Although DNA microarrays are now widely used in research settings, they have been slow to penetrate clinical practice in spite of their apparent advantages. This is due to the very different requirements for a clinical test in contrast to a research tool, and to a strict necessity for demonstrated clinical utility. There is a clear differentiation between two types of DNA array tests: “genomic” diagnostics, developed to ascertain the presence or absence of mutations, deletions or duplications, and for which (...) clinical evidence is already established, and tests using expression profiling for prognosis or predictive purposes, in which case the clinical correlate must be proven. Most array diagnostics currently used belong, understandably, to the “genomic” variety. It is to be expected that future improvements in tailored technology, as well as a logical trend towards measuring an ever‐increasing number of parameters, will ensure an important diagnostic role for DNA arrays in the coming decade. BioEssays 29:699–705, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

We argue that the most‐promising area of clinical application of microarrays in the foreseeable future is the diagnostics and monitoring of infectious diseases. Microarrays for the detection and characterization of human pathogens have already found their way into clinical practice in some countries. After discussing the persistent, yet often underestimated, importance of infectious diseases for public health, we consider the technologies that are best suited for the detection and clinical investigation of pathogens. Clinical application of microarray technologies for (...) the detection of mycobacteria, Bacillus anthracis, HIV, hepatitis and influenza viruses, and other major pathogens, as well as the analysis of their drug‐resistance patterns, illustrate our main thesis. BioEssays 30:673–682, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Edwin Southern developed a blotting technique for DNA in 1973, thereby creating a staple of molecular biology laboratory procedures still used after several decades. It became a seminal technology for studying the structure of DNA. The story of the creation and dissemination of this technology, which was not patented and was freely distributed throughout the scientific community, stands as a case study in open science. The Southern blot was developed at a time when attitudes about commercial intrusion into health research (...) were beginning to change and the practical value of molecular genetics was becoming apparent to industry. Interest from industry in fundamental molecular biological techniques meant that scientists began to think about commercial uses of their work even in otherwise "basic" research. The unpatented Southern blot is contrasted with later patented technologies, particularly microarray methods, which were created in the same environment by many of the same people, but which followed significant changes to UK policies encouraging commercialization of academic research and a norm shift friendlier to such commercialization within academic molecular biology. Professor Southern's personal experience illuminates how the technologies evolved, and his views provide insight into how scientists' attitudes about commercialization have changed. (shrink)

DNA microarrays are perfectly suited for comparing gene expression in different populations of cells. An important application of microarray techniques is identifying genes which are activated by a particular drug of interest. This process will allow biologists to identify therapies targeted to particular diseases, and, eventually, to gain more knowledge about the biological processes in organisms. Such an application is described in this paper. It is focused on diabetes and obesity, which is a genetically heterogeneous disease, meaning that multiple (...) defective genes are responsible for the diseases. The paper is divided in three parts, each dealing with a different problem addressed to our study. First we validate the data from our microarray experiment. We identified significant systematic sources of variability which are potentially issues for other microarray datasets. Second, we applied multiple hypothesis testing to identify differentially expressed genes. We found a set of genes which appear to change in expression level over time in response to a drug treatment. Third, we tried to address the problem of identification of co-expressed genes using cluster analysis. This last problem is still under discussion. (shrink)

The ethically controversial option of genetic population screening used to be restricted to a small number of rather rare diseases by methodological limitations which are now about to be overcome. With the new technology of DNA microarrays ("DNA chip"), emerging from the synthesis of microelectronics and molecular biology, methods are now at hand for the development of mass screening programmes for a wide spectrum of genetic traits. Thus, the DNA chip may be the key technology for a refined preventive (...) medicine as well as a new dimension of eugenics. The forthcoming introduction of the DNA chip technology into medical practice urgently requires an internationally consistent framework of ethical standards and legal limitations if we do not want it to become a new Pandora's box. (shrink)

In this post‐sequencing era, geneticists can focus on functional genomics on a much larger scale than ever before. One goal is the discovery and elucidation of the intricate genetic networks that co‐ordinate transcriptional activation in different regulatory circuitries. High‐throughput gene expression measurement using DNA arrays has thus become routine strategy. This approach, however, does not directly identify gene loci that belong to the same regulatory group; e.g., those that are bound by a common (set of) transcription factor(s). Working in yeast, (...) two groups have recently published an elegant method that could circumvent this problem, by combining chromatin immunoprecipitation and DNA microarrays.(1,2) The method is likely to provide a powerful tool for the dissection of global regulatory networks in eukaryotic cells. BioEssays 23:473–476, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

DNA arrays have become the preferred method for large-scale expression measurement. Such data are needed in view of the large amounts of sequence data available: expression levels in a number of different tissues or situations provide a first step toward functional characterisation of new entities revealed by DNA sequencing. Although the basic principle of measurement is in all cases based on hybridisation of a mixed probe derived from tissue RNA to large sets of DNA fragments representing many genes, a number (...) of different forms of implementation of this principle are at hand. They are briefly described and compared, emphasizing the important issue of sensitivity and sample requirements and the accessibility of the methods to academic scientists. When these factors are taken into account, it appears that, contrary to a largely prevalent impression, the “best” approach is not necessarily always provided by the widely advertised glass microarrays or oligonucleotide chips. BioEssays 21:781–790, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The generation of patterns and the diversity of cell types in a multicellular organism require differential gene regulation. At the heart of this process are enhancers or cis‐regulatory modules (CRMs), genomic regions that are bound by transcription factors (TFs) that control spatio‐temporal gene expression in developmental networks. To date, only a few CRMs have been studied in detail and the underlying cis‐regulatory code is not well understood. Here, we review recent progress on the genome‐wide identification of CRMs with chromatin immunoprecipitation (...) of TF‐DNA complexes followed by microarrays (ChIP‐on‐chip). We focus on two computational approaches that have succeeded in predicting the expression pattern driven by a CRM either based on TF binding site preferences and their expression levels, or quantitative analysis of CRM occupancy by key TFs. We also discuss the current limits of these methods and highlight some of the key problems that have to be solved to gain a more complete understanding of the structure and function of CRMs. (shrink)

After a vertebrate dies, many of its organ systems, tissues, and cells remain functional while its body no longer works as a whole. We define this state as the “twilight of death” − the transition from a living body to a decomposed corpse. We claim that the study of the twilight of death is important to ethical, legal and medical science. We examined gene expression at the twilight of death in the zebrafish and mouse reaching the conclusion that apparently thousands (...) of transcripts significantly increase in abundance from life to several hours/days postmortem relative to live controls. Transcript dynamics of different genes provided “proof-of-principle” that models accurately predict an individual's elapsed-time-of-death. While many transcripts were associated with survival and stress compensation, others were associated with epigenetic factors, developmental control, and cancer. Future studies are needed to determine whether the high incidence of cancer in transplant recipients is due to the postmortem processes in donor organs. In organismal death, some organ systems, tissues and cells remain functional while the body no longer works as a whole. In the “twilight of death” − the transition from a living body to a decomposed corpse − thousands of gene transcripts increase in abundance relative to live controls. (shrink)

A flurry of technological advances in molecular, cellular and developmental biology during the past decade has provided a clearer understanding of mechanisms underlying phenotypic diversification. Building upon such momentum, a recent paper tackles one of the foremost topics in evolution, that is the origin of species‐specific beak morphology in Darwin's finches.1 Previous work involving both domesticated and wild birds implicated a well‐known signaling pathway (i.e. bone morphogenetic proteins) and one population of progenitor cells in particular (i.e. cranial neural crest), as (...) primary factors for establishing beak size and shape. But these results were limited in their ability to explain fully the morphogenetic bases of patterned outgrowth. So in a quest to identify novel genes whose expression correlated with differences in beak anatomy among Darwin's finches, a DNA microarray approach was undertaken using tissues harvested from the Galápagos Islands. The results are striking and point to a protein called calmodulin, which is a mediator of cellular calcium signaling, as a key determinant of beak length. BioEssays 29: 1–6, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

Cytogenetic research has had a major impact on the field of reproductive medicine, providing an insight into the frequency of chromosomal abnormalities that occur during gametogenesis, embryonic development and pregnancy. In humans, aneuploidy has been found to be relatively common during fetal life, necessitating prenatal screening of high‐risk pregnancies. Aneuploidy rates are higher still during the preimplantation stage of development. An increasing number of IVF laboratories have attempted to improve pregnancy rates by using preimplantation genetic diagnosis (PGD) to ensure that (...) the embryos transferred to the mother are chromosomally normal. This paper reviews some of the techniques that are key to the detection of aneuploidy in reproductive samples including comparative genomic hybridization (CGH). CGH has provided an unparalleled insight into the nature of chromosome imbalance in human embryos and polar bodies. The clinical application of CGH for the purposes of PGD and the future extensions of the methodology, including DNA microarrays, are discussed. BioEssays 25:289–300, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

At the beginning of the 21st century, biology will try to address the function of a large number of new genes. From the perspective of technologies applied today to functional genomics, this task appears to be more complex than the effort invested in the sequencing of the human genome. Conceptually, a high-throughput approach permitting correlation between newly discovered genes and functional properties of their protein products has yet to be developed. To address relationships between tens of thousands of genes and (...) their cognate proteins, novel interdisciplinary technologies need to emerge. In this paper, a new idea of immunomics is presented and an experimental strategy is outlined to circumvent some of the restrictions associated with methodologies currently in use. It is proposed that cloned segments of genomic DNA are used for genetic immunization to obtain a large collection of antibodies, and to generate microarrays of these antibodies for tracing differentially expressed cellular proteins. (shrink)

Increasingly, genomic analysis is being utilized to diagnose children with developmental delay or dysmorphic facial features suggestive of a congenital disorder. Genetic testing has rapidly evolved, and the genome-wide tests that we use today are significantly different from the more targeted single-gene tests of the last decade. Chromosomal microarray analysis is now a first line test for children with multiple birth defects, children with intellectual impairment, and children with an unusual constellation of symptoms that do not fit with a known (...) disease. There are three types of CMA that are currently clinically available. CMA by oligonucleotide array-based comparative genomic hybridization compares the hybridization signal from the patient's DNA to that of a reference DNA sample for each oligonucleotide on the array. Depending on the specific array, this can range from tens of thousands to hundreds of thousands of oligonucleotides. (shrink)

This paper calls fresh attention to ethical problems surrounding prenatal testing by focusing on genetic knowledge gained through evolving testing procedures. Advances in reproductive and prenatal genetic testing include non-invasive tests, such as Verifi and Materniti21, designed to gather detailed information regarding fetal DNA as early as 10 weeks. Meanwhile, a new method of chromosomal microarray has proved more reliable than karyotyping in detecting fetal abnormality. This method detects abnormalities in 1 out of every 60 pregnancies in which karyotyping identified (...) the fetus as “normal.” Chromosomal microarray directly compares fetal DNA to DNA from a presumptively “healthy person” to identify genetic deviations. The chromosomal microarray method thus assumes a human genetic blueprint—that is, a normal genotype, deviance from which is risky and open to medical diagnosis. But, according to philosopher and geneticist Jackie Leach Scully, there is no genetic blueprint for human beings. Rather, genetic variation is constant. Thus, notes Scully, genetic discourse could free medical discourse from the dictates of the binary between normal and abnormal, although mistaken belief in a genetic blueprint can foil this alternative way of speaking and thinking. Prenatal testing has received critical philosophical attention from both disability theorists and feminists. Adrienne Asch suggests that prenatal testing and diagnosis stigmatizes already-existing persons with disabilities by suggesting that bodily deviance is intolerable. Licia Carlson coined the phrase “prenatal prototypes” to describe the obfuscating results of genetic profiling carried out on the fetus. The philosophical conversation Asch and Carlson stimulate involves higher stakes now that testing uncovers fetal genotype and reveals mere genetic deviation in order to aid reproductive decision-making. I argue that prenatal testing, and especially the most recently developed testing procedures described above, forecloses Scully’s alternative discourse of genetic variation by supporting an ideal of a singular “healthy genotype,” deviance from which is to be uncovered and avoided. Mobilizing this insight by drawing on the work of feminist disability scholars like Asch and Carlson, I seek to foreground the play between norm and deviance. I expose the normalizing field of statistical risk, operating in excess of medical diagnosis, which requires potential parents to manage and avoid deviance itself. (shrink)

Increasingly, genomic analysis is being utilized to diagnose children with developmental delay or dysmorphic facial features suggestive of a congenital disorder. Genetic testing has rapidly evolved, and the genome-wide tests that we use today are significantly different from the more targeted single-gene tests of the last decade. Chromosomal microarray analysis is now a first line test for children with multiple birth defects, children with intellectual impairment, and children with an unusual constellation of symptoms that do not fit with a known (...) disease. There are three types of CMA that are currently clinically available. CMA by oligonucleotide array-based comparative genomic hybridization compares the hybridization signal from the patient's DNA to that of a reference DNA sample for each oligonucleotide on the array. Depending on the specific array, this can range from tens of thousands to hundreds of thousands of oligonucleotides. (shrink)

Detection of genetic aberrations in prenatal samples, obtained through amniocentesis or chorion villus biopsy, is increasingly performed using chromosomal microarray, a technique that can uncover both aneuploidies and copy number variants throughout the genome. Despite the obvious benefits of CMA, the decision on implementing the technology is complicated by ethical issues concerning variant interpretation and reporting. In Belgium, uniform guidelines were composed and a shared database for prenatal CMA findings was established. This Belgian approach sparks discussion: it is evidence-based, prevents (...) inconsistencies and avoids parental anxiety, but can be considered paternalistic. Here, we reflect on the cultural and moral bases of the Belgian reporting system of prenatally detected variants. (shrink)

DNA topoisomerases, capable of manipulating DNA topology, are ubiquitous and indispensable for cellular survival due to the numerous roles they play during DNA metabolism. As we review here, current structural approaches have revealed unprecedented insights into the complex DNA‐topoisomerase interaction and strand passage mechanism, helping to advance our understanding of their activities in vivo. This has been complemented by single‐molecule techniques, which have facilitated the detailed dissection of the various topoisomerase reactions. Recent work has also revealed the importance of topoisomerase (...) interactions with accessory proteins and other DNA‐associated proteins, supporting the idea that they often function as part of multi‐enzyme assemblies in vivo. In addition, novel topoisomerases have been identified and explored, such as topo VIII and Mini‐A. These new findings are advancing our understanding of DNA‐related processes and the vital functions topos fulfil, demonstrating their indispensability in virtually every aspect of DNA metabolism. (shrink)

DNA methylation is a repressive epigenetic mark vital for normal development. Recent studies have uncovered an unexpected role for the DNA methylome in ensuring the correct targeting of the Polycomb repressive complexes throughout the genome. Here, we discuss the implications of these findings for cancer, where DNA methylation patterns are widely reprogrammed. We speculate that cancer‐associated reprogramming of the DNA methylome leads to an altered Polycomb binding landscape, influencing gene expression by multiple modes. As the Polycomb system is responsible for (...) the regulation of genes with key roles in cell fate decisions and cell cycle regulation, DNA methylation induced Polycomb mis‐targeting could directly drive carcinogenesis and disease progression.Editor's suggested further reading in BioEssays Unmasking risk loci: DNA methylation illuminates the biology of cancer predisposition Abstract. (shrink)

DNA methylation can be considered a component of epigenetic memory with a critical role during embryo development, and which undergoes dramatic reprogramming after fertilization. Though it has been a focus of research for many years, the reprogramming mechanism is still not fully understood. Recent results suggest that absence of maintenance at DNA replication is a major factor, and that there is an unexpected role for TET3-mediated oxidation of 5mC to 5hmC in guarding against de novo methylation. Base-resolution and genome-wide profiling (...) methods are enabling more comprehensive assessments of the extent to which ART might impair DNA methylation reprogramming, and which sequence elements are most vulnerable. Indeed, as we also review here, studies showing the effect of culture media, ovarian stimulation or embryo transfer on the methylation pattern of embryos emphasize the need to face ART-associated defects and search for strategies to mitigate adverse effects on the health of ART-derived children. DNA methylation, critical for embryo development, suffers significant changes after fertilization, including demethylation, remethylation and TET3-mediated oxidation of 5 mC to 5 hmC. In addition to infertility and environmental insults, ART could impact DNA methylation and ART related consequences in the offspring have been reported. (shrink)

The nuclear pore complex (NPC) is emerging as a center for recruitment of a class of “difficult to repair” lesions such as double‐strand breaks without a repair template and eroded telomeres in telomerase‐deficient cells. In addition to such pathological situations, a recent study by Su and colleagues shows that also physiological threats to genome integrity such as DNA secondary structure‐forming triplet repeat sequences relocalize to the NPC during DNA replication. Mutants that fail to reposition the triplet repeat locus to the (...) NPC cause repeat instability. Here, we review the types of DNA lesions that relocalize to the NPC, the putative mechanisms of relocalization, and the types of recombinational repair that are stimulated by the NPC, and present a model for NPC‐facilitated repair. (shrink)

DNA barcodes, like traditional sources of taxonomic information, are potentially powerful heuristics in the identification of described species but require mindful analytical interpretation. The role of DNA barcoding in generating hypotheses of new taxa in need of formal taxonomic treatment is discussed, and it is emphasized that the recursive process of character evaluation is both necessary and best served by understanding the empirical mechanics of the discovery process. These undertakings carry enormous ramifications not only for the translation of DNA sequence (...) data into taxonomic information but also for our comprehension of the magnitude of species diversity and its disappearance. This paper examines the potential strengths and pitfalls of integrating DNA sequence data, specifically in the form of DNA barcodes as they are currently generated and analyzed, with taxonomic practice. (shrink)

This Christian sermon uses a DNA lab experience as a basis for theological reflection on ourselves and our offering. Who are we to God? What determines the self that we offer? Can the alphabet of DNA shed light for us on the Word of God in our lives? This first attempt to introduce the language and laboratory environment of genetic testing (represented by DNA fingerprinting) within a parish preaching context juxtaposes liturgical, scientific, and biblical language and settings for fresh insights.

Through analysis of film sequences focusing on DNA in two British Broadcasting Corporation nonfiction science television programs, Wonders of Life and Bang! Goes the Theory, first broadcast in 2013, contrasting “religious” and “secular” representations of science are identified. In the “religious” portrayal, immutable scientific knowledge is revealed to humanity by nature with minimal human intervention. Science provides a creation story, “explanatory omnicompetence,” and makes life existentially meaningful. In the “secular” portrayal, scientific knowledge is changeable; is produced through technical skill in (...) expert communities; and is ambiguous, potentially positive and negative for society. Television representations of science affect audience understandings, and this is particularly the case for nonfiction representations of science, as they are likely to be “taken more seriously” than fictional representations. The consequences of the “religious” representation of science are discussed, and it is argued that a widespread understanding of science as presented in the religious portrayal would negatively impact democracy. (shrink)

This paper focuses on the question of whether DNA patents help or hinder scientific discovery and innovation. While DNA patents create a wide variety of possible benefits and harms for science and technology, the evidence we have at this point in time supports the conclusion that they will probably promote rather than hamper scientific discovery and innovation. However, since DNA patenting is a relatively recent phenomena and the biotechnology industry is in its infancy, we should continue to gather evidence about (...) the effects of DNA patenting on scientific innovation and discovery as well the economic, social, and legal conditions relating to intellectual property in biotechnology. We should give the free market, the courts, researchers, and patent offices a chance to settle issues related to innovation and discovery, before we seek legislative remedies, since new laws proposed at this point would lack adequate foresight and could do more harm than good. However, we should be open to new laws or regulations on DNA patents if they are required to in order to deal with some of the biases and limitations of the free market. (shrink)

Science; Ethics; Politics; Beyond recombinant dna.

DNA supercoiling is one of the mechanisms that can help unlinking of newly replicated DNA molecules. Although DNA topoisomerases, which catalyze the strand passing of DNA segments through one another, make the unlinking problem solvable in principle, it remains difficult to complete the process that enables the separation of the sister duplexes. A few different mechanisms were developed by nature to solve the problem. Some of the mechanisms are very intuitive while the others, like topology simplification by type II DNA (...) topoisomerases and DNA supercoiling, are not so evident. A computer simulation and analysis of linked sister plasmids formed inEscherichia colicells with suppressed topoisomerase IV suggests an insight into the latter mechanism. (shrink)

Abstract6‐methyladenine (6mA) is fairly abundant in nuclear DNA of basal fungi, ciliates and green algae. In these organisms, 6mA is maintained near transcription start sites in ApT context by a parental‐strand instruction dependent maintenance methyltransferase and is positively associated with transcription. In animals and plants, 6mA levels are high only in organellar DNA. The 6mA levels in nuclear DNA are very low. They are attributable to nucleotide salvage and the activity of otherwise mitochondrial METTL4, and may be considered as a (...) price that cells pay for adenine methylation in RNA and/or organellar DNA. Cells minimize this price by sanitizing dNTP pools to limit 6mA incorporation, and by converting 6mA that has been incorporated into DNA back to adenine. Hence, 6mA in nuclear DNA should be described as an epigenetic mark only in basal fungi, ciliates and green algae, but not in animals and plants. (shrink)

The aim of this paper is to explain the emergence and use of DNA fingerprinting technology in India, noting the specific concerns faced by the Indian Legal System related to the use of this novel forensic technology in the justice process. Furthermore, the proposed construction of a National DNA Data Bank is discussed taking into consideration the challenges faced by the government in legislating the DNA Bill into law. A critical analysis of the DNA Technology (Use and Application) Regulation Bill, (...) 2019 is provided to throw light upon many ethical, social, and legal issues that need to be addressed before the operationalization of the Bill to ensure that this technology is governed democratically to protect the civil liberties of citizens. (shrink)

The regulation of DNA replication is a fascinating biological problem both from a mechanistic angle—How is replication timing regulated?—and from an evolutionary one—Why is replication timing regulated? Recent work has provided significant insight into the first question. Detailed biochemical understanding of the mechanism and regulation of replication initiation has made possible robust hypotheses for how replication timing is regulated. Moreover, technical progress, including high‐throughput, single‐molecule mapping of replication initiation and single‐cell assays of replication timing, has allowed for direct testing of (...) these hypotheses in mammalian cells. This work has consolidated the conclusion that differential replication timing is a consequence of the varying probability of replication origin initiation. The second question is more difficult to directly address experimentally. Nonetheless, plausible hypotheses can be made and one—that replication timing contributes to the regulation of chromatin structure—has received new experimental support. (shrink)

The pedagogical function of science teaching may benefit from an analysis of the historical-epistemic dimension, without neglecting the socio-political context in which a given research was carried out. In the case of DNA structure, the background of its discovery is particularly complex. Starting from the analysis of some papers, the view on the circumstances that led to their drafting broadens. We try to answer the fundamental question for any educator: why teach all that? Ethics issues are related to the general (...) organisation of research, increasingly focused on speed and competition. Even teaching is affected by these dynamics, not only in higher education, but also at secondary level; students should be made aware of this trend. The history of science could therefore favour a more general awareness. _SUNTO_ La funzione pedagogica dell’insegnamento scientifico può trarre vantaggio da un’analisi della dimensione storico-epistemica, senza trascurare il contesto socio-politico nel quale una determinata ricerca è stata condotta. Nel caso della struttura del DNA, i retroscena della sua scoperta sono particolarmente complessi. Dopo l’analisi di alcuni articoli, si allarga gradualmente la vista sulle circostanze che hanno condotto alla loro stesura. Si cerca di rispondere a una domanda fondamentale per ogni educatore: perché insegnare tutto ciò? Le questioni etiche riguardano l’organizzazione generale della ricerca, sempre più tesa alla velocità e alla competizione. Persino l’insegnamento è influenzato da dinamiche simili, non solo in ambito accademico, ma anche a livello secondario; gli studenti dovrebbero essere a conoscenza di questa tendenza. La storia della scienza può dunque favorire una maggiore consapevolezza. (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)

Phage DNA packaging occurs by DNA translocation into a prohead. Terminases are enzymes which initiate DNA packaging by cutting the DNA concatemer, and they are closely fitted structurally to the portal vertex of the prohead to form a ‘packasome’. Analysis among a number of phages supports an active role of the terminases in coupling ATP hydrolysis to DNA translocation through the portal. In phage T4 the small terminase subunit promotes a sequence‐specific terminase gene amplification within the chromosome. This link between (...) recombination and packaging suggests a DNA synapsis mechanism by the terminase to control packaging initiation, formally homologous to eukaryotic chromosome segregation. (shrink)

The sciences of genetics and genomics are revealing more all the time regarding our statuses as individuals relative to our particular genomes. Geographical isolation is presumably the greatest factor in allowing for populations of a species to change genetically over time, in response to environmental pressures and genetic drift accelerated by the mechanism of sexual reproduction. In order to develop a robust account of what rights individual members of the human species might have to either their own particular DNA or (...) the human genome in general, one need to explain the relations between individuals and species in regards to deoxyribonucleic acid (DNA). The fact that genes carry over from species to species does not mean that those genes are completely identical across all species. Laws and regulations exist that govern the use of human tissues and property rights over their products. (shrink)

The model of DNA-histones has the following elements: The hydrogen bonds between the complementary nucleotide bases function as informational gates. When the electrons π of one nucleotide base are excited, an exchange of protons is produced between the two complementary bases. The result is the displacement of the conjugated double bonds which facilitates the inter-molecular transmission of the electronic wave of excitation by electro-magnetic coupling. Each triplet of nucleotide bases of DNA fixes one definite amino acid . Between the nucleotide (...) bases and the amino acids there are constituted informational gates, which ensure the circulation of the electronic wave of excitation. An input signal molecule arrives at the receiver gene and unleashes the activity of the enzymes which introduce in the DNA-histones system the electronic wave of excitation. The electronic wave of excitation arises as a result of the break of the high-energy bonds of ATP. Then, the electronic excitation is transmitted to the productor gene where it represents the signal for starting the synthesis of the mRNA.Le modèle de système ADN-Histone a les éléments suivants: Les liaisons d'hydrogène entre les bases nucléotidiques complémentaires fonctionnent comme des portes informationnelles. Quand les électrons π d'une base nucléotidique sont excités, il se produit un échange de protons entre les bases complémentaires. Le résultat est un déplacement des doubles liaisons conjugées qui facilite la transmission de l'onde d'excitation électronique par un couplage électromagnétique. Chaque triplet de bases nucléotidiques de l'ADN fixe un certain amino-acide . Entre les bases nucléodiques et les amino-acides se constituent des portes informationnelles qui assurent la circulation de l'onde d'excitation dlectronique. Une molécule signal d'entrée arrive au gène récepteur et déclenche l'activité des enzymes qui introduisent dans le système ADN-histone l'excitation électronique. L'excitation électronique apparait comme résultat de la rupture des liaisons de haute énergie del' ATP. l'Onde d'excitation électronique est transmise au gène producteur, où elle rdprésente le signal pour faire commencer la synthèse de l'ARNm.Das Modell des DNS-Histonen Systems weist folgende Elemente auf: Die Wasserstoffbindungen zwischen den komplementäaren Nukleotidbasen funktionieren wie informationale Pforten. Wenn die π Elektronen einer Nukleotidbase erregt werden, ensteht ein Protonenwechsel zwischen den Komplementären Basen. Das Ergebnis ist eine Verschiebung der konjugierten Doppelbindungen, die die Weiterleitung der elektronischen Erregungswelle durch eine elektromagnetische Kupplung erleichtert. Jedes Nukleotidbasentriplett der DNS fixiert eine bestimmte Aminosäure . Zwischen den Nukelotidbasen und den Aminosäuren entstehen Informationspforten, welche den Umlauf der elektronischen Erregungswelle sichern. Ein Eintrittsignal Moleküul gelangt zur Rezeptorgen und löst die Aktivität von Enzymen aus, welche die elektronische Erregungswelle in das DNS-Histonen System einführen werden. Die elektronische Erregungswelle erscheint als Ergebnis der Spaltung der hochenergetischen Bindungen des ATP-s. Die elektronische Erregungswelle wird alsdann zur Produktorgen weitergeleitet, wo sie das Signal zum Beginn der Synthese der mRNS darstellt. (shrink)

Type II DNA topoisomerase activity is required to change DNA topology. It is important in the relaxation of DNA supercoils generated by cellular processes, such as transcription and replication, and it is essential for the condensation of chromosomes and their segregation during mitosis. In mammals this activity is derived from at least two isoforms, termed DNA topoisomerase IIα and β. The α isoform is involved in chromosome condensation and segregation, whereas the role of the β isoform is not yet clear. (...) DNA topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the last 10 years. BioEssays 20:215–226, 1998.© 1998 John Wiley & Sons, Inc. (shrink)

Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its regulation. Dissection (...) of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control. Torsional stress, and supercoiling generated by transcription, shape the topology of DNA. Furthermore, the resultant secondary DNA structures and their interacting partners provide feedback to regulate gene expression. Emerging evidence suggests these mechanisms, identified through analysis of the MYC promoter, are applicable genome-wide. (shrink)

Over 30 million people worldwide have taken a commercial at-home DNA test, because they were interested in their genetic ancestry, disease predisposition or inherited traits. Yet, these consumer DNA data are also increasingly used for a very different purpose: to identify suspects in criminal investigations. By matching a suspect’s DNA with DNA from a suspect’s distant relatives who have taken a commercial at-home DNA test, law enforcement can zero in on a perpetrator. Such forensic use of consumer DNA data has (...) been performed in over 200 criminal investigations. However, this practice of so-called investigative genetic genealogy raises ethical concerns. In this paper, we aim to broaden the bioethical analysis on IGG by showing the limitations of an individual-based model. We discuss two concerns central in the debate: privacy and informed consent. However, we argue that IGG raises pressing ethical concerns that extend beyond these individual-focused issues. The very nature of the genetic information entails that relatives may also be affected by the individual customer’s choices. In this respect, we explore to what extent the ethical approach in the biomedical genetic context on consent and consequences for relatives can be helpful for the debate on IGG. We argue that an individual-based model has significant limitations in an IGG context. The ethical debate is further complicated by the international, transgenerational and commercial nature of IGG. We conclude that IGG should not only be approached as an individual but also—and perhaps primarily—as a collective issue. There are no data in this work. (shrink)

Eminent scientists are well-placed to bring the novel works of others, even if not in their own areas of expertise, to general attention. In so doing, they may be able to extend original accounts or introduce new terminologies, but they are basically messengers, not innovators. In the 1940s an evolutionary theory of biological aging was explained by Peter Medawar, and informational concepts relating to DNA were explained by Erwin Schrödinger. Both explanations were eventually traced back to the Victorian polymath Samuel (...) Butler—one by Medawar’s research associate Alex Comfort, and the other, albeit indirectly, by Schrödinger himself. In his time Butler’s works were too erudite for general readers and too laden with populist jargon for contemporary experts to take seriously. However, today it appears counterfactually plausible that an early acceptance of his ideas would have greatly quickened the pace of research. (shrink)

Recent studies based on next‐generation DNA sequencing have revealed that the female inactive X chromosome is replicated in a rapid, unorganized manner, and undergoes increased rates of mutation. These observations link the organization of DNA replication timing to gene regulation on one hand, and to the generation of mutations on the other hand. More generally, the exceptional biology of the inactive X chromosome highlights general principles of genome replication. Cells may control replication timing by a combination of intrinsic replication origin (...) properties, local chromatin states and global levels of replication factors, leading to a functional separation between the activity of genes and their mutation. (shrink)

DNA helicases catalyze the disruption of the hydrogen bonds that hold the two strands of double‐stranded DNA together. This energy‐requiring unwinding reaction results in the formation of the single‐stranded DNA required as a template or reaction intermediate in DNA replication, repair and recombination. A combination of biochemical and genetic studies have been used to probe and define the roles of the multiple DNA helicases found in E. coli. This work and similar efforts in eukaryotic cells, although far from complete, have (...) established that DNA helicases are essential components of the machinery that interacts with the DNA molecule. (shrink)

DNA methylation is a quintessential epigenetic mechanism. Widely considered a stable regulator of gene silencing, it represents a form of “molecular braille,” chemically printed on DNA to regulate its structure and the expression of genetic information. However, there was a time when methyl groups simply existed in cells, mysteriously speckled across the cytosine building blocks of DNA. Why was the code of life chemically modified, apparently by “no accident of enzyme action” (Wyatt 1951 )? If all cells in a body (...) share the same genome sequence, how do they adopt unique functions and maintain stable developmental states? Do cells remember? In this historical perspective, I review epigenetic history and principles and the tools, key scientists, and concepts that brought us the synthesis and discovery of prokaryotic and eukaryotic methylated DNA. Drawing heavily on Gerard Wyatt’s observation of asymmetric levels of methylated DNA across species, as well as to a pair of visionary 1975 DNA methylation papers, 5-methylcytosine is connected to DNA methylating enzymes in bacteria, the maintenance of stable cellular states over development, and to the regulation of gene expression through protein-DNA binding. These works have not only shaped our views on heritability and gene regulation but also remind us that core epigenetic concepts emerged from the intrinsic requirement for epigenetic mechanisms to exist. Driven by observations across prokaryotic and eukaryotic worlds, epigenetic systems function to access and interpret genetic information across all forms of life. Collectively, these works offer many guiding principles for our epigenetic understanding for today, and for the next generation of epigenetic inquiry in a postgenomics world. (shrink)

For nearly two decades, nonengineered human DNA was patented without challenge. The US Supreme Court recently agreed that many of those patents do not fit accurately into any currently accepted scheme of intellectual property protection. One should consider: whether DNA fits into other forms of property protection (land, moveables, chattels, etc.); whether DNA warrants a new and unique form of property protection, or whether DNA belongs to the class of objects generally considered to be as “the commons.” Current schemes of (...) patent protection for genes are entirely new, unwarranted by precedent, and utterly aberrant in applying the law of patent. Nonetheless, it bears examining how intellectual property schemes might serve as guidance for new forms of intellectual property protection for genes, if indeed those genes fit into classical dimensions of intellectual property. Private ownership of property has emerged as the dominant legal institution covering modes of possession. (shrink)

This chapter contains sections titled: Current Schemes of Intellectual Property Protection Existing Forms of Property Protection Brute Facts and Genes Unique Property Protection for DNA? The Notion of the Commons The Commons as a Choice The Commons by Necessity DNA as a Commons Is DNA More like Ideas or Radio Spectra?

DNA topoisomerases are enzymes that can modify, and may regulate, the topological state of DNA through concerted breaking and rejoining of the DNA strands. They have been believed to be directly involved in DNA excision repair, and perhaps to be required for the control of repair as well. The vicissitudes of this hypothesis provide a noteworthy example of the dangers of interpreting cellular phenomena without genetic information and vice versa.

While large portions of the mammalian genome are known to replicate sequentially in a distinct, tissue‐specific order, recent studies suggest that the inactive X chromosome is duplicated rapidly via random, synchronous DNA synthesis at numerous adjacent regions. The rapid duplication of the inactive X chromosome was observed in high‐resolution studies visualizing DNA replication patterns in the nucleus, and by allele‐specific DNA sequencing studies measuring the extent of DNA synthesis. These studies conclude that inactive X chromosomes complete replication earlier than previously (...) thought and suggest that the strict order of DNA replication detected in the majority of genomic regions is not preserved in non‐transcribed, “silent” chromatin. These observations alter current concepts about the regulation of DNA replication in non‐transcribed portions of the genome in general and in the inactive X‐chromosome in particular. (shrink)

DNA with a curved trajectory of its helix axis is called bent DNA, or curved DNA. Interestingly, biologically important DNA regions often contain this structure, irrespective of the origin of DNA. In the last decade, considerable progress has been made in clarifying one role of bent DNA in prokaryotic transcription and its mechanism of action. However, the role of bent DNA in eukaryotic transcription remains unclear. Our recent study raises the possibility that bent DNA is implicated in the “functional packaging” (...) of transcriptional regulatory regions into chromatin. In this article, I review recent progress in bent DNA research in eukaryotic transcription, and summarize the history of bent DNA research and several subjects relevant to this theme. Finally, I propose a hypothesis that bent DNA structures that mimic a negative supercoil, or have a right‐handed superhelical writhe, organize local chromatin infrastructure to help the very first interaction between cis‐acting DNA elements and activators that trigger transcription. BioEssays 23:708–715, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

As nation-states make greater efforts to regulate the flow of people on the move—refugees, economic migrants, and international travelers alike—advocates of DNA profiling technologies claim DNA testing provides a reliable and objective way of revealing a person’s true identity for immigration procedures. This article examines the use of DNA testing for family reunification in immigration cases in Finland, Germany, and the United States—the first transatlantic analysis of such cases—to explore the relationship between technology, the meaning of family, and immigration. Drawing (...) on our analyses of archival records, government documents, and interviews with immigration stakeholders, we argue that DNA testing is not conclusive about the meaning of family. While the technology may facilitate decision making for both would-be immigrants and state officials, our study shows hesitancy among the latter to let DNA testing make the final determination. We introduce the concept of social validity—whether the interpretation of test results matches social or political meanings in a given local context—in order to make sense of the complexities and challenges of DNA testing in practice. We show that DNA testing is not just a technology of belonging or a way to claim citizenship rights. It may also enable exclusion and denial of rights. (shrink)

Methylation of DNA plays an important role in the control of gene expression in higher eukaryotes. This is largely achieved by the packaging of methylated DNA into chromatin structures that are inaccessible to transcription factors and other proteins. Methylation involves the addition of a methyl group to the 5‐position of the cytosine base in DNA, a reaction catalysed by a DNA (cytosine‐5) methyltransferase. This reaction occurs in nuclear replication foci where the chromatin structure is loosened for replication, thereby allowing access (...) to methyltransferases. Partly as a result of their recognising the presence of a methylcytosine on the parental strand following replication, these large enzymes are able to maintain the distribution of methyl groups along the DNA of somatic cells and, thereby, maintain tissue‐specific patterns of gene expression. (shrink)

Paradoxically, DNA sequence polymorphisms in cancer risk loci rarely correlate with the expression of cancer genes. Therefore, the molecular mechanism underlying an individual's susceptibility to cancer has remained largely unknown. However, recent evaluations of the correlations between DNA methylation and gene expression levels across healthy and cancerous genomes have revealed enrichment of disease‐related DNA methylation variations within disease‐associated risk loci. Moreover, it appears that transcriptional enhancers embedded in cancer risk loci often contain DNA methylation sites that closely define the expression (...) of prominent cancer genes, despite the lack of significant correlations between gene expression levels and the surrounding disease‐associated polymorphic sequences. We suggest that DNA methylation variations may obscure the effect of co‐residing risk sequence alleles. Analysis of enhancer methylation data may help to reveal the regulatory circuits underlying predisposition to cancers and other common diseases.Editor's suggested further reading in BioEssays DNA methylation reprogramming in cancer: Does it act by re‐configuring the binding landscape of Polycomb repressive complexes? Abstract. (shrink)