Forensic DNA phenotyping (FDP) is an emerging technology that seeks to make probabilistic inferences regarding a person’s observable characteristics (“phenotype”) from DNA. The aim is to aid criminal investigations by helping to identify unknown suspected perpetrators, or to help with non-criminal missing persons cases. Here we provide results from the analysis of 36 interviews with those who have a professional stake in FDP, including forensic scientists, police officers, lawyers, government agencies and social scientists. Located in eight EU countries, these (...) individuals were asked for their views on the benefits and problems associated with the prospective use of FDP. While all interviewees distinguished between those phenotypic tests perceived to either raise ethical, social or political concerns from those tests viewed as less ethically and socially problematic, there was wide variation regarding the criteria they used to make this distinction. We discuss the implications of this in terms of responsible technology development. (shrink)

Forensic DNA phenotyping is a genetic technology that might be used in criminal investigations. Based on DNA samples of the human body found at crime scenes, it allows to infer externally visible characteristics (such as eye, hair and skin colour) and continental-based biogeographical ancestry. By indicating the probable visible appearance of a criminal suspect, forensic DNA phenotyping allows to narrow down the focus of a criminal investigation. In this article, drawing on interviews with forensic geneticists, we explore how (...) their narratives translate contemporary focus on criminal molecularized bodies. We propose the concept of (de)materialization to approach three aspects of the forensic geneticists’ views. The first regards considering bodies as mutable entities. The second relates to socially contingent meanings attributed to bodies. The third regards to controversies surrounding data reliability. By reflecting upon the (de)materialization of criminal bodies, forensic geneticists juxtapose the defence and unsettling of forensic DNA phenotyping claims. (shrink)

There is a concern according to which analyzing crime scene DNA to determine biogeographic origin and skin color of suspects can lead to discrimination against minority populations. This article summarizes and explains some of those parts of the investigation process that can give rise to discrimination. The second part of the paper offers an analysis of the notion of discrimination and presents different accounts of the exact ground of its moral wrongness. As it will emerge, these different accounts lead to (...) different assessments of the use of DNA phenotype analyses in police investigations. -/- ----- Dieser Beitrag befasst sich mit der Befürchtung, dass eine Erweiterung der DNA-Analyse von Tatortspuren für Zwecke der Polizeiarbeit zu Diskriminierungen führen wird. Diese Erwartung bezieht sich insbesondere auf die Ermittlung der sogenannten biogeografischen Abstammung und der Hautschattierung. In dieser Untersuchung werden einige Stellen im Ermittlungsprozess, an denen auf Grundlage solcher Analysen Diskriminierungspotential auftreten könnte, zunächst gesammelt und dargelegt. Im zweiten Teil wird dann der Diskriminierungsbegriff genauer beleuchtet. Dabei wird sich zeigen, dass verschiedene Positionen zu der Frage, was genau eine Diskriminierung moralisch problematisch macht, zu unterschiedlichen Einschätzungen der DNA-Phänotypisierung in der Polizeiarbeit führen. (shrink)

The great majority of phenotypic characteristics are complex traits, complicating the identification of the genes underlying their expression. However, both methodological and theoretical progress in genome‐wide association studies have resulted in a much better understanding of the underlying genetics of many phenotypic traits, including externally visible characteristics (EVCs) such as eye and hair color. Consequently, it has become possible to predict EVCs from human samples lacking phenotypic information. Predicting EVCs from genetic evidence is clearly appealing for forensic applications involving the (...) personal identification of human remains. Now, a recent paper has reported the genetic determination of eye and hair color in samples up to 800 years old. The ability to predict EVCs from ancient human remains opens up promising perspectives for ancient DNA research, as this could allow studies to directly address archaeological and evolutionary questions related to the temporal and geographical origins of the genetic variants underlying phenotypes. (shrink)

Although genome‐scale analyses have provided insights into the connection between genetic variability and complex human phenotypes, much trait variation is still not fully understood. Genetic variation within repetitive elements, such as the multi‐copy, multi‐locus ribosomal DNA (rDNA), has emerged as a potential contributor to trait variation. Whereas rDNA was long believed to be largely uniform within a species, recent studies have revealed substantial variability in the locus, both within and across individuals. This variation, which takes the form of copy number, (...) structural arrangement, and sequence differences, has been found to be associated with human phenotypes. This review summarizes what is currently known about human rDNA variation, its causes, and its association with phenotypic outcomes, highlighting the technical challenges the field faces and the solutions proposed to address them. Finally, we suggest experimental approaches that can help clarify the elusive mechanisms underlying the phenotypic consequences of rDNA variation. (shrink)

The distinction between phenotype and genotype is fundamental to the understanding of heredity and development of organisms. The genotype of an organism is the class to which that organism belongs as determined by the description of the actual physical material made up of DNA that was passed to the organism by its parents at the organism's conception. For sexually reproducing organisms that physical material consists of the DNA contributed to the fertilized egg by the sperm and egg of its two (...) parents. For asexually reproducing organisms, for example bacteria, the inherited material is a direct copy of the DNA of its parent. The phenotype of an organism is the class to which that organism belongs as determined by the description of the physical and behavioral characteristics of the organism, for example its size and shape, its metabolic activities and its pattern of movement. (shrink)

ZusammenfassungDurch eine Gesetzesänderung im Dezember 2019 ist im Rahmen von Strafermittlungsverfahren nunmehr der Einsatz des „Forensic DNA Phenotyping“, d. h. von Technologien zur Vorhersage von Haut-, Haar- und Augenfarbe sowie biologischem Alter, erlaubt. Dieser Beitrag diskutiert die Verlässlichkeit, Nützlichkeit und Legitimität von solchen Erweiterten DNATechnologien und damit die Rahmenbedingungen ihres Einsatzes in Deutschland. Dabei wird aufgezeigt wie kompliziert, fehleranfällig, voraussetzungsreich, anspruchsvoll und heikel der Einsatz dieser Technologien in Ermittlungen sein kann, wenn nicht entsprechende Vorkehrungen getroffen werden, und wenn sie (...) nicht auf umsichtig begleitete Einzelfälle beschränkt bleiben. Aufbauend auf dieser Analyse werden schließlich Maßnahmen für die Anwendung und Regulierung Erweiterter DNA-Technologien in Deutschland vorgeschlagen. (shrink)

DNA sequence variation is abundant in wild populations. While molecular biologists use genetically homogeneous strains of model organisms to avoid this variation, evolutionary biologists embrace genetic variation as the material of evolution since heritable differences in fitness drive evolutionary change. Yet, the relationship between the phenotypic variation affecting fitness and the genotypic variation producing it is complex. Genetic buffering mechanisms modify this relationship by concealing the effects of genetic and environmental variation on phenotype. Genetic buffering allows the build-up and storage (...) of genetic variation in phenotypically normal populations. When buffering breaks down, thresholds governing the expression of previously silent variation are crossed. At these thresholds, phenotypic differences suddenly appear and are available for selection. Thus, buffering mechanisms modulate evolution and regulate a balance between evolutionary stasis and change. Recent work provides a glimpse of the molecular details governing some types of genetic buffering. BioEssays 22:1095–1105, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

The Genotype-Phenotype (G-P) distinction was proposed in the context of Mendelian genetics, in the wake of late 19th century studies about heredity. In this paper, we provide a conceptual analysis that highlights that the G-P distinction was grounded on three pillars: observability, transmissibility, and causality. Originally, the genotype is the non-observable and transmissible cause of the phenotype, which is its observable and non-transmissible effect. We argue that the current developments of biology have called the validity of such pillars into question. (...) First, molecular biology has unveiled the putative material substrate of the genotype (qua DNA), making it an observable object. Second, numerous findings on nongenetic heredity suggest that some phenotypic traits can be directly transmitted. Third, recent organicist approaches to biological phenomena have emphasized the reciprocal causality between parts of a biological system, which notably applies to the relations between genotypes and phenotypes. As a consequence, we submit that the G-P distinction has lost its general validity, although it can still apply to specific situations. This calls for forging new frameworks and concepts to better describe heredity and development. (shrink)

In this paper we explore shifts in how the law and ethics allow European law enforcement officers to use forensic genetic technologies. We do so by reviewing three technologies, ‘traditional’ (STR-based) forensic DNA profiling, forensic DNA phenotyping and the searching of genetic genealogy databases. In particular, we discuss changes in how ethical boundaries have been placed around what is seen as an appropriate use of genetic technologies in European criminal justice systems. While the ‘type’ of DNA that law enforcement (...) officers are permitted to analyse offers a useful ethical reference point, for newer forensic genomic technologies, ethical scrutiny, we argue, would also look at the specific purpose or use of the technology. (shrink)

Conventional forensic DNA analysis involves a matching principle, which compares DNA profiles from evidential samples to those from reference samples of known origin. In casework, however, the accessibility to a reference sample is not guaranteed which limits the use of DNA as an investigative tool. This has led to the development of phenotype prediction, which uses SNP analysis to estimate the physical appearance of the sample donor. Physical traits, such as eye, hair and skin colour, have been associated with certain (...) alleles within specific genes involved in the melanogenesis pathways. These genetic markers are also associated with ancestry and their trait prediction ability has mainly been assessed in European and North American populations. This has prompted research investigating the discriminatory power of these markers in other populations, especially those exhibiting admixture. South Africa is well known for its diversity, and the viability of these particular SNPs still needs to be assessed within this population. South African law currently restricts the use of DNA for molecular phenotyping, and there are also numerous ethical and social considerations, all of which are discussed. (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)

Wasted Chances? The Current Political Debate on DNA Phenotyping and Biogeographical Ancestry Analysis in Criminal Investigation in Germany. This paper discusses diverse understandings of ‘responsible science’ in heated political debates. It takes a current public debate around a German law amendment draft concerning the use of novel forensic genetic techniques, namely DNA‐phenotyping and biogeographical ancestry analysis, as an example. A distinction is being made between an understanding that emphasizes scientific debate and precision, and another one that focuses on (...) political agency. The paper also addresses the question whether and how science studies scholars, given their depth of expertise in the analysis of complex problems spanning disciplinary boundaries, should contribute to national debates in policy fields where no such dialogue exists yet. (shrink)

DNA methylation is a repressive epigenetic modification that is essential for development and its disruption is widely implicated in disease. Yet, remarkably, ablation of DNA methylation in transgenic mouse models has limited impact on transcriptional states. Across multiple tissues and developmental contexts, the predominant transcriptional signature upon loss of DNA methylation is the de‐repression of a subset of germline genes, normally expressed in gametogenesis. We recently reported loss of de novo DNA methyltransferase DNMT3B resulted in up‐regulation of germline genes and (...) impaired syncytiotrophoblast formation in the murine placenta. This defect led to embryonic lethality. We hypothesize that de‐repression of germline genes in the Dnmt3b knockout underpins aspects of the placental phenotype by interfering with normal developmental processes. Specifically, we discuss molecular mechanisms by which aberrant expression of the piRNA pathway, meiotic proteins or germline transcriptional regulators may disrupt syncytiotrophoblast development. (shrink)

DNA mismatch repair is an important pathway of mutation avoidance. It also contributes to the cytotoxic effects of some kinds of DNA damage, and cells defective in mismatch repair are resistant, or tolerant, to the presence of some normally cytotoxic base analogues in their DNA. The absence of a particular mismatch binding function from some mammalian cells confers resistance to the base analogues O6‐methylguanine and 6‐thioguanine in DNA. Cells also acquire a spontaneous mutator phenotype as a consequence of this defect. (...) Impaired mismatch binding can cause an instability in DNA microsatellite regions that comprise repeated dinucleotides. Microsatellite DNA instability is common in familial and sporadic colon carcinomas as well as in a number of other tumours. Several independent lines of investigation have identified defects in mismatch repair proteins that are causally related to these cancers. (shrink)

A foundational idea of evo‐devo is that morphological variation is not isotropic, that is, it does not occur in all directions. Instead, some directions of morphological variation are more likely than others from DNA‐level variation and these largely depend on development. We argue that this evo‐devo perspective should apply not only to morphology but to evolution at all phenotypic levels. At other phenotypic levels there is no development, but there are processes that can be seen, in analogy to development, as (...) constructing the phenotype (e.g., protein folding, learning for behavior, etc.). We argue that to explain the direction of evolution two types of arguments need to be combined: generative arguments about which phenotypic variation arises in each generation and selective arguments about which of it passes to the next generation. We explain how a full consideration of the two types of arguments improves the explanatory power of evolutionary theory. Also see the video abstract here: https://youtu.be/Egbvma_uaKc. (shrink)

Developmental biology is expanding into several new areas. One new area of study concerns the production of adult-onset phenotypes by exposure of the fetus or neonate to environmental agents. These agents include maternal nutrients, developmental modulators (endocrine disruptors), and maternal care. In all three cases, a major mechanism for the generation of the altered phenotype is chromatin modification. Nutrient conditions, developmental modulators, and even maternal care appear to alter DNA methylation and other associated changes in chromatin that regulate gene expression. (...) This brings a new, under-appreciated, dimension of gene regulation into developmental biology, and it also demonstrates the poverty of the nature versus nurture framework for discussing phenotype production. Moreover, while such epigenetic mechanisms undermine genetic determinism, they add a layer of probabilistic biological causality for the maintenance of social inequalities. (shrink)

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

DNA methylation plays a key role in neural cell fate and provides a molecular link between early life stress and later-life behavioral phenotypes. Here, studies that combine neuroimaging methods and DNA methylation analysis in pediatric population with a history of adverse experiences were systematically reviewed focusing on: targeted genes and neural correlates; statistical models used to examine the link between DNA methylation and neuroimaging data also considering early life stress and behavioral outcomes. We identified 8 studies that report associations between (...) DNA methylation and brain structure/functions in infants, school age children and adolescents faced with early life stress condition. Results showed that several genes were investigated and different neuroimaging techniques were performed. Statistical model used ranged from correlational to more complex moderated mediation models. Most of the studies considered DNA methylation and neural correlates as mediators in the relationship between early life stress and behavioral phenotypes. Understanding what role DNA methylation and neural correlates play in interaction with early life stress and behavioral outcomes is crucial to promote theory-driven studies as the future direction of this research fields. (shrink)

Adaptation by means of natural selection depends on the ability of populations to maintain variation in heritable traits. According to the Modern Synthesis this variation is sustained by mutations and genetic drift. Epigenetics, evodevo, niche construction and cultural factors have more recently been shown to contribute to heritable variation, however, leading an increasing number of biologists to call for an extended view of speciation and evolution. An additional common feature across the animal kingdom is learning, defined as the ability to (...) change behavior according to novel experiences or skills. Learning constitutes an additional source for phenotypic variation, and change in behavior may induce long lasting shifts in fitness, and hence favor evolutionary novelties. Based on published studies, I demonstrate how learning about food, mate choice and habitats has contributed substantially to speciation in the canonical story of Darwin’s finches on the Galapagos Islands. Learning cannot be reduced to genetics, because it demands decisions, which requires a subject. Evolutionary novelties may hence emerge both from shifts in allelic frequencies and from shifts in learned, subject driven behavior. The existence of two principally different sources of variation also prevents the Modern Synthesis from self-referring explanations. (shrink)

At metaphase, DNA in a human chromosome is estimated to be compacted at least 10,000 fold in length.1,2 However, the higher order mechanisms by which the chromosomes are organized in interphase and subsequently further condensed in mitosis have largely remained elusive. One generally overlooked participant in chromosome condensation is DNA replication. Many early studies of eukaryotic chromosome organization and cell fusions have suggested that DNA replication plays a role in chromosome compaction. Recent phenotypic analysis of Drosophila DNA replication mutants has (...) revitalized this old idea. In this review, the role of DNA replication in chromosome condensation will be examined. BioEssays 24:411–418, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The growing number of cloned eukaryotic genes lacking a defined or proven biological function poses a major challenge in ‘reverse genetics’. A method is described here that permits efficient screening for new lesions in, or close to, genes corresponding to cloned DNA sequences of interest. The technique involves transposon mutagenesis, followed by screening of DNA isolated from a population of mutagenised individuals (or their progeny) for evidence that the population contains at least one individual in which transposon insertion has occurred (...) at the target locus. Detection of rare individuals within the population is facilitated by the use of the polymerase chain reaction (PCR). Once recognised, specific individuals (or their progeny) are isolated from the population by a process of sib‐selection. In cases where insertion of the transposon has occurred close to, but not within, the target locus, secondary events involving imprecise excision of the transposon will nonetheless allow the isolation of mutant individuals. Though the method was developed specifically for the transposon‐mutagenesis of Drosophila, extensions to other organisms and to other mutagenic strategies are feasible and some of the possibilities are discussed. (shrink)

Recent investigations with non‐model species and whole‐genome approaches have challenged several paradigms in animal epigenetics. They revealed that epigenetic variation in populations is not the mere consequence of genetic variation, but is a semi‐independent or independent source of phenotypic variation, depending on mode of reproduction. DNA methylation is not positively correlated with genome size and phylogenetic position as earlier believed, but has evolved differently between and within higher taxa. Epigenetic marks are usually not completely erased in the zygote and germ (...) cells as generalized from mouse, but often persist and can be transgenerationally inherited, making them evolutionarily relevant. Gene body methylation and promoter methylation are similar in vertebrates and invertebrates with well methylated genomes but transposon silencing through methylation is variable. The new data also suggest that animals use epigenetic mechanisms to cope with rapid environmental changes and to adapt to new environments. The main benefiters are asexual populations, invaders, sessile taxa and long‐lived species. (shrink)

Sociological accounts usually emphasise the primacy of phenotype (cor, colour) over ancestry for orienting concepts of ‘race’ in Brazil. In this paper, I present an alternative account of the cultural and political significance of ancestry in contemporary Brazil, drawing on qualitative interviews conducted with 50 Brazilians who had recently taken personalised DNA ancestry tests. The interviewees’ attitudes towards their ancestry are interpreted in relation to Brazil’s longstanding national myth of mestiçagem and the history of eugenic Whitening ideologies (ideologias do branqueamento) (...) that have sought to erase traces of Brazil’s African origins. However, they are also interpreted also against the backdrop of contemporary Black Movement activism that aims to actively recovering Afro-Brazilian histories and memories from these processes of erasure. (shrink)

Constructivist biosemiotics foundations imply the first-person basis of cognition. CBF are developed by the biology of cognition, relational biology, enactive approach, ecology of mind, second order cybernetics, genetic epistemology, gestalt, ecological perception and affordances, and active inference by minimization of free energy. CBF reject the idea of an objective independent reality to be represented by information processing in order to be the fittest. CBF assumes that perception is the behavioral configuration of an object and objects are tokens for eigen-behaviors. Cognition (...) takes place in the organism-environment structural coupling during the ontogeny and phylogeny of all biological unities including unicellular organisms. Therefore, if exogenous DNA particles are just tokens for the cell signalling eigen-behaviors, if there is no ‘information’ in the DNA sequence, how can we explain that the same virus or trans- sequence is associated with a similar phenotype? We call this ‘exogenomic problem’. With this basic example, but sufficiently generic to the whole biological world, we agree respectively with Autopoiesis, -system, and Gaia theory: i) ‘Information, code and meaning’ in the DNA sequence belong to the domain of the observer’s description. ii) Genetic ‘information’ is not a program or algorithmic software in DNA sequence. Rather it is a microphysical observable mode of eigen-behaviors in biological unities. iii) The transfer and acquisition of DNA particles is a biospheric phenomenon that maintains its homeorhesis, symbiotic and biosemiotic entailment. Based on the theoretical and experimental results of these theories, it is concluded that genetic ‘information’ is not a genomic sequence, nor any kind of information, but for the cell DNA must embody physical forcing. Genetic characters are the effects and not the cause of phenotype and DNA particles do not ‘use or manipulate’ cellular metabolism. Rather, any cellular configuration change that occurred before or during DNA perturbation is determined on the basis of the cellular standpoint. (shrink)

It took a long time for humanity to know about biogenetics. And yet its role as a determinant in the living system was not proven until the twentieth century when DNA was discovered. Similarly, it took a long time for humanity to know about culture and civilization. And yet until now there is neither definite standards for differentiating them nor a definition that is commonly acceptable. By taking an evolutionary pluralism as ontology framework and the transdisciplinary research method of the (...) systems science, we have in the new social system model discovered the central rules that govern the social?cultural heredity: Culture?Production?Civilization. The relationship between culture and civilization is exactly that of genotype and phenotype. Culture is the S-cDNA within the social system while civilization is the social phenotype. Culture is a determinant that ultimately determines the existence, stagnation, change, and evolution of the social system. (shrink)

Ovarian cancer is the most lethal gynecological malignancy and is often associated with both DNA repair deficiency and extensive metabolic reprogramming. While still emerging, the interplay between these pathways can affect ovarian cancer phenotypes, including therapeutic resistance to the DNA damaging agents that are standard‐of‐care for this tumor type. In this review, we will discuss what is currently known about cellular metabolic rewiring in ovarian cancer that may impact DNA damage and repair in addition to highlighting how specific DNA repair (...) proteins also promote metabolic changes. We will also discuss relevant data from other cancers that could be used to inform ovarian cancer therapeutic strategies. Changes in the choice of DNA repair mechanism adopted by ovarian cancer are a major factor in promoting therapeutic resistance. Therefore, the impact of metabolic reprogramming on DNA repair mechanisms in ovarian cancer has major clinical implications for targeted combination therapies for the treatment of this devastating disease. (shrink)

Cockayne syndrome is a rare autosomal recessive disease characterized by a complex clinical phenotype. Most Cockayne syndrome cells are hypersensitive to killing by ultraviolet radiation. This observation has prompted a wealth of studies on the DNA repair capacity of Cockayne syndrome cells in vitro. Many studies support the notion that such cells are defective in a DNA repair mode(s) that is transcription‐dependent. However, it remains to be established that this is a primary molecular defect in Cockayne syndrome cells and that (...) it explains the complex clinical phenotype associated with the disease. An alternative hypothesis is that Cockayne syndrome cells have a defect in transcription affecting the expression of certain genes, which is compatible with embryogenesis but not with normal post‐natal development. Defective transcription may impair the normal processing of DNA damage during transcription‐dependent repair.‘“Curiouser and curiouser” cried Alice.’ (Lewis Carroll, Alice's Adventures in Wonderland). (shrink)

As recently as six years ago, three human diseases with similar phenotypes were mistakenly believed to be caused by a single genetic defect. The three diseases, Ataxia-telangiectasia, Nijmegen breakage syndrome, and an AT-like disorder are now known, however, to have defects in three separate genes: ATM, NBS1, and MRE11. Furthermore, new recent studies have shown now that all three gene products interact; the ATM kinase phosphorylates NBS1,1 which, in turn, associates with MRE11 to regulate DNA repair. Remarkably or expectedly, depending (...) on one's point of view, the similarity in disease phenotypes is evidently due to defects in a common DNA repair pathway. BioEssays 22:966–969, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

This chapter is concerned with the Cambrian explosion. It considers only one particular kind of explanation for the Cambrian radiation: that major innovations in animal body plan were produced from relatively few genetic changes of large phenotypic effect. It investigates the developmental genetic hypothesis of the origin and maintenance of body plans. This chapter suggests that the genetic architecture underlying body plans was not set during the Cambrian and has been immutable since. It shows that the link between body plan (...) and phylum can become blurry when the minor phyla are considered. (shrink)

Mouse embryo cells, primed to differentiate with the hypomethylating agent 5‐azacytidine (5‐aza‐CR), provide an excellent model system in which cellular differentiation can be studied at the molecular level. An inherent advantage of this system is the availability of clonal populations of cells representative of the non‐differentiated precursor, those whose determinative state is that of a specific lineage, and the end stage, phenotypically mature cell. Analysis of these cultures at the cellular and molecular level will advance our understanding of requirements for (...) and the mechanism of action of growth modulators as well as the necessity for controlled expression of certain proto‐oncogenes. At a more fundamental level, the system can be used to identify, isolate and characterize genes whose expression alters the phenotypic fate of cells. (shrink)

This article is about the governance of expectations of forensic DNA phenotyping (FDP) innovations in Germany used for the prediction of human externally visible traits such as eye, hair, and skin color, as well as biological age and biogeographic ancestry. In 2019, FDP technologies were regulated under the label “extended DNA analysis”. We focus on the expectations of members of the forensic genetics’ community in Germany, in anticipation and response to those of regulators who advocated for such technologies. Confronted (...) with regulators’ expectations of omnipotent technologies and the optimistic promise that they will enhance public security, forensic geneticists responded with attempts to adjust such expectations, specifying limits and risks, along with a particular logic sorting matters of concern. We reflect on how forensic geneticists’ govern expectations through forms of distributed anticipatory governance, delimiting their obligations, and distributing accountability across the criminal justice system. (shrink)

Alternative non‐B‐DNA conformations formed under physiological conditions by sequences called flipons include left‐handed Z‐DNA, three‐stranded triplexes, and four‐stranded i‐motifs and quadruplexes. These conformations accumulate and release energy to enable the local assembly of cellular machines in a context specific manner. In these transactions, nucleosomes store power, serving like rechargeable batteries, while flipons smooth energy flows from source to sink by acting as capacitors or resistors. Here, I review the known biological roles for flipons. I present recent and unequivocal findings showing (...) how innate immune responses are regulated by Z‐flipons that identify endogenous RNAs as self. Evidence is also presented supporting important roles for other flipon classes. In these examples, the dynamic exchange of energy between flipons and nucleosomes enables rapid switching of genetic programs without altering flipon sequence. The increased phenotypic diversity enabled by flipons drives their natural selection, with adaptations evolving faster than is possible by codon mutation alone. (shrink)

The science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, (...) and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology. (shrink)

The “DNA is a program” metaphor is still widely used in Molecular Biology and its popularization. There are good historical reasons for the use of such a metaphor or theoretical model. Yet we argue that both the metaphor and the model are essentially inadequate also from the point of view of Physics and Computer Science. Relevant work has already been done, in Biology, criticizing the programming paradigm. We will refer to empirical evidence and theoretical writings in Biology, although our arguments (...) will be mostly based on a comparison with the use of differential methods (in Molecular Biology: a mutation or alike is observed or induced and its phenotypic consequences are observed) as applied in Computer Science and in Physics, where this fundamental tool for empirical investigation originated and acquired a well-justified status. In particular, as we will argue, the programming paradigm is not theoretically sound as a causal(as in Physics) or deductive(as in Programming) framework for relating the genome to the phenotype, in contrast to the physicalist and computational grounds that this paradigm claims to propose. (shrink)

Transcription‐coupled repair (TCR) is a phenomenon that exists in a wide variety of organisms from bacteria to humans. This mechanism allows cells to repair the actively transcribed DNA strand much faster than the non‐transcribed one. At the sites of bulky DNA damage RNA polymerase stalls, initiating recruitment of the repair machinery. It is a commonly accepted paradigm that bacterial cells utilize a sole coupling factor, called Mfd to initiate TCR. According to that model, Mfd removes transcription complexes stalled at the (...) lesion site and simultaneously recruits repair machinery. However, this model was recently put in doubt by various discrepancies between the proposed universal role of Mfd in the TCR and its biochemical and phenotypical properties. Here, I present a second pathway of bacterial TCR recently discovered in my laboratory, which does not involve Mfd but implicates a common repair factor, UvrD, in a central position in the process. (shrink)

DNA copy number variation (CNV) represents a considerable source of human genetic diversity. Recently,1 a global map of copy number variation in the human genome has been drawn up which reveals not only the ubiquity but also the complexity of this type of variation. Thus, two human genomes may differ by more than 20 Mb and it is likely that the full extent of CNV still remains to be discovered. Nearly 3000 genes are associated with CNV. This high degree of (...) variability with regard to gene copy number between two individuals challenges definitions of normality. Many CNVs are located in regions of complex genomic structure and this currently limits the extent to which these variants can be genotyped by using tagging SNPs. However, some CNVs are already amenable to genome‐wide association studies so that their influence on human phenotypic diversity and disease susceptibility may soon be determined. BioEssays 29:311–313, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

While heredity is predominantly controlled by what deoxyribonucleic acid (DNA) sequences are passed from parents to their offspring, a small but growing number of traits have been shown to be regulated in part by the non‐genetic inheritance of information. Transgenerational epigenetic inheritance is defined as heritable information passed from parents to their offspring without changing the DNA sequence. Work of the past seven decades has transitioned what was previously viewed as rare phenomenology, into well‐established paradigms by which numerous traits can (...) be modulated. For the most part, studies in model organisms have correlated transgenerational epigenetic inheritance phenotypes with changes in epigenetic modifications. The next steps for this field will entail transitioning from correlative studies to causal ones. Here, we delineate the major molecules that have been implicated in transgenerational epigenetic inheritance in both mammalian and non‐mammalian models, speculate on additional molecules that could be involved, and highlight some of the tools which might help transition this field from correlation to causation. (shrink)

Parental effects are a major source of phenotypic plasticity and may influence offspring phenotype in concert with environmental demands. Studies of “environmental epigenetics” suggest that (1) DNA methylation states are variable and that both demethylation and remethylation occur in post‐mitotic cells, and (2) that remodeling of DNA methylation can occur in response to environmentally driven intracellular signaling pathways. Studies of mother‐offspring interactions in rodents suggest that parental signals influence the DNA methylation, leading to stable changes in gene expression. If parental (...) effects do indeed enhance the “match” between prevailing environmental demands and offspring phenotype, then the potential for variation in environmental conditions over time would suggest a mechanism that requires active maintenance across generations through parental signaling. We suggest that parental regulation of DNA methylation states is thus an ideal candidate mechanism for parental effects on phenotypic variation. (shrink)

Genomes are inherently unstable because of the need for DNA sequence variation as a substrate for evolution through natural selection. However, most multicellular organisms have postmitotic tissues, with limited opportunity for selective removal of cells harboring persistent damage and deleterious mutations, which can therefore contribute to functional decline, disease, and death. Key in this process is the role of genome maintenance, the network of protein products that repair DNA damage and signal DNA damage response pathways. Genome maintenance is beneficial early (...) in life by swiftly eliminating DNA damage or damaged cells, facilitating rapid cell proliferation. However, at later ages accumulation of unrepaired damage and mutations, as well as ongoing cell depletion, promotes cancer, atrophy, and other deleterious effects associated with aging. As such, genome maintenance and its phenotypic sequelae provide yet another example of antagonistic pleiotropy in aging and longevity. (shrink)

The current tendency to moderate expectations that DNA barcode can be a method of discovering new species is due to the essentialist interpretation of this scientific analogy that is conceptually unsustainable. Something similar has happened in the philosophical field with the weakening of the initial versions of intrinsic biological essentialism. To examine the nature of this transition, I propose two principles that define a moderate EBI: one that assumes that the history of the taxon is metaphysically dependent on the evolution (...) of its intrinsic properties and another that assumes the necessary coextensivity between the intrinsic properties that explain the phenotype of the species and the bearers of identity conditions of a species. I argue that both principles are conceptually and empirically unsatisfactory. (shrink)

The gain of a selective advantage in cancer as well as the establishment of complex traits during evolution require multiple genetic alterations, but how these mutations accumulate over time is currently unclear. There is increasing evidence that a mutator phenotype perpetuates the development of many human cancers. While in some cases the increased mutation rate is the result of a genetic disruption of DNA repair and replication or environmental exposures, other evidence suggests that endogenous DNA damage induced by AID/APOBEC cytidine (...) deaminases can result in transient localized hypermutation generating simultaneous, closely spaced (i.e. “clustered”) multiple mutations. Here, we discuss mechanisms that lead to mutation cluster formation, the biological consequences of their formation in cancer and evidence suggesting that APOBEC mutagenesis can also occur genome‐wide. This raises the possibility that dysregulation of these enzymes may enable rapid malignant transformation by increasing mutation rates without the loss of fitness associated with permanent mutators. (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.

Studies on Neurospora chromosome segment duplications (Dps) performed since the publication of Perkins's comprehensive review in 1997 form the focus of this article. We present a brief summary of Perkins's seminal work on chromosome rearrangements, specifically, the identification of insertional and quasiterminal translocations that can segregate Dp progeny when crossed with normal sequence strains (i.e., T × N). We describe the genome defense process called meiotic silencing by unpaired DNA that renders Dp‐heterozygous crosses (i.e., Dp × N) barren, which provides (...) a basis for identifying Dps, and discuss whether other processes also might contribute to the barren phenotype of Dp × N and Dp × Dp crosses. We then turn to studies suggesting that large Dps (i.e., >300 kbp) can allow smaller gene‐sized duplications to escape another genome defense process called repeat‐induced point mutation (RIP), possibly by titration of the RIP machinery. Finally, we assess whether in natural populations dominant RIP suppressor Dps provide an “RIP‐free” niche for evolution of new genes following the duplication of existing genes. (shrink)

High‐capacity sequencing technologies have dramatically reduced both the cost and time required to generate complete human genome sequences. Besides expanding our knowledge about existing diversity, the nature of these technologies makes it possible to extend knowledge in yet another dimension: time. Recently, the complete genome sequence of a 4,000‐year‐old human from the Saqqaq culture of Greenland was determined to 20‐fold coverage. These data make it possible to investigate the population affinities of this enigmatic culture and, by identifying several phenotypic traits (...) of this individual, provide a limited glimpse into how these people may have looked. While undoubtedly a milestone in ancient DNA research, the cost to generate an ancient genome, even from such an exceptionally preserved specimen, remains out of reach for most. Nonetheless, recently developed DNA capture methods, already applied to Neanderthal and fossil human mitochondrial DNA, may soon make large‐scale genome‐wide analysis of ancient human diversity a reality, providing a fresh look at human population history. (shrink)

How to interpret the “molecular gene” concept is discussed in this paper. I argue that the architecture of biological systems is hierarchical and multi-layered, exhibiting striking similarities to that of modern computers. Multiple layers exist between the genotype and system level property, the phenotype. This architectural complexity gives rise to the intrinsic complexity of the genotype-phenotype relationships. The notion of a gene being for a phenotypic trait or traits lacks adequate consideration of this complexity and has limitations in explaining the (...) genotype-phenotype relationships. I explore ways toward an integrative interpretation of the gene in the context of multi-layered biological systems. A gene, I argue, should be interpreted as a functional unit that is responsible for the trans-generation passage of the capacity to dynamically produce a biochemical activity or biochemical activities. At the molecular level, a gene is a genetic unit, a stretch of DNA sequence, which dictates the behavior and the dynamic production of the encoded cellular component(s). Embedded in a gene’s quadruple DNA code are the regulatory signals, such as those for RNA splicing and/or editing, as well as for transcription factor binding. A regulatory signal can be recognized by the gene expression machinery in one state, but not in another. The confusion caused by RNA splicing, editing, and a gene’s selective tissue distribution pattern is addressed. Instead of a context-dependent definition of the gene, I argue for the view that it is the same gene displaying multiple meanings, subject to differential interpretation by the cellular machinery in different states. In other words, the same gene gives rise to different products and expression levels under different conditions. (shrink)

Although molecular biology has meant different things at different times, the term is often associated with a tendency to view cellular causation as conforming to simple linear schemas in which macro-scale effects are specified by micro-scale structures. The early achievements of molecular biologists were important for the formation of such an outlook, one to which the discovery of recombinant DNA techniques, and a number of other findings, gave new life even after the complexity of genotype–phenotype
relations had become apparent. Against this (...) background we outline how a range of scientific developments and conceptual considerations can be regarded as enabling and perhaps necessitating contemporary systems approaches. We suggest that philosophical ideas have a valuable part to play in making sense of complex scientific and disciplinary issues. (shrink)

The dialectic discourse of the ‘gene’ as the unit of heredity deduced from the phenotype, whether an intervening variable or a hypothetical construct, appeared to be settled with the presentation of the molecular model of DNA: the gene was reduced to a sequence of DNA that is transcribed into RNA that is translated into a polypeptide; the polypeptides may fold into proteins that are involved in cellular metabolism and structure, and hence function. This path turned out to be more bewildering (...) the more the regulation of products and functions were uncovered in the contexts of integrated cellular systems. Philosophers struggling to define a unified concept of the gene as the basic entity of genetics confronted those who suggested several different ‘genes’ according to the conceptual frameworks of the experimentalists. Researchers increasingly regarded genes de facto as generic terms for describing their empiric data, and with improved DNA-sequencing capacities these entities were as a rule bottom-up nucleotide sequences that determine functions. Only recently did empiricists return to discuss conceptual considerations, including top-down definitions of units of function that through cellular mechanisms select the DNA sequences which comprise ‘genomic-footprints’ of functional entities. (shrink)

Evolutionary stasis is discussed in light of the idea that the common output of every successful evolution is the creation of the entities that are increasingly resistant to further change. The moving force of evolution is entropy. This general aspiration for chaos is a cause of the mortality of organisms and extinction of species. However, being a prerequisite for any motion, entropy generates (by chance) novelties, which may happen to be (by chance) more resistant to further decay and thus survive. (...) The entities that change rapidly disappear. All existing entities are endowed with an ability to resist further change. In simple organisms, the stasis is primarily achieved by means of the high fidelity of DNA reproduction. In organisms with a large genome and complex development, the achievable fidelity of genome reproduction fails to guarantee homeorhetic reproduction: there is more mutation than reproduction. Such species must be capable of surviving and remain phenotypically unchanged at continuous changes of their genes. This capability (canalization or robustness) reflects a global degeneracy of the link structure-function: there are more genotypes than phenotypes. Hence, function (i.e. meaning), not structure, is selected. The selection for successful ontogenesis in a varying environment creates developmental robustness to mutational and environmental perturbations and, consequently, to the halt of evolution. Evolution is resistance to entropy, the adaptation to environment being only one of the means of this resistance. Everything essential in biology is determined not by physical causality but by semantic rules and goal-directed programs. This principal operates on various levels of biological organization. (shrink)

Knowing how introns originated should greatly enhance our understanding of the information we carry in our DNA. Gilbert’s suggestion that introns initially arose to facilitate recombination still stands, though not for the reason he gave. Reanney’s alternative, that evolution, from the early “RNA world” to today’s DNA-based world, would require the ability to detect and correct errors by recombination, now seems more likely. Consistent with this, introns are richer than exons in the potential to extrude the stem-loop structures needed for (...) the homology search that can lead to heteroduplex formation and the recognition of base mismatches. In nucleic acid sequences that were unable concomitantly to encode sufficient stem-loop potential, protein-encoding potential was constrained to arise as segments (exons) interrupted by segments rich in stem-loop potential (introns). Thus, sequences with properties that we now deem intronic are likely to have preceded the emergence of exons. (shrink)