism have accordingly been theorized as due to different modular dysfunctions—typically of cortical origin, i.e., failures of “theory of mind” (Baron-Cohen et al., 1985), of the “mirror neuron system” (Ramachandran and Oberman, 2006), of “weak central coherence” (Happe and Frith, 2006) or of the balance of “empathizing” and “systemizing” (Baron-Cohen, 2009), just to list a few. -/- The broad array of autonomic (Ming et al., 2005; Cheshire, 2012) and sensorimotor (Damasio and Maurer, 1978; Maurer and Damasio, 1982; Donnellan and Leary, 1995; Leary and Hill, 1996; Donnellan and Leary, 2012; Donnellan et al., 2012) differences experienced and reported by people with autism have by such theories typically been sidelined as “co-morbidities,” possibly sharing genetic causes, but rendered as incidental and decisively behaviorally irrelevant symptoms—surely disconnected from cognition. But what if the development of cortically based mental processes and autonomous control relies on the complexities and proper function of the peripheral nervous systems? Through such an “embodied” lens the heterogeneous symptoms of autism invites new interpretations. We propose here that many behavioral-level findings can be re-defined as downstream effects of how developing nervous systems attempt to cope and adapt to the challenges of having various noisy, unpredictable, and unreliable peripheral inputs. (shrink)

Behavior genetics is a controversial science. For decades, scholars have sought to understand the role of heredity in human behavior and life-course outcomes. Recently, technological advances and the rapid expansion of genomic databases have facilitated the discovery of genes associated with human phenotypes such as educational attainment and substance use disorders. To maximize the potential of this flourishing science, and to minimize potential harms, careful analysis of what it would mean for genes to be causes of human behavior is needed. (...) In this paper, we advance a framework for identifying instances of genetic causes, interpreting those causal relationships, and applying them to advance causal knowledge more generally in the social sciences. Central to thinking about genes as causes is counterfactual reasoning, the cornerstone of causal thinking in statistics, medicine, and philosophy. We argue that within-family genetic effects represent the product of a counterfactual comparison in the same way as average treatment effects (ATEs) from randomized controlled trials (RCTs). Both ATEs from RCTs and within-family genetic effects are shallow causes: They operate within intricate causal systems (non-unitary), produce heterogeneous effects across individuals (non-uniform), and are not mechanistically informative (non-explanatory). Despite these limitations, shallow causal knowledge can be used to improve understanding of the etiology of human behavior and to explore sources of heterogeneity and fade-out in treatment effects. (shrink)

In this paper, I present an emerging explanatory framework about ageing and care. In particular, I focus on how, in contrast to most classical accounts of ageing, biomedicine today construes the ageing process as a modifiable trajectory. This framing turns ageing from a stage of inexorable decline into the focus of preventive strategies, harnessing the functional plasticity of the ageing organism. I illustrate this shift by focusing on studies of the demographic dynamics in human population, observations of ageing as an (...) intraspecifically heterogenous phenotype, and the experimental manipulation of longevity, in both model organisms and humans. I suggest that such an explanatory framework about ageing creates the epistemological conditions for the rise of a peculiar form of prevention that does not aim to address a specific condition. Rather it seeks to stall the age-related accumulation of molecular damage and functional deficits, boosting individual resilience against age-related decline. I call this preventive paradigm “ground-state prevention.” While new, ground-state prevention bears conceptual resemblance to forms of medical wisdom prominent in classic Galenic medicine, as well as in the Renaissance period. (shrink)

A wide range of ecological and evolutionary models predict variety in phenotype or behavior when a population is at equilibrium. This heterogeneity can be realized in different ways. For example, it can be realized through a complex population of individuals exhibiting different simple behaviors, or through a simple population of individuals exhibiting complex, varying behaviors. In some theoretical frameworks these different realizations are treated as equivalent, but natural selection distinguishes between these two alternatives in subtle ways. By investigating an (...) increasingly complex series of models, from a simple fluctuating selection model up to a finite population hawk/dove game, we explore the selective pressures which discriminate between pure strategists, mixed at the population level, and individual mixed strategists. Our analysis reveals some important limitations to the ESS framework often employed to investigate the evolution of complex behavior. (shrink)

The current COVID-19 pandemic and the previous SARS/MERS outbreaks of 2003 and 2012 have resulted in a series of major global public health crises. We argue that in the interest of developing effective and safe vaccines and drugs and to better understand coronaviruses and associated disease mechenisms it is necessary to integrate the large and exponentially growing body of heterogeneous coronavirus data. Ontologies play an important role in standard-based knowledge and data representation, integration, sharing, and analysis. Accordingly, we initiated the (...) development of the community-based Coronavirus Infectious Disease Ontology in early 2020. -/- As an Open Biomedical Ontology (OBO) library ontology, CIDO is open source and interoperable with other existing OBO ontologies. CIDO is aligned with the Basic Formal Ontology and Viral Infectious Disease Ontology. CIDO has imported terms from over 30 OBO ontologies. For example, CIDO imports all SARS-CoV-2 protein terms from the Protein Ontology, COVID-19-related phenotype terms from the Human Phenotype Ontology, and over 100 COVID-19 terms for vaccines (both authorized and in clinical trial) from the Vaccine Ontology. CIDO systematically represents variants of SARS-CoV-2 viruses and over 300 amino acid substitutions therein, along with over 300 diagnostic kits and methods. CIDO also describes hundreds of host-coronavirus protein-protein interactions (PPIs) and the drugs that target proteins in these PPIs. CIDO has been used to model COVID-19 related phenomena in areas such as epidemiology. The scope of CIDO was evaluated by visual analysis supported by a summarization network method. CIDO has been used in various applications such as term standardization, inference, natural language processing (NLP) and clinical data integration. We have applied the amino acid variant knowledge present in CIDO to analyze differences between SARS-CoV-2 Delta and Omicron variants. CIDO's integrative host-coronavirus PPIs and drug-target knowledge has also been used to support drug repurposing for COVID-19 treatment. -/- CIDO represents entities and relations in the domain of coronavirus diseases with a special focus on COVID-19. It supports shared knowledge representation, data and metadata standardization and integration, and has been used in a range of applications. (shrink)

Transposable elements (TEs) are powerful facilitators of genome evolution, and hence of phenotypic diversity as they can cause genetic changes of great magnitude and variety. TEs are ubiquitous and extremely ancient, and although harmful to some individuals, they can be very beneficial to lineages. TEs can build, sculpt, and reformat genomes by both active and passive means. Lineages with active TEs or with abundant homogeneous inactive populations of TEs that can act passively by causing ectopic recombination are potentially fecund, (...) adaptable, and taxonate readily. Conversely, taxa deficient in TEs or possessing heterogeneous populations of inactive TEs may be well adapted in their niche, but tend to prolonged stasis and may risk extinction by lacking the capacity to adapt to change, or diversify. Because of recurring intermittent waves of TE infestation, available data indicate a compatibility with punctuated equilibrium, in keeping with widely accepted interpretations of evidence from the fossil record. We propose a general and holistic synthesis on how the presence of TEs within genomes makes them flexible and dynamic, so that genomes themselves are powerful facilitators of their own evolution. (shrink)

Current COVID-19 pandemic and previous SARS/MERS outbreaks have caused a series of major crises to global public health. We must integrate the large and exponentially growing amount of heterogeneous coronavirus data to better understand coronaviruses and associated disease mechanisms, in the interest of developing effective and safe vaccines and drugs. Ontologies have emerged to play an important role in standard knowledge and data representation, integration, sharing, and analysis. We have initiated the development of the community-based Coronavirus Infectious Disease Ontology (CIDO). (...) As an Open Biomedical Ontology (OBO) library ontology, CIDO is an open source and interoperable with other existing OBO ontologies. In this article, the general architecture and the design patterns of the CIDO are introduced, CIDO representation of coronaviruses, phenotypes, anti-coronavirus drugs and medical devices (e.g. ventilators) are illustrated, and an application of CIDO implemented to identify repurposable drug candidates for effective and safe COVID-19 treatment is presented. (shrink)

The use of a reporter gene in transgenic mice indicates that there are many local mutations and large genomic rearrangements per somatic cell that accumulate with age at different rates per organ and without visible effects. Dissociation of the cells for monolayer culture brings out great heterogeneity of size and loss of function among cells that presumably reflect genetic and epigenetic differences among the cells, but are masked in organized tissue. The regulatory power of a mass of contiguous normal (...) cells is expressed in its capacity to normalize the appearance and growth behavior of solitary homophilic neoplastic cells, and to redirect differentiation of solitary heterophilic stem‐like cells. Intimate contact between the interacting cells is required to induce these changes. The normalization of the neoplastic phenotype does not require gap junctional communication between cells, though transdifferentiation might. These varied relationships are manifestations of the unifying biological principle of “order in the large over heterogeneity in the small”. BioEssays 28: 515–524, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Over one hundred genes have been isolated from the human genome and shown to be causally related to specific human genetic diseases. Studies with gene‐specific probes have demonstrated that the mutations resulting in a particular phenotype are highly heterogeneous as a group, ranging from alterations in transcription or RNA processing in the nucleus, through to errors in mRNA translation in the cytoplasm. Even where the gene‐specific probe is not available, defects have been localized to chromosomal regions by family studies. Recently (...) developed methods for moving along the chromosome from a linked marker to the mutation are resulting in rapid advances in the understanding of many monogenic disorders. (shrink)

Delays in early language development are characteristic of young autistic children, and one of the most recognizable first concerns that motivate parents to seek a diagnostic evaluation for their child. Although early language abilities are one of the strongest predictors of long-term outcomes, there is still much to be understood about the role of language impairment in the heterogeneous phenotypic presentation of autism. Using a person-centered, Latent Profile Analysis, we first aimed to identify distinct patterns of language and social (...) communication ability in a clinic-based sample of 498 autistic children, ranging in age from 18 to 60 months. Next, a multinomial logistic regression analysis was implemented to examine sociodemographic and child-based developmental differences among the identified language and social communication profiles. Three clinically meaningful profiles were identified from parent-rated and clinician-administered measures: Profile 1 “Relatively Low Language and Social Communication Abilities,” Profile 2 “Relatively Elevated Language and Social Communication Abilities,” and Profile 3 “Informant Discrepant Language and Relatively Elevated Social Communication Abilities.” Overall, young autistic children from the lowest-resource households exhibited the lowest language and social communication abilities, and the lowest non-verbal problem-solving and fine-motor skills, along with more features of attention-deficit/hyperactivity disorder and atypical auditory processing. These findings highlight the need for effective community-based implementation strategies for young autistic children from low-resource households and underrepresented communities to improve access to individualized quality care. (shrink)

Age‐related and cancer‐related epigenomic modifications have been associated with enhanced cell‐to‐cell gene expression variability that characterizes increased cellular stochasticity. Since gene expression variability appears to be highly reduced by—and epigenetic and phenotypic stability acquired through—direct or long‐range cellular interactions during cell differentiation, we propose a common origin for aging and cancer in the failure to control cellular stochasticity by cell–cell interactions. Tissue‐disruption‐induced cellular stochasticity associated with epigenetic drift would be at the origin of organ dysfunction because of an increase (...) in phenotypic variation among cells, ultimately leading to cell death and organ failure through a loss of coordination in cellular functions, and eventually to cancerization. We propose mechanistic research perspectives to corroborate this hypothesis and explore its evolutionary consequences, highlighting a positive correlation between the median age of mass loss onset (a proxy for the onset of organ aging) and the median age at cancer diagnosis. (shrink)

Recent work by Fernández‐Sánchez and coworkers examining the impact of applied pressure on the malignant phenotype of murine colon tissue in vivo revealed that mechanical perturbations can drive malignant behavior in genetically normal cells. Their findings build upon an existing understanding of how the mechanical cues experienced by cells within a tissue become progressively modified as the tissue transforms. Using magnetically stimulated ultra‐magnetic liposomes to mimic tumor growth ‐induced solid stress, Fernández‐Sánchez and coworkers were able to stimulate β‐catenin to promote (...) the cancerous behavior of both a normal and genetically modified colon epithelium. In this perspective, we discuss their findings in the context of what is currently known regarding the role of the mechanical landscape in cancer progression and β‐catenin as a mechanotransducer. We review data that suggest that mechanically regulated activation of β‐catenin fosters development of a malignant phenotype in tissue and predict that mechanical cues may contribute to tumor heterogeneity. (shrink)

Mutations that disrupt biological rhythms have existed in microbial and metazoan eukaryotes for some time. They have recently begun to be studied with increasing intensity, both in terms of phenotypic effects of the relevant genetic variants, and with regard to molecular isolation and analysis of the genes defined by two of the ‘clock mutations’. These genetic loci, called period (per) in Drosophila and frequency (frq) in Neurospora, influence not only the basic characteristics of circadian rhythmicity, but also temperature compensation (...) of such daily cycle durations, ‘re‐setting’ of the rhythms' phases, and (for the per mutants) behavioral oscillations associated with much shorter than circadian periodicities. Molecular cloning of Drosophila's per gene, accompanied crucially by the locus's identification in germ‐line transformants, has led to information on its expression ‐ temporally, spatially, and in regard to heterogeneity of mRNA types. Nucleotide‐sequencing analyses of genomic DNA (and/or cDNA) from normal and mutated per alleles have (1) led to the suggestion that this clock gene encodes a family of proteoglycans (which was further indicated by application of antibody reagents obtained by manipulation of one of the gene's exons); and (2) shown that the three types of per mutations ‐ which shorten or lengthen rhythm periodicities or appear to eliminate them ‐ are associated with interesting amino‐acid substitutions or a stop codon, respectively. Analogous molecular findings are awaited from Neurospora, whose frq gene has very recently been cloned and definitively identified, in part via transformation experiments. (shrink)

Most behavioural genetic studies focus on genetic and environmental influences on inter-individual phenotypic differences at the population level. The growing collection of intensive longitudinal data in social and behavioural science offers a unique opportunity to examine genetic and environmental influences on intra-individual phenotypic variability at the individual level. The current study introduces a novel idiographic approach and one novel method to investigate genetic and environmental influences on intra-individual variability by a simple empirical demonstration. Person-specific non-shared environmental influences on (...) intra-individual variability of daily school feelings were estimated using time series data from twenty-one pairs of monozygotic twins over two consecutive weeks. Results showed substantial inter-individual heterogeneity in person- specific non-shared environmental influences. The current study represents a first step in investigating environmental influences on intra-individual variability with an idiographic approach, and provides implications for future behavioural genetic studies to examine developmental processes from a microscopic angle. (shrink)

Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen in (...) one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. (shrink)

Disorders of sexual development are a heterogeneous group of disorders in which chromosomal, gonadal or anatomical sex development is atypical. The majority of these children are recognized at birth by ambiguous genitalia. Legal and societal pressures require the physician and parents to assign sex rapidly. Though sex assignment is undebated in several disorders of sexual development, many others need an individualized approach to gender-related concerns. Gender dysphoria is prevalent in disorders of sexual development, and early gender-defining surgeries have potentially lifelong (...) consequences. We use two cases, one of partial androgen insensitivity and another of simple virilizing congenital adrenal hyperplasia to illustrate that in disorders of sexual development, the ethical management principles remain the same at their core despite the vast differences in phenotypes. Sex assignment should maximize functional, psychological and sexual needs. Sex assigned should coincide with gender identity. We propose that we manage such children with the mutual participation of the physician, parents and the child. Though the parents and the physician have the child's best interests when making a decision, the child's developing autonomy should be protected. The communication of the health provider to the parent must be honest if early sex assignment is difficult. (shrink)

The macrophage plays an important role in host development and physiology, and in pathogenesis of many infectious, immunologic and degenerative disease processes. It displays marked heterogeneity of phenotype in different tissues, reflecting local interactions with other cell types, and contributes to host homeostasis through a varied repertoire of plasma membrane and secretory molecules. Upon isolation from the body it continues to express special, as well as general, features of cellular organisation and function, which make it a delight to study (...) in cell culture. (shrink)

The sciences, from their ancient beginnings, use a double way of investigation. One was applied to mineral and astronomical bodies, another to living ones. A ruling, tacit, common sense methodological or epistemological principle was this: The method of description should respect the inner essential properties of the object. For instance, neither the movements of the astronomical bodies, nor the behavior of the living bodies should be described in the scale of subatomic interactions. In modern times quite another methodological principle has (...) been enthroned. The cosmos, astronomical, mineral and alive bodies altogether, have, allegedly, to be considered as a single natural whole, ruled by essentially the same set of principles. The properties of the mineral world are accepted as a universal model of descriptive concepts, and the explanatory concepts proper to the mineral world are accepted as a universal model of explanation in biology. So, up to now, the academic sciences have been dominated by the philosophical option of materialist monism, or panmaterialism. This option—we may call it antiteleologism and fragmentarism—has a profound impact on empirical research and the way biological phenomena are described. This strange, unnatural, arbitrarily imposed conceptual framework ignores the most fundamental biological dynamisms, and precludes our intellect from seeing the right questions and striving towards the right answers. Consequently it arbitrarily reduces the range of “scientifically acceptable” explanations. This antiteleological methodology of sciences, imposed on biological mind by philosophers, led to major change in the ideas of philosophers of nature. The physiology and anatomy of the fully developed living bodies has become their central object of study. Much less attention is paid to developmental processes such as biosynthesis, morphogenesis, embryogenesis, phenotypic adaptation and regeneration. The fully shaped structures and their functional properties are considered a hopeful basis of all the necessary explanations. For instance the structure of tile DNA molecule has become more important than the problem of its origin, and the structure of the brain more important than the developmental processes which lead to its construction. However, the enormous progress of biological sciences in spite of the widespread, dominating antiteleological and fragmentarist approach corroborates the very ancient, Aristotelian insight, which put the principal stress on the developmental aspect of life. Aristotle, and his more modern followers, was fascinated by the integrated and intrinsically heterogenous tendencies visible in the course of life. Today, we can say that at least eight such tendencies are universal, i.e. appear in every single form of life : The tendency to select the proper kind of raw material and the proper kind of raw energy present in the environment. The tendency to synthesize new, highly selective forms of chemical structures. The tendency to utilize biological material in the process of building the nano-, micro-, and macro-machines. The tendency for a relatively rapid, continuous production and replacement of all the elements of the functional structures of the body. The tendency for a relatively rapid, continuous modification of the functional structures in a way which makes them more efficient within a changing environment. The tendency to repair and to regenerate the damaged elements of the functional structures of the body. The tendency for multiplication, which means the production of such structures and the depots of the biological material as seeds, eggs, spores or buds. These structures, providing the environmental conditions are favorable, are starting points of new instances of the above described tendencies. The tendency—possibly universal—to provide all the structures of the body with the “recognition marks” which help to eliminate all the, “alien” bodies and to recognize members of the own kind. These tendencies are not homogeneous. Homogeneous tendencies can be illustrated by the tendency of bodies to attract one another. This kind of tendency was the empirical source of such abstract concepts as gravitation, electrostatic force or magnetic force. Biological tendencies are heterogeneous and, at the same time, integrated. Human intellect is capable of recognizing the fundamental indivisibility of the set. A great number of observations and experiments have revealed and verified the fundamental indivisibility of the whole set of these tendencies. The concrete, bodily outcomes of these tendencies, however, are quite different in different families and orders of living things. Because of these differences the existence of different kinds of integrative principles was postulated. In this way a plurality of living substances was assumed. (shrink)

The sciences, from their ancient beginnings, use a double way of investigation. One was applied to mineral and astronomical bodies, another to living ones. A ruling, tacit, common sense methodological or epistemological principle was this: The method of description should respect the inner essential properties of the object. For instance, neither the movements of the astronomical bodies, nor the behavior of the living bodies should be described in the scale of subatomic interactions. In modern times quite another methodological principle has (...) been enthroned. The cosmos, astronomical, mineral and alive bodies altogether, have, allegedly, to be considered as a single natural whole, ruled by essentially the same set of principles. The properties of the mineral world are accepted as a universal model of descriptive concepts, and the explanatory concepts proper to the mineral world are accepted as a universal model of explanation in biology. So, up to now, the academic sciences have been dominated by the philosophical option of materialist monism, or panmaterialism. This option—we may call it antiteleologism and fragmentarism—has a profound impact on empirical research and the way biological phenomena are described. This strange, unnatural, arbitrarily imposed conceptual framework ignores the most fundamental biological dynamisms, and precludes our intellect from seeing the right questions and striving towards the right answers. Consequently it arbitrarily reduces the range of “scientifically acceptable” explanations. This antiteleological methodology of sciences, imposed on biological mind by philosophers, led to major change in the ideas of philosophers of nature. The physiology and anatomy of the fully developed living bodies has become their central object of study. Much less attention is paid to developmental processes such as biosynthesis, morphogenesis, embryogenesis, phenotypic adaptation and regeneration. The fully shaped structures and their functional properties are considered a hopeful basis of all the necessary explanations. For instance the structure of tile DNA molecule has become more important than the problem of its origin, and the structure of the brain more important than the developmental processes which lead to its construction. However, the enormous progress of biological sciences in spite of the widespread, dominating antiteleological and fragmentarist approach corroborates the very ancient, Aristotelian insight, which put the principal stress on the developmental aspect of life. Aristotle, and his more modern followers, was fascinated by the integrated and intrinsically heterogenous tendencies visible in the course of life. Today, we can say that at least eight such tendencies are universal, i.e. appear in every single form of life : The tendency to select the proper kind of raw material and the proper kind of raw energy present in the environment. The tendency to synthesize new, highly selective forms of chemical structures. The tendency to utilize biological material in the process of building the nano-, micro-, and macro-machines. The tendency for a relatively rapid, continuous production and replacement of all the elements of the functional structures of the body. The tendency for a relatively rapid, continuous modification of the functional structures in a way which makes them more efficient within a changing environment. The tendency to repair and to regenerate the damaged elements of the functional structures of the body. The tendency for multiplication, which means the production of such structures and the depots of the biological material as seeds, eggs, spores or buds. These structures, providing the environmental conditions are favorable, are starting points of new instances of the above described tendencies. The tendency—possibly universal—to provide all the structures of the body with the “recognition marks” which help to eliminate all the, “alien” bodies and to recognize members of the own kind. These tendencies are not homogeneous. Homogeneous tendencies can be illustrated by the tendency of bodies to attract one another. This kind of tendency was the empirical source of such abstract concepts as gravitation, electrostatic force or magnetic force. Biological tendencies are heterogeneous and, at the same time, integrated. Human intellect is capable of recognizing the fundamental indivisibility of the set. A great number of observations and experiments have revealed and verified the fundamental indivisibility of the whole set of these tendencies. The concrete, bodily outcomes of these tendencies, however, are quite different in different families and orders of living things. Because of these differences the existence of different kinds of integrative principles was postulated. In this way a plurality of living substances was assumed. (shrink)

The sciences, from their ancient beginnings, use a double way of investigation. One was applied to mineral and astronomical bodies, another to living ones. A ruling, tacit, common sense methodological or epistemological principle was this: The method of description should respect the inner essential properties of the object. For instance, neither the movements of the astronomical bodies, nor the behavior of the living bodies should be described in the scale of subatomic interactions. In modern times quite another methodological principle has (...) been enthroned. The cosmos, astronomical, mineral and alive bodies altogether, have, allegedly, to be considered as a single natural whole, ruled by essentially the same set of principles. The properties of the mineral world are accepted as a universal model of descriptive concepts, and the explanatory concepts proper to the mineral world are accepted as a universal model of explanation in biology. So, up to now, the academic sciences have been dominated by the philosophical option of materialist monism, or panmaterialism. This option—we may call it antiteleologism and fragmentarism—has a profound impact on empirical research and the way biological phenomena are described. This strange, unnatural, arbitrarily imposed conceptual framework ignores the most fundamental biological dynamisms, and precludes our intellect from seeing the right questions and striving towards the right answers. Consequently it arbitrarily reduces the range of “scientifically acceptable” explanations. This antiteleological methodology of sciences, imposed on biological mind by philosophers, led to major change in the ideas of philosophers of nature. The physiology and anatomy of the fully developed living bodies has become their central object of study. Much less attention is paid to developmental processes such as biosynthesis, morphogenesis, embryogenesis, phenotypic adaptation and regeneration. The fully shaped structures and their functional properties are considered a hopeful basis of all the necessary explanations. For instance the structure of tile DNA molecule has become more important than the problem of its origin, and the structure of the brain more important than the developmental processes which lead to its construction. However, the enormous progress of biological sciences in spite of the widespread, dominating antiteleological and fragmentarist approach corroborates the very ancient, Aristotelian insight, which put the principal stress on the developmental aspect of life. Aristotle, and his more modern followers, was fascinated by the integrated and intrinsically heterogenous tendencies visible in the course of life. Today, we can say that at least eight such tendencies are universal, i.e. appear in every single form of life : The tendency to select the proper kind of raw material and the proper kind of raw energy present in the environment. The tendency to synthesize new, highly selective forms of chemical structures. The tendency to utilize biological material in the process of building the nano-, micro-, and macro-machines. The tendency for a relatively rapid, continuous production and replacement of all the elements of the functional structures of the body. The tendency for a relatively rapid, continuous modification of the functional structures in a way which makes them more efficient within a changing environment. The tendency to repair and to regenerate the damaged elements of the functional structures of the body. The tendency for multiplication, which means the production of such structures and the depots of the biological material as seeds, eggs, spores or buds. These structures, providing the environmental conditions are favorable, are starting points of new instances of the above described tendencies. The tendency—possibly universal—to provide all the structures of the body with the “recognition marks” which help to eliminate all the, “alien” bodies and to recognize members of the own kind. These tendencies are not homogeneous. Homogeneous tendencies can be illustrated by the tendency of bodies to attract one another. This kind of tendency was the empirical source of such abstract concepts as gravitation, electrostatic force or magnetic force. Biological tendencies are heterogeneous and, at the same time, integrated. Human intellect is capable of recognizing the fundamental indivisibility of the set. A great number of observations and experiments have revealed and verified the fundamental indivisibility of the whole set of these tendencies. The concrete, bodily outcomes of these tendencies, however, are quite different in different families and orders of living things. Because of these differences the existence of different kinds of integrative principles was postulated. In this way a plurality of living substances was assumed. (shrink)

Muscular dystrophies are associated with mutations in genes encoding several classes of proteins. These range from extracellular matrix and integral membrane proteins to cytoskeletal proteins, but also include a heterogeneous group of proteins including proteases, nuclear proteins, and signalling molecules. Muscular dystrophy phenotypes have also become evident in studies on various knockout mice defective in proteins not previously considered or known to be mutated in muscular dystrophies. Some unifying themes are beginning to emerge from all of these data. This review (...) will consider recent advances in our understanding of the molecules involved and bring together data that suggest a role for the cytoskeleton and cell adhesion in muscular dystrophies. BioEssays 24:542–552, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Jaswal & Akhtar offer evidence against lack of social motivation in “autistic people,” providing no further phenotypic details as to the autism spectrum disorder subgroups that they refer to. I will argue that given the extensive behavioral and neurobiological heterogeneity among people who receive the diagnosis, reference to “autistic people” is misleading. As a consequence, J&A's claims are difficult to interpret.

IntroductionSymptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structure, is suspected in schizophrenia, we aimed to first seek patient subgroups with different neurobiological signatures and then quantify linguistic indices that capture the symptoms of “negative formal thought disorder”.MethodsAtlas-based cortical thickness values of (...) 66 patients with first-episode psychosis and 36 healthy controls were analyzed with hierarchical clustering algorithms to produce neuroanatomical subtypes. We then examined the generated subtypes and investigated the quantitative differences in MRS-based glutamate levels [in the dorsal anterior cingulate cortex ] as well as in three aspects of language production features: fluency, syntactic complexity, and lexical cohesion.ResultsTwo neuroanatomical subtypes among patients were observed, one with near-normal cortical thickness patterns while the other with widespread cortical thinning. Compared to the subgroup of patients with relatively normal cortical thickness patterns, the subgroup with widespread cortical thinning was older, with higher glutamate concentration in dACC and produced speech with reduced mean length of T-units and lower repeats of content words, despite being equally fluent.ConclusionWe characterized a patient subgroup with thinner cortex in first-episode psychosis. This subgroup, identifiable through macroscopic changes, is also distinguishable in terms of neurochemistry and language behavior. This study supports the hypothesis that glutamate-mediated cortical thinning may contribute to a phenotype that is detectable using the tools of computational linguistics in schizophrenia. (shrink)

In the mouse, at least 16 genes regulate vesicle trafficking to specialized lysosome‐related organelles, including platelet dense granules and melanosomes. Fourteen of these genes have been identified by positional cloning. All 16 mouse mutants are models for the genetically heterogeneous human disease, Hermansky–Pudlak Syndrome (HPS). Five HPS genes encode known vesicle trafficking proteins. Nine genes are novel, are found only in higher eukaryotes and encode members of three protein complexes termed BLOCs (Biogenesis of Lysosome‐related Organelles Complexes). Mutations in murine HPS (...) genes, which encode protein co‐members of BLOCs, produce essentially identical phenotypes. In addition to their well‐known effects on pigmentation, platelet function and lysosome secretion, HPS genes control a wide range of physiological processes including immune recognition, neuronal functions and lung surfactant trafficking. Studies of the molecular functions of HPS proteins will reveal important details of vesicle trafficking and may lead to therapies for HPS. BioEssays 26:616–628, 2004. © 2004 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)