The paper addresses a central problem in evolutionary biology and cognitive science; evolution of a neural based learning phenotype from a structured genotype. It describes morphogenesis of a neural network-based cognitive system, starting from a single genotype having a modulon control structure. It further shows how such a system, denoted as GALA architecture, growing its own recurrent axon connections, can further develop into various structures capable of learning in different learning modes, such as advice learning, reinforcement learning, and emotion learning. (...) The paper particularly considers the emotion learning systems and their motivational structure. A simulation experiment is provided to illustrate the theoretical issues discussed. (shrink)

The cryptomonads and chlorarachniophytes are two unicellular algal lineages with complex cellular structures and fascinating evolutionary histories. Both groups acquired their photosynthetic abilities through the assimilation of eukaryotic endosymbionts. As a result, they possess two distinct cytosolic compartments and four genomes—two nuclear genomes, an endosymbiont‐derived plastid genome and a mitochondrial genome derived from the host cell. Like mitochondrial and plastid genomes, the genome of the endosymbiont nucleus, or ‘nucleomorph’, of cryptomonad and chlorarachniophyte cells has been greatly reduced through the combined (...) effects of gene loss and intracellular gene transfer. This article focuses on the structure, function, origin and evolution of cryptomonad and chlorarachniophyte nucleomorph genomes in light of recent comparisons of genome sequence data from both groups. It is now possible to speculate on the reasons that nucleomorphs persist in cryptomonads and chlorarachniophytes but have been lost in all other algae with plastids of secondary endosymbiotic origin. BioEssays 29:392–402, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Recent investigations have revealed 1) that the isochores of the human genome group into two super‐families characterized by two different long‐range 3D structures, and 2) that these structures, essentially based on the distribution and topology of short sequences, mold primary chromatin domains (and define nucleosome binding). More specifically, GC‐poor, gene‐poor isochores are low‐heterogeneity sequences with oligo‐A spikes that mold the lamina‐associated domains (LADs), whereas GC‐rich, gene‐rich isochores are characterized by single or multiple GC peaks that mold the topologically associating domains (...) (TADs). The formation of these “primary TADs” may be followed by extrusion under the action of cohesin and CTCF. Finally, the genomic code, which is responsible for the pervasive encoding and molding of primary chromatin domains (LADs and primary TADs, namely the “gene spaces”/“spatial compartments”) resolves the longstanding problems of “non‐coding DNA,” “junk DNA,” and “selfish DNA” leading to a new vision of the genome as shaped by DNA sequences. (shrink)

Adverse developmental exposures and pathologies of the social environment make vastly greater contributions to the leading health burdens in society than currently known genotypic information. Yet, while patients now commonly bring information on single alleles to the attention of their healthcare team, the former conditions are only rarely considered with respect to future health outcomes. This manuscript aims to integrate social environmental influences in genetic predictive models of disease risk. Healthcare providers must be educated to better understand genetic risks for (...) complex diseases and the specific health consequences of societal adversities, to facilitate patient education, disease prevention, and the optimal care in order to achieve positive health outcomes for those with early trauma or other social disadvantage. (shrink)

High‐throughput genomic technologies are revolutionizing human genetics. So far the focus has been on the 1.5% of the genome, which is coding, in spite of the fact that the great majority of genomic variants fall outside the coding regions. Recent efforts to annotate the non‐coding sequence show that over 80% of the genome is biochemically active. The genome is divided into regulatory domains consisting of sequence regions that enhance and/or silence the expression of nearby genes and are, in (...) some cases, separated by boundaries with insulator activity. In this paper, we review the recent advances in the identification of variations that influence gene regulation and their consequences for human disease. We hypothesize that structural variations outside of the coding genome can interfere with normal gene regulation by disrupting the regulatory landscape. Therefore, the regulatory landscape of the genome has also to be taken into consideration when investigating the pathology of human disease. (shrink)

The advent of deep sequencing technology has unexpectedly advanced our structural understanding of molecules composed of nucleic acids. A significant amount of progress has been made recently extrapolating the chemical methods to probe RNA structure into sequencing methods. Herein we review some of the canonical methods to analyze RNA structure, and then we outline how these have been used to probe the structure of many RNAs in parallel. The key is the transformation of structural biology problems into sequencing (...) problems, whereby sequencing power can be interpreted to understand nucleic acid proximity, nucleic acid conformation, or nucleic acid‐protein interactions. Utilizing such technologies in this way has the promise to provide novel structural insights into the mechanisms that control normal cellular physiology and provide insight into how structure could be perturbed in disease. (shrink)

Next‐generation sequencing (NGS) technologies have revolutionised the analysis of genomic structural variants (SVs), providing significant insights into SV de novo formation based on analyses of rearrangement breakpoint junctions. The short DNA reads generated by NGS, however, have also created novel obstacles by biasing the ascertainment of SVs, an aspect that we refer to as the ‘short‐read dilemma’. For example, recent studies have found that SVs are often complex, with SV formation generating large numbers of breakpoints in a single (...) event (multi‐breakpoint SVs) or structurally polymorphic loci having multiple allelic states (multi‐allelic SVs). This complexity may be obscured in short reads, unless the data is analysed and interpreted within its wider genomic context. We discuss how novel approaches will help to overcome the short‐read dilemma, and how integration of other sources of information, including the structure of chromatin, may help in the future to deepen the understanding of SV formation processes. (shrink)

This chapter analyzes the revolutionary impact of genomic science on the study of evolution, and addresses the issues that modern evolutionary biology has either learned or needs to grapple with in the age of genomics. It suggests that transposable elements are genomic constituents which can result in novel genes or gene functions. The chapter proposes that although epigenetic changes remain compatible with the Modern Synthesis, dissecting the details could possibly result in new insights into the dynamics of the (...) evolutionary process which are not currently considered. It shows that the nature of epistasis is increasingly gaining prominence, and offers new avenues of research into the genetic architecture of evolutionary change. (shrink)

The majority of human, animal and plant viral pathogens possess genomes composed of RNA. The strategies evolved for expression and replication of viral RNA genomes can differ significantly from those utilized for expression and replication of host‐cell genetic material. Consequently, knowledge of the molecular details of these strategies can lead to a clearer understanding of the origin, evolution and control of viral pathogens. We describe recent progress in identifying important structural and functional domains of the RNA genomes and associated (...) replicative enzymes for two very different viruses: vesicular stomatitis virus, which possesses a single‐stranded RNA genome of negative polarity, and wound tumor virus, which contains a genome composed of 12 discrete segments of double‐stranded RNA. (shrink)

1900 was a remarkable year for science. Several ground-breaking events took place, in physics, biology and psychology. Planck introduced the quantum concept, the work of Mendel was rediscovered, and Sigmund Freud published The Interpretation of Dreams . These events heralded the emergence of completely new areas of inquiry, all of which greatly affected the intellectual landscape of the 20 th century, namely quantum physics, genetics and psychoanalysis. What do these developments have in common? Can we discern a family likeness, a (...) basic affinity between them, so that we can use the one to deepen our understanding of the other? One common denominator is that they open up realms of inquiry that are significantly different from the world of everyday experience, namely the realm of elementary particles, of genes and genomes, and of the unconscious. But to what extent can we meaningfully argue, for instance, that the genome is the biological unconscious, and the unconscious the psychic genome? To address these questions, I will build on the work of two key intellectual figures who have explored the affinities of these developments in depth, namely Erwin Schrödinger (a quantum physicist and avid reader of Schopenhauer who initiated molecular biology) and Jacques Lacan (who reframed the specificity of psychoanalysis with the help of 20 th century science: the era of structural linguistics, but also of quantum physics, molecular biology, bioinformatics and DNA). (shrink)

Tumour‐associated genetic changes frequently involve DNA translocation or deletion. Many of these events will have arisen from initial genomic damage, induced by either the activity of endogenous metabolic processes or from exposure to environmental genotoxic agents. Although initial genomic damage will have been widely distributed, tumorigenic events are confined to certain DNA target sites. Furthermore, within these target sites there appear to be regions of preferential DNA rearrangement, and examination of these sites implies that the location and extent (...) of such rearrangement may be influenced by DNA primary and secondary structure rather than simply by the point of damage. We selectively review evidence relating to DNA structures that may predispose certain regions of the genome to damage‐induced rearrangement, and discuss the possible role of interstitial, inverted telomere‐like sequence arrays in promoting chromosomal events of a type known to be associated with some human and animal tumours. (shrink)

A genome of a living organism consists of a long string of symbols over a finite alphabet carrying critical information for the organism. This includes its ability to control post natal growth, homeostasis, adaptation to changes in the surrounding environment, or to biochemically respond at the cellular level to various specific regulatory signals. In this sense, a genome represents a symbolic encoding of a highly organized system of information whose functioning may be revealed as a natural multilayer structure in terms (...) of complexity and prominence. In this paper we use the mathematical theory of symbolic extensions as a framework to shed light onto how this multilayer organization is reflected in the symbolic coding of the genome. The distribution of data in an element of a standard symbolic extension of a dynamical system has a specific form: the symbolic sequence is divided into several subsequences (which we call layers) encoding the dynamics on various “scales”. We propose that a similar structure resides within the genomes, building our analogy on some of the most recent findings in the field of regulation of genomic DNA functioning. (shrink)

Genomics is increasingly becoming an integral component of health research and clinical care. The perceived difficulties associated with genetic research involving Aboriginal and Torres Strait Islander people mean that they have largely been excluded as research participants. This limits the applicability of research findings for Aboriginal and Torres Strait Islander patients. Emergent use of genomic technologies and personalised medicine therefore risk contributing to an increase in existing health disparities unless urgent action is taken. To allow the potential benefits of (...) genomics to be more equitably distributed, and minimise potential harms, we recommend five actions: ensure diversity of participants by implementing appropriate protocols at the study design stage; target diseases that disproportionately affect disadvantaged groups; prioritise capacity building to promote Indigenous leadership across research professions; develop resources for consenting patients or participants from different cultural and linguistic backgrounds; and integrate awareness of issues relating to Indigenous people into the governance structures, formal reviews, data collection protocols and analytical pipelines of health services and research projects. (shrink)

A hypothesis of genome structural evolution is explored. Rapid and cohesive alterations in genome organization are viewed as resulting from the dynamic and constrained interactions of chromosomal subsystem components. A combination of macromolecular boundary conditions and DNA element involvement in far-from-equilibrium reactions is proposed to increase the complexity of genomic subsystems via the channelling of genome turnover; interactions between subsystems create higher-order subsystems expanding the phase space for further genetic evolution. The operation of generic constraints on structuration in (...) genome evolution is suggested by i) universal, homoplasic features of chromosome organization and ii) the metastable nature of genome structures where lower-level flux is constrained by higher-order structures. Phenomena such as genomic shock, bursts of transposable element activity, concerted evolution, etc., are hypothesized to result from constrained systemic responses to endogenous/exogenous, micro/macro perturbations. The constraints operating on genome turnover are expected to increase with chromosomal structural complexity, the number of interacting subsystems, and the degree to which interactions between genomic components are tightly ordered. (shrink)

Cells are cognitive entities possessing great computational power. DNA serves as a multivalent information storage medium for these computations at various time scales. Information is stored in sequences, epigenetic modifications, and rapidly changing nucleoprotein complexes. Because DNA must operate through complexes formed with other molecules in the cell, genome functions are inherently interactive and involve two-way communication with various cellular compartments. Both coding sequences and repetitive sequences contribute to the hierarchical systemic organization of the genome. By virtue of nucleoprotein complexes, (...) epigenetic modifications, and natural genetic engineering activities, the genome can serve as a read-write storage system. An interactive informatic conceptualization of the genome allows us to understand the functional importance of DNA that does not code for protein or RNA structure, clarifies the essential multidirectional and systemic nature of genomic information transfer, and emphasizes the need to investigate how cellular computation operates in reproduction and evolution. (shrink)

Retrotransposon-derived elements (RDEs) can disrupt gene expression, but are nevertheless widespread in metazoan genomes. This review presents a hypothesis that repressive RNA-binding proteins (RBPs) facilitate the large-scale accumulation of RDEs. Many RBPs bind RDEs in pre-mRNAs to repress the effects of RDEs on RNA processing, or the formation of inverted repeat RNA structures. RDE-binding RBPs often assemble on extended, multivalent binding sites across the RDE, which ensures repression of cryptic splice or polyA sites. RBPs thereby minimize the effects of RDEs (...) on gene expression, which likely reduces the negative selection against RDEs. While mutations that change splice sites in RDEs act as an off-on switch in exon formation, mutations that decrease the multivalency of RBP binding sites resemble a rheostat that enables a more gradual evolution of new RDE-derived exons. RBPs might also repress aberrant processing of active retrotransposons, thus increasing the chance that full-length copies are made. Taken together, in this review, it is proposed that RBPs facilitate the widespread accumulation of intronic RDEs by repressing RNA processing while chaperoning their potential to gradually evolve into new exons. (shrink)

The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct.

The reductionistic vision of evolutionary theory, "the gene's eye view of evolution" is the dominant view among evolutionary biologists today. On this view, the gene is the only unit with sufficient stability to act as a unit of selection, with individuals and groups being more ephemeral units of function, but not of selection. This view is argued to be incorrect, on several grounds. The empirical and theoretical bases for the existence of higher-level units of selection are explored, and alternative analyses (...) discussed critically. The success of a multi-level selection theory demands the recognition and development of a multi-level genetics. The way to accomplish this is suggested. The genotype/phenotype distinction also requires further analysis to see how it applies at higher levels of organization. This analysis provides a way of defining genotype and phenotype for cultural evolution, and a treatment of the innate-acquired distinction which are both generalizeable to analyze problems of the nature and focus of scientific change. (shrink)

Cis‐regulatory elements govern gene expression programs to determine cell identity during development. Recently, the possibility that multiple enhancers are orchestrated in clusters of enhancers has been suggested. How these elements are arranged in the 3D space to control the activation of a specific promoter remains unclear. Our recent work revealed that the TGFβ pathway drives the assembly of enhancer clusters and precise gene activation during neurogenesis. We discovered that the TGFβ pathway coactivator JMJD3 was essential in maintaining these structures in (...) the 3D space. To do that, JMJD3 required an intrinsically disordered region involved in forming phase‐separated biomolecular condensates found in the enhancer clusters. Our data support the existence of a relationship between 3D‐conformation of the chromatin, biomolecular condensates, and TGFβ‐driven response during mammalian neurogenesis. In this review, we discuss how signaling (TGFβ), epigenetics (JMJD3), and biochemical properties (biomolecular condensates nucleation) are coordinated to modulate the genome structure to guarantee proper neural development. Moreover, we comment on the potential underlying mechanisms and implications of the enhancer‐mediated regulation. Finally, we point out the knowledge gaps that still need to be addressed. (shrink)

Realizing the benefits of translating psychiatric genomics research into mental health care is not straightforward. The translation process gives rise to ethical challenges that are distinctive from challenges posed within psychiatric genomics research itself, or that form part of the delivery of clinical psychiatric genetics services. This article outlines and considers three distinct ethical concerns posed by the process of translating genomic research into frontline psychiatric practice and policy making. First, the genetic essentialism that is commonly associated with the (...) genomics revolution in health care might inadvertently exacerbate stigma towards people with mental disorders. Secondly, the promises of genomic medicine advance a narrative of individual empowerment. This narrative could promote a fatalism towards patients' biology in ways that function in practice to undermine patients' agency and autonomy, or, alternatively, a heightened sense of subjective genetic responsibility could become embedded within mental health services that leads to psychosocial therapeutic approaches and the clinician-patient therapeutic alliance being undermined. Finally, adopting a genomics-focused approach to public mental health risks shifting attention away from the complex causal relationships between inequitable socio-economic, political, and cultural structures and negative mental health outcomes. The article concludes by outlining a number of potential pathways for future ethics research that emphasizes the importance of examining appropriate translation mechanisms, the complementarity between genetic and psychosocial models of mental disorder, the implications of genomic information for the clinician-patient relationship, and funding priorities and resource allocation decision making in mental health. (shrink)

Merleau-Ponty, la passivité et la scienceJe soutiens qu’il y a plus en jeu dans l’intérêt de Merleau-Ponty pour la science qu’une simple dialectique entre disciplines. C’est parce que son évolutionméthodologique le conduit à trouver dans la science un moyen spécifique d’approfondir ses recherches ontologiques, que celle-ci hante de plus en plus sa philosophie. En effet, dans le chapitre « champ phénoménal » de la Phénoménologie de la perception, il est possible de rapprocher certains aspects de son défi méthodologique et l’idée (...) selon laquelle la philosophie tient son origine d’une conscience réflexive, active et autonome dans son ensemble. Je lie cela aux problèmes de la passivité de telle sorte que la science apparaisse comme une façon de saisir la réflexion non pas comme autonome, mais comme une opération du champ phénomenal, comme réflexion radicale. Grâce à l’analyse critique des recherches récentes sur le génome, je montre ensuite commentl’embryologie peut nous aider à conceptualiser la vie comme un champ phénoménal, c’est-à-dire comme un champ qui engendre ce même genre d’opérations qui caractérisent aussi la phénoménalité. Cela nous conduit à voir la phénomenologie non plus comme une réflexion de survol sur les phénomènes, mais plutôt comme une réflexion radicale qui se realise à travers un phénoménalité plus « ancienne », qui appartient à la vie ellemême. Cela ouvre également des perspectives sur quelques problèmes difficiles de la dernière philosophie de Merleau-Ponty; ceux-ci sont abordés d’une manière nouvelle, grâce au rapprochement de sa première philosophie et de la science actuelle.Merleau-Ponty, la passività e la scienzaRitengo che, nell’interesse che Merleau-Ponty rivolge alla scienza, vi sia in gioco qualcosa di più del semplice confronto dialettico con un’altra disciplina. Il motivo è che il suo impegno metodologico finisce per individuare nella scienza una speciale risorsa per l’indagine di quelle profonde questioni ontologiche che investono in modo crescente la sua filosofia. Intendo argomentare tale ipotesi, connettendo dei passi del capitolo di Fenomenologia della percezione “Il campo fenomenico” con la sua sfida metodologica all’idea che la filosofia abbia inizio da una coscienza riflessiva autonoma e interamente attiva. Collego questo alle questioni della passività in un modo che rivela la scienza come una potenziale risorsa per comprendere la riflessione non come autonoma, bensì in quanto operazione di e nel campo fenomenico – come riflessione radicale. Poi, attraverso un’analisi critica dei risultati recenti riguardanti il DNA regolatore, mostrocome l’attuale embriologia può aiutarci a concettualizzare la vita come un campo fenomenico che implicitamente produce i tipi di operazioni rivelatrici distintive della fenomenalità. Questo ci permette di collocare la fenomenologia non semplicemente come una riflessione dall’alto sui fenomeni, ma come una riflessione radicale che opera grazie ad una “più antica” fenomenalità della vita. Questo ci fornisce degli spunti su alcune difficili questioni nella filosofia dell’ultimo Merleau-Ponty, suggerendo un nuovo percorso che giunga a queste combinando il primo periodo della sua filosofia con la scienza recente. (shrink)

Merleau-Ponty, la passivité et la scienceJe soutiens qu’il y a plus en jeu dans l’intérêt de Merleau-Ponty pour la science qu’une simple dialectique entre disciplines. C’est parce que son évolutionméthodologique le conduit à trouver dans la science un moyen spécifique d’approfondir ses recherches ontologiques, que celle-ci hante de plus en plus sa philosophie. En effet, dans le chapitre « champ phénoménal » de la Phénoménologie de la perception, il est possible de rapprocher certains aspects de son défi méthodologique et l’idée (...) selon laquelle la philosophie tient son origine d’une conscience réflexive, active et autonome dans son ensemble. Je lie cela aux problèmes de la passivité de telle sorte que la science apparaisse comme une façon de saisir la réflexion non pas comme autonome, mais comme une opération du champ phénomenal, comme réflexion radicale. Grâce à l’analyse critique des recherches récentes sur le génome, je montre ensuite commentl’embryologie peut nous aider à conceptualiser la vie comme un champ phénoménal, c’est-à-dire comme un champ qui engendre ce même genre d’opérations qui caractérisent aussi la phénoménalité. Cela nous conduit à voir la phénomenologie non plus comme une réflexion de survol sur les phénomènes, mais plutôt comme une réflexion radicale qui se realise à travers un phénoménalité plus « ancienne », qui appartient à la vie ellemême. Cela ouvre également des perspectives sur quelques problèmes difficiles de la dernière philosophie de Merleau-Ponty; ceux-ci sont abordés d’une manière nouvelle, grâce au rapprochement de sa première philosophie et de la science actuelle.Merleau-Ponty, la passività e la scienzaRitengo che, nell’interesse che Merleau-Ponty rivolge alla scienza, vi sia in gioco qualcosa di più del semplice confronto dialettico con un’altra disciplina. Il motivo è che il suo impegno metodologico finisce per individuare nella scienza una speciale risorsa per l’indagine di quelle profonde questioni ontologiche che investono in modo crescente la sua filosofia. Intendo argomentare tale ipotesi, connettendo dei passi del capitolo di Fenomenologia della percezione “Il campo fenomenico” con la sua sfida metodologica all’idea che la filosofia abbia inizio da una coscienza riflessiva autonoma e interamente attiva. Collego questo alle questioni della passività in un modo che rivela la scienza come una potenziale risorsa per comprendere la riflessione non come autonoma, bensì in quanto operazione di e nel campo fenomenico – come riflessione radicale. Poi, attraverso un’analisi critica dei risultati recenti riguardanti il DNA regolatore, mostrocome l’attuale embriologia può aiutarci a concettualizzare la vita come un campo fenomenico che implicitamente produce i tipi di operazioni rivelatrici distintive della fenomenalità. Questo ci permette di collocare la fenomenologia non semplicemente come una riflessione dall’alto sui fenomeni, ma come una riflessione radicale che opera grazie ad una “più antica” fenomenalità della vita. Questo ci fornisce degli spunti su alcune difficili questioni nella filosofia dell’ultimo Merleau-Ponty, suggerendo un nuovo percorso che giunga a queste combinando il primo periodo della sua filosofia con la scienza recente. (shrink)

In this article, I explore the ethical dimensions of same-sex reproduction achieved through epigenome editing—an innovative and transformative technique. For the first time, I analyse the potential normativity of this disruptive approach for reproductive purposes, focusing on its implications for lesbian couples seeking genetically related offspring. Epigenome editing offers a compelling solution to the complex ethical challenges posed by traditional gene editing, as it sidesteps genome modifications and potential long-term genetic consequences. The focus of this article is to systematically analyse (...) the bioethical issues related to the use of epigenome editing for same-sex reproduction. I critically assess the ethical acceptability of epigenome editing with reproductive purposes from multiple angles, considering harm perspectives, the comparison of ethical issues related to gene and epigenome editing, and feminist theories. This analysis reveals that epigenome editing emerges as an ethically acceptable means for lesbian couples to have genetically related children. Moreover, the experiments of a reproductive use of epigenome editing discussed in this article transcend bioethics, shedding light on the broader societal implications of same-sex reproduction. It challenges established notions of biological reproduction and prompts a reevaluation of how we define the human embryo, while poses some issues in the context of gender self-identification and family structures. In a world that increasingly values inclusivity and diversity, this article aims to reveal a progressive pathway for reproductive medicine and bioethics, as well as underscores the need for further philosophical research in this emerging and fertile domain. (shrink)

The RecQ family of DNA helicases have been shown to be important for the maintenance of genomic integrity in all organisms analysed to date. In human cells, representatives of this family include the proteins defective in the cancer predisposition disorder Bloom's syndrome and the premature ageing condition, Werner's syndrome. Several pieces of evidence suggest that RecQ family helicases form associations with one or more of the cellular topoisomerases, and together these heteromeric complexes manipulate DNA structure to effect efficient DNA (...) replication, genetic recombination, or both. Here, we propose that RecQ helicases are required for ensuring that structural abnormalities arising during replication, such as at sites where replication forks encounter DNA lesions, are corrected with high fidelity. In mutants defective in these proteins, not only is replication abnormal, but cells display aberrant responses to DNA-damaging agents or inhibitors of DNA synthesis. We suggest that RecQ helicases may be important for the integration of cellular responses to these insults, such as by linking cell cycle checkpoint responses to recombinational repair. BioEssays 21:286–294, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Since the late 1990s, the characterization of complete DNA sequences for a large and taxonomically diverse set of species has continued to gain in speed and accuracy. Sequence analyses have indicated a strikingly baroque structure for most eukaryotic genomes, with multiple repeats of DNA sequences and with very little of the DNA specifying proteins. Much of the DNA in these genomes has no known function. These results have generated strong interest in the factors that govern the evolution of genome architecture. (...) While adaptationist ‘just so’ stories have been offered, recent theoretical analyses based on mathematical population genetics strongly suggest that non-adaptive processes dominate genome architecture evolution. This article critically synthesizes and develops these arguments, explicating a core argument along with several variants. It provides a critical assessment of the evidence that supports these arguments’ premises. It also analyses adaptationist responses to these arguments and notes potential problems with the core argument. These theoretical analyses continue the molecular reinterpretation of evolution initiated by the neutral theory in 1968. The article ends by noting that some of these arguments can also be extended to evolution at higher levels of organization which raises questions about adaptationism in general. This remains a puzzle because there is probably little reason to doubt that many organismic features are genuine adaptations. 1 Introduction2 Preliminaries: Senses of Adaptationism3 Genome Architecture3.1 Surprises of early eukaryotic genetics3.2 Genome structure, post-20014 The Case against Adaptationism4.1 Just so stories versus population genetics4.2 The core argument4.3 Three variants of the core argument4.4 Examples: Non-adaptive features of the genome5 Adaptationist Responses6 Concluding Remarks. (shrink)

Recent systematic studies using newly developed genomic approaches have revealed common mechanisms and principles that underpin the spatial organization of eukaryotic genomes and allow them to respond and adapt to diverse functional demands. Genomes harbor, interpret, and propagate genetic and epigenetic information, and the three‐dimensional (3D) organization of genomes in the nucleus should be intrinsically linked to their biological functions. However, our understanding of the mechanisms underlying both the topological organization of genomes and the various nuclear processes is still (...) largely incomplete. In this essay, we focus on the functional relevance as well as the biophysical properties of common organizational themes in genomes (e.g. looping, clustering, compartmentalization, and dynamics), and examine the interconnection between genome structure and function from this angle. Present evidence supports the idea that, in general, genome architecture reflects and influences genome function, and is relatively stable. However, the answer as to whether genome architecture is a hallmark of cell identity remains elusive. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Human Genome Research in an Interdependent WorldAlexander Morgan Capron (bio)This has been the year of agenda-setting conferences for the ambitious ELSI (ethical, legal and social issues) program of the Human Genome Project (HGP). But of the dozen or more major meetings of this sort held across the country, the one held at the National Institutes of Heakh (NIH) in Bethesda, MD, June 2-4, 1991, was distinctive in several respects.1As (...) its name implies, "Human Genome Research in an Interdependent World" was a global look at the issues raised by gene mapping and sequencing. Unlike previous conferences, however, this meeting looked beyond a comparative analysis of clinical and domestic legal issues, and concentrated on topics that may require responses on a truly international level if they are to be successfully resolved.The meeting's organizers gathered an impressive group of more than seventy participants from fifteen countries, including the first significant contingent of Soviet and Japanese scientists, physicians, and philosophers at an ELSI meeting. In addition to talks by the heads of the genome projects in the Soviet Union, Japan, and the United States, the meeting was keynoted by Dr. James Wyngaarden, director general of the Human Genome Organization (HUGO), and I had the honor of serving as its general chairman.The goal of the meeting was to consider an array of issues that scientists, philosophers, and lawyers from around the world suggested might have international significance, with an eye to deciding three things: (1) Does the issue deserve further attention? (2) Is the issue best addressed in an international or domestic context? and (3) Do structures exist to which the issue can be referred for resolution? In the final sessions, the entire group debated proposed resolutions on the various topics and narrowed the list needing further, intensive exploration.To provide an international framework for this process, the conference [End Page 247] established a Global Steering Committee on Ethical and Social Issues in Genome Research, which will coordinate the efforts of several task forces charged with refining the tentative resolutions adopted by the conference participants on June 4. The task forces are expected to be able to complete work on some topics by the time of the steering committee's first meeting, which was described by one participant as a "check point," probably within the coming year; on other topics, the task forces will provide interim reports and arrange to continue their analysis. Several topics—less complex or more embryonic—were referred directly to the steering committee. On all issues, a major objective will be to ascertain what existing or newly created structure or structures are capable of implementing the group's recommendations and then to monitor the issue to ensure that appropriate implementation is occurring.Issues to be Explored by Task ForcesInsurance and EmploymentWhile individuals may derive medically useful information from the expanded range of genetic tests that will flow from the HGP, they could also be harmed if test results become a basis for discrimination. An area of particular concern at the conference in Bethesda was whether genetic information should be used to decide eligibility for employment or the scope and cost of health and life insurance. The complexity of this issue is increased as barriers to worker migration fall (especially in Europe) and as more firms carry on business internationally. Furthermore, questions arise about the limits of required testing and whether individuals may decline to be informed of the results of tests.The task force will not only gather information on practices and legal standards throughout the world—especially in light of the differences among nations with regard to the linkage of employment and various forms of insurance—but will also examine international anti-discrimination laws as a possible means of supplementing domestic statutes and regulations. As a starting point, the Bethesda meeting agreed on a set of principles for the task force to refine.2ForensicsAlthough their legal status is not fully resolved, DNA tests are being used increasingly in judicial proceedings and civil and criminal investigations as a highly probative means to identify people. Most forensic uses of "DNA fingerprints" are domestic, but international cooperation among investigative bodies... (shrink)

New concepts may prove necessary to profit from the avalanche of sequence data on the genome, transcriptome, proteome and interactome and to relate this information to cell physiology. Here, we focus on the concept of large activity-based structures, or hyperstructures, in which a variety of types of molecules are brought together to perform a function. We review the evidence for the existence of hyperstructures responsible for the initiation of DNA replication, the sequestration of newly replicated origins of replication, cell division (...) and for metabolism. The processes responsible for hyperstructure formation include changes in enzyme affinities due to metabolite-induction, lipid-protein affinities, elevated local concentrations of proteins and their binding sites on DNA and RNA, and transertion. Experimental techniques exist that can be used to study hyperstructures and we review some of the ones less familiar to biologists. Finally, we speculate on how a variety of in silico approaches involving cellular automata and multi-agent systems could be combined to develop new concepts in the form of an Integrated cell (I-cell) which would undergo selection for growth and survival in a world of artificial microbiology. (shrink)

Sperm, eggs and embryos are made up of more than genes, and there are indications that changes to non‐genetic structures in these elements of the germline can also be inherited. It is, therefore, a mistake to treat phrases like ‘germline inheritance’ and ‘genetic inheritance’ as simple synonyms, and bioethical discussion should expand its focus beyond alterations to the genome when considering the ethics of germline modification. Moreover, additional research on non‐genetic inheritance draws attention to a variety of means whereby differences (...) can be inherited in offspring generations that do not rely on differences in germline structures. Research on these diverse forms of inheritance challenges the notion that there is some special form of ethical concern that falls on germline interventions in general, and on interventions to the nuclear genome within the germline in particular. (shrink)

Natural genome editing from a biocommunicative perspective is the competent agent-driven generation and integration of meaningful nucleotide sequences into pre-existing genomic content arrangements, and the ability to (re-)combine and (re-)regulate them according to context-dependent (i.e. adaptational) purposes of the host organism. Natural genome editing integrates both natural editing of genetic code and epigenetic marking that determines genetic reading patterns. As agents that edit genetic code and epigenetically mark genomic structures, viral and subviral agents have been suggested because they (...) may be evolutionarily older than cellular life. This hypothesis that viruses and viral-like agents edit genetic code is developed according to three well investigated examples that represent key evolutionary inventions in which non-lytic viral swarms act symbiotically in a persistent lifestyle within cellular host genomes: origin of eukaryotic nucleus, adaptive immunity, placental mammals. Additionally an abundance of various RNA elements cooperate in a variety of steps and substeps as regulatory and catalytic units with multiple competencies to act on the genetic code. Most of these RNA agents such as transposons, retroposons and small non-coding RNAs act consortially and are remnants of persistent viral infections that now act as co-opted adaptations in cellular key processes. (shrink)

Australia is thought of as the home of marsupials, but South America has 60 or so species of these interesting mammals. The genome of one of these, the South American grey short-tailed opossum, Monodelphis domestica, has just been sequenced and published in June.1 The high quality 6× coverage is the first marsupial genome completed, pipping the 2× coverage of the Australian tammar wallaby at the post by half a year. The opossum genome has an unusual structure with fewer chromosomes than (...) the human genome (9 pairs versus 23 pairs) but a longer total length (3.4 billion versus 3 billion bases). The opossum autosomes, like those of all marsupials, are extremely large but, in contrast, the X chromosome is only 76 Mb long. The opossum genome has turned up several surprises and provided critical new information on the evolution of mammalian genomes2-6. BioEssays 29:1073–1076, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The exponential growth of genetic knowledge and precision medicine research raises hopes for improved prevention, diagnosis, and treatment options for children with behavioral and psychiatric conditions. Although well-intended, this prospect also raise the possibility — and concern — that behavioral, including psychiatric genetic data would be increasingly used — or misused — outside the clinical context, such as educational settings. Indeed, there are ongoing calls to endorse a “personalized education” model that would tailor educational interventions to children's behavioral and psychiatric (...) genetic makeup. This article explores the justifications for, and prospects and pitfalls of such endeavors. It considers the scientific challenges and highlights the ethical, legal, and social issues that will likely arise should behavioral genetic data become available and are routinely incorporated in student education records. These include: when to disclose students' behavioral and psychiatric genetic profile; whose genomic privacy is protected and by whom; and how students' genetic data may affect education-related decisions. I argue that the introduction of behavioral genetics in schools may overshadow the need to address underlying structural and environmental factors that increase the risk for psychiatric conditions of all students, and that the unregulated use of student behavioral genetic profiles may lead to unintended consequences that are detrimental for individuals, families and communities. Relevant stakeholders — from parents and students to health professionals, educators, and policy-makers — ought to consider these issues before we forge ahead with a genomically informed education system. (shrink)

The history of research on pseudoalleles, closely linked genes that have similar functions, is rich and complex. Because pseudoalleles’ proximity on the chromosome makes their distinction by the complementation tests traditionally used by geneticists difficult, and because they have similar functions, they were initially often considered as allelic forms of the same gene, hence their name. The Hox cluster is an emblematic example of a pseudoallelic gene complex. The first observations of pseudoalleles were made very early but remained puzzling until (...) a simple model explaining their formation and characteristics emerged in the middle of the 1930s. This model suggested that pseudoalleles originated by gene.. (shrink)

This year’s topic is “Genomics and Philosophy of Race.” Different researchers might work on distinct subsets of the six thematic clusters below, which are neither mutually exclusive nor collectively exhaustive: (1) Concepts of ‘Race’; (2) Mathematical Modeling of Human History and Population Structure; (3) Data and Technologies of Human Genomics; (4) Biological Reality of Race; (5) Racialized Selves in a Global Context; (6) Pragmatic Consequences of ‘Race Talk’ among Biologists.

It is becoming increasingly evident that the driving forces of evolutionary novelty are not randomly derived chance mutations of the genetic text, but a precise genome editing by omnipresent viral agents. These competences integrate the whole toolbox of natural genetic engineering, replication, transcription, translation, genomic imprinting, genomic creativity, enzymatic inventions and all types of genetic repair patterns. Even the non-coding, repetitive DNA sequences which were interpreted as being ancient remnants of former evolutionary stages are now recognized as being (...) of viral descent and crucial for higher-order regulatory and constitutional functions of protein structural vocabulary. In this article I argue that non-randomly derived natural genome editing can be envisioned as (a) combinatorial (syntactic), (b) context-specific (pragmatic) and (c) content-sensitive (semantic) competences of viral agents. These three-leveled biosemiotic competences could explain the emergence of complex new phenotypes in single evolutionary events. After short descriptions of the non-coding regulatory networks, major viral life strategies and pre-cellular viral life three of the major steps in evolution serve as examples: There is growing evidence that natural genome-editing competences of viruses are essential (1) for the evolution of the eukaryotic nucleus, (2) the adaptive immune system and (3) the placental mammals. (shrink)

The human genome is not a uniform structure but, instead, is a mosaic of bands. Some of these bands can be seen by the eye. Stained with Giemsa and viewed under the microscope each human chromosome has a prototypical pattern of light and dark bands (G and R bands respectively). Other bands are not so easily viewed. The human genome is, for example, a mosaic of isochores, blocks of DNA within which the proportion of the bases G and C at (...) silent sites (introns, third positions in codons, intergene spacer) is fairly uniform. Recent work by Matassi and colleagues(1) has revealed what might be a new and unexpected banding pattern. They have found that the genes which are close together on the chromosome have similar rates of evolution. BioEssays 22:105–107, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

BackgroundObtaining informed consent for participation in genomic research in low-income settings presents specific ethical issues requiring attention. These include the challenges that arise when providing information about unfamiliar and technical research methods, the implications of complicated infrastructure and data sharing requirements, and the potential consequences of future research with samples and data. This study investigated researchers’ and participants’ parents’ experiences of a consent process and understandings of a genome-wide association study of malaria involving children aged five and under in (...) Mali. It aimed to inform best practices in recruiting participants into genomic research.MethodsA qualitative rapid ethical assessment was undertaken. Fifty-five semi-structured interviews were conducted with the parents of research participants. An additional nine semi-structured interviews were conducted with senior research scientists, research assistants and with a member of an ethics committee. A focus group with five parents of research participants and direct observations of four consent processes were also conducted. French and translated English transcripts were descriptively and thematically coded using OpenCode software.ResultsParticipants’ parents in the MalariaGEN study had differing understandings of the causes of malaria, the rationale for collecting blood samples, the purposes of the study and the kinds of information the study would generate. Genomic aspects of the research, including the gene/environment interaction underlying susceptibility or resistance to severe malaria, proved particularly challenging to explain and understand.ConclusionsThis study identifies a number of areas to be addressed in the design of consent processes for genomic research, some of which require careful ethical analysis. These include determining how much information should be provided about differing aspects of the research and how best to promote understandings of genomic research. We conclude that it is important to build capacity in the design and conduct of effective and appropriate consent processes for genomic research in low and middle-income settings. Additionally, consideration should be given to the role of review committees and community consultation activities in protecting the interests of participants in genomic research. (shrink)

The human genome contains about 30,000 genes, each creating several transcripts per gene. Transcript structures and expression are studied by high‐throughput transcriptomic techniques using microarrays. Generally, transcripts are not directly operating molecules, but are translated into functional proteins, post‐translationally modified by proteolysis, glycosylation, phosphorylation, etc., sometimes with great functional impact. Proteins need to be analyzed by proteomic techniques, less suited for high‐throughput. Two‐dimensional polyacrylamide gel electrophoresis (2D‐PAGE), separating thousands of proteins has developed slowly over the past quarter of a century. (...) This technique is now quite reproducible and suitable for differential proteomics, comparing normal and diseased cells/tissues revealing differentially regulated proteins. 2D‐PAGE is combined with protein‐identification methods, currently mass spectrometry (MS), which has been significantly improved over the last decade. Other proteomic techniques studying protein–protein interactions are now either established or still being developed, such as peptide or protein arrays, phage display, and the yeast two‐hybrid system. The strengths and weaknesses of these techniques are discussed. BioEssays 26:901–915, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

According to the proponents of Developmental Systems Theory and the Causal Parity Thesis, the privileging of the genome as “first among equals” with respect to the development of phenotypic traits is more a reflection of our own heuristic prejudice than of ontology - the underlying causal structures responsible for that specified development no more single out the genome as primary than they do other broadly “environmental” factors. Parting with the methodology of the popular responses to the Thesis, this paper offers (...) a novel criterion for ‘causal primacy’, one that is grounded in the ontology of the unique causal role of dispositional properties. This paper argues that, if the genome is conceptualised as realising dispositional properties that are “directed toward” phenotypic traits, the parity of ‘causal roles’ between genetic and extra-genetic factors is no longer apparent, and further, that the causal primacy of the genome is both plausible and defensible. (shrink)

Chromosomes are not randomly packed and positioned into the nucleus but folded in higher‐order chromatin structures with defined functions. However, the genome of a fertilized embryo undergoes a dramatic epigenetic reprogramming characterized by extensive chromatin relaxation and the lack of a defined three‐dimensional structure. This reprogramming is followed by a slow genome refolding that gradually strengthens the chromatin architecture during preimplantation development. Interestingly, genome refolding during early development coincides with a progressive loss of developmental potential suggesting a link between chromatin (...) organization and cell plasticity. In agreement, loss of chromatin architecture upon depletion of the insulator transcription factor CTCF in embryonic stem cells led to the upregulation of the transcriptional program found in totipotent cells of the embryo, those with the highest developmental potential. This essay will discuss the impact of genome folding in controlling the expression of transcriptional programs involved in early development and their plastic‐associated features. (shrink)

The spatial organization of genomes is becoming increasingly understood. In mammals, where it is most investigated, this organization ties in with transcription, so an important research objective is to understand whether gene activity is a cause or a consequence of genome folding in space. In this regard, the phenomena of X‐chromosome inactivation and reactivation open a unique window of investigation because of the singularities of the inactive X chromosome. Here we focus on the cause–consequence nexus between genome conformation and transcription (...) and explain how recent results about the structural changes associated with inactivation and reactivation of the X chromosome shed light on this problem. (shrink)

Biomedical research recruitment today focuses on including participants representative of global genetic variation—rightfully so. But ethnographic attention to practices of inclusion highlights how this agenda often transforms into “predatory inclusion,” simplistic pushes to get Black and brown people into genomic databases. As anthropologists of medicine, we argue that the question of how to get from diverse data to concrete benefit for people who are marginalized cannot be presumed to work itself out as a byproduct of diverse datasets. To actualize (...) the equitable translation of genomics, practitioners need to place the impacts of ancestral genetic difference in the scope of much more impactful social determinants. For this to happen, multidisciplinary expertise needs to be leveraged, and current, structurally unequal health care systems ultimately need to transform. As modest steps toward this goal, new models for benefit‐sharing must be developed and implemented to mitigate existing inequality between data donors and the entities profiting from that data. (shrink)

This paper identifies several kinds of intellectual mistakes that proponents of genetic engineering make, in defending their views and characterizing the views of their opponents. Results from research in the social sciences and humanities illuminate the nature of these mistakes. The mistakes themselves play a role in allowing proponents to gather support from other protagonists in the social controversies involving science and technology. Understanding the controversies requires understanding that innovations are components of complex and ill-structured social problems; the “right answer” (...) does not follow from scientific or technological breakthroughs. If the problems are identified correctly, issues of non-economic or non-market values and political and individual rights will need to be addressed. (shrink)

The Plant Ontology (PO; http://www.plantontology.org/) is a publicly-available, collaborative effort to develop and maintain a controlled, structured vocabulary (“ontology”) of terms to describe plant anatomy, morphology and the stages of plant development. The goals of the PO are to link (annotate) gene expression and phenotype data to plant structures and stages of plant development, using the data model adopted by the Gene Ontology. From its original design covering only rice, maize and Arabidopsis, the scope of the PO has been expanded (...) to include all green plants. The PO was the first multi-species anatomy ontology developed for the annotation of genes and phenotypes. Also, to our knowledge, it was one of the first biological ontologies that provides translations (via synonyms) in non-English languages such as Japanese and Spanish. There are about 2.2 million annotations linking PO terms to over 110,000 unique data objects representing genes or gene models, proteins, RNAs, germplasm and Quantitative Traits Loci (QTLs) from 22 plant species. In this paper, we focus on the plant anatomical entity branch of the PO, describing the organizing principles, resources available to users, and examples of how the PO is integrated into other plant genomics databases and web portals. We also provide two examples of comparative analyses, demonstrating how the ontology structure and PO-annotated data can be used to discover the patterns of expression of the LEAFY (LFY) and terpene synthase (TPS) gene homologs. (shrink)

Recent molecular biology has seen the development of genomics as a successor to traditional genetics. This paper offers an overview of the structure, epistemology, and history of contemporary genomics. A particular focus is on the question to what extent the genome contains, or is composed of, anything that corresponds to traditional conceptions of genes. It is concluded that the only interpretation of genes that has much contemporary scientific relevance is what is described as the "developmental defect" gene concept. However, developmental (...) defect genes typically only correspond to general areas of the genome and not to precise chemical structures . The parts of the genome to be identified for an account of the processes of normal development are highly diverse, little correlated with traditional genes, and act in ways that are highly dependent on the cellular and higher level environment. Despite its historical development out of genetics, genomics represents a radically different kind of scientific project. (shrink)

Community engagement (CE) contributes to successful research. There is, however, a lack of literature on the effectiveness of different models of CE and, specifically, on CE strategies for the conduct of genomic research in sub-Saharan Africa. There is also a need for models of CE that transcend the recruitment stage of engaging prospective individuals and communities and embed CE throughout the research process and after the research has concluded. The qualitative study reported here was designed to address these knowledge (...) gaps and comprised of 36 key informant semi-structured interviews and fifteen focus groups with 50 participants. We interviewed selected stakeholders in genomic research in Nigeria: biomedical researchers, community rulers, opinion leaders, community health workers, and prospective research participants. We explored these stakeholders’ views on their understanding of community engagement, their expectations, experiences, and their opinions on acceptable processes of community consultation in genomic research. The methodological design, adapted from grounded theory, used the constant comparative method of data analysis; while normative conclusions were made using the symbiotic empirical ethics approach. Data analysis revealed five main themes important for successfully engaging communities in genomic research: effective communication, diversity of community gatekeeping, trust, cultural integration of research, and conservation of the research setting. From these themes, we have developed a four-stage model of community engagement that covers all stages of the research process; namely, the Community Approach, Intermediate phase, Collaboration and Post-research Cordiality model (CICP). This model could be used to improve the integration of CE in genomic research among local communities. (shrink)

Community engagement (CE) contributes to successful research. There is, however, a lack of literature on the effectiveness of different models of CE and, specifically, on CE strategies for the conduct of genomic research in sub-Saharan Africa. There is also a need for models of CE that transcend the recruitment stage of engaging prospective individuals and communities and embed CE throughout the research process and after the research has concluded. The qualitative study reported here was designed to address these knowledge (...) gaps and comprised of 36 key informant semi-structured interviews and fifteen focus groups with 50 participants. We interviewed selected stakeholders in genomic research in Nigeria: biomedical researchers, community rulers, opinion leaders, community health workers, and prospective research participants. We explored these stakeholders’ views on their understanding of community engagement, their expectations, experiences, and their opinions on acceptable processes of community consultation in genomic research. The methodological design, adapted from grounded theory, used the constant comparative method of data analysis; while normative conclusions were made using the symbiotic empirical ethics approach. Data analysis revealed five main themes important for successfully engaging communities in genomic research: effective communication, diversity of community gatekeeping, trust, cultural integration of research, and conservation of the research setting. From these themes, we have developed a four-stage model of community engagement that covers all stages of the research process; namely, the Community Approach, Intermediate phase, Collaboration and Post-research Cordiality model (CICP). This model could be used to improve the integration of CE in genomic research among local communities. (shrink)