During the last few months, several pioneer genome‐wide transcriptomic, proteomic and metabolomic studies have revolutionised the understanding of bacterial biological processes, leading to a picture that resembles eukaryotic complexity. Technological advances such as next‐generation high‐throughput sequencing and high‐density oligonucleotide microarrays have allowed the determination, in several bacteria, of the entire boundaries of all expressed transcripts. Consequently, novel RNA‐mediated regulatory mechanisms have been discovered including multifunctional RNAs. Moreover, resolution of bacterial proteome organisation (interactome) and global protein localisation (localizome) have (...) unveiled an unanticipated complexity that highlights the significance of protein multifunctionality and localisation in the cell. Also, analysis of a complete bacterial metabolic network has again revealed a high fraction of multifunctional enzymes and an unexpectedly high level of metabolic responses and adaptation. Altogether, these novel approaches have permitted the deciphering of the entire physiological landscape of one of the smallest bacteria, Mycoplasma pneumoniae. Here, we summarise and discuss recent findings aimed at defining the blueprint of any prokaryote. (shrink)

In this review we highlight the importance of defining the untranslated parts of transcripts, and present a number of computational approaches for the discovery and quantification of alternative transcription start and poly-adenylation events in high-throughput transcriptomic data. The fate of eukaryotic transcripts is closely linked to their untranslated regions, which are determined by the position at which transcription starts and ends at a genomic locus. Although the extent of alternative transcription starts and alternative poly-adenylation sites has been revealed by sequencing (...) methods focused on the ends of transcripts, the application of these methods is not yet widely adopted by the community. We suggest that computational methods applied to standard high-throughput technologies are a useful, albeit less accurate, alternative to the expertise-demanding 5′ and 3′ sequencing and they are the only option for analysing legacy transcriptomic data. We review these methods here, focusing on technical challenges and arguing for the need to include better normalization of the data and more appropriate statistical models of the expected variation in the signal. We highlight the importance of defining the untranslated parts of transcripts, and present a number of computational approaches for the discovery and quantification of alternative transcription start site and alternative poly-adenylation events from standard high-throughput transcriptomic data. We discuss the challenges faced by these methods and argue for the use of better statistical models for dealing with biases in the data and variation in the signal. (shrink)

New genes have frequently formed and spread to fixation in a wide variety of organisms, constituting abundant sets of lineage‐specific genes. It was recently reported that an excess of primate‐specific and human‐specific genes were upregulated in the brains of fetuses and infants, and especially in the prefrontal cortex, which is involved in cognition. These findings reveal the prevalent addition of new genetic components to the transcriptome of the human brain. More generally, these findings suggest that genomes are continually evolving (...) in both sequence and content, eroding the conservation endowed by common ancestry. Despite increasing recognition of the importance of new genes, we highlight here that these genes are still seriously under‐characterized in functional studies and that new gene annotation is inconsistent in current practice. We propose an integrative approach to annotate new genes, taking advantage of functional and evolutionary genomic methods. We finally discuss how the refinement of new gene annotation will be important for the detection of evolutionary forces governing new gene origination. (shrink)

The role of gene expression in evolutionary adaptation has been a subject of debate for over 40 years.cis‐regulation of transcription has been proposed to be the primary source of morphological novelty in evolution, though this is based on only a handful of examples. Recently the first genome‐wide studies of gene expression adaptation have been published, giving us an initial global view of this process. Systematic studies such as these will allow a number of key questions currently facing the (...) field of gene expression evolution to be addressed. (shrink)

Madole & Harden's assertion that the effects derived from within-family genome-wide association studies (GWASs) and from randomized controlled trials (RCTs) are equivalent is misleading. GWASs are substantially more “non-unitary, non-uniform, and non-explanatory” than RCTs. While the within-family GWAS bring us closer to identifying genetic causes, whether it will change behavioral genetics into a causal science is an open question.

Higher states of consciousness in which the human mind can transcend the boundaries of logic and reason are envisioned as natural to the experience and potential growth of every human being. So far they have been mostly monitored by electrophysiological methods. In this study we were particularly interested in discovering the molecular transcriptional basis of higher states of consciousness. In addition to phenomenological reports of meditators who participated in this study the generated higher states of consciousness were also EEG recorded. (...) We assessed the whole genome gene expression analysis of long-term meditators in four separate trials and detected significant differential gene expression in association with higher states of consciousness. The number of differently expressed genes as well as high proportion of genes themselves differed between meditators. Despite this, gene ontology enrichment analysis found significant biological and molecular processes shared among meditators’ higher state of consciousness. (shrink)

Polygenic scores (PGSs) have several limitations. They are confounded with environmental effects on behavior and cannot be used to study how mutations affect brain function and behavior. For this, mutations with large effects, which often arise in only one geographical population are needed. Genome-wide association studies (GWASs), commonly used for identifying mutations, have difficulty detecting these mutations. A strategy that overcomes this challenge is discussed.

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)

Whether, and to what degree, do patents granted on human genes cast a shadow of uncertainty over genomics and its applications? Will owners of patents on individual genes or clusters of genes sue those performing whole-genome analyses on human samples for patent infringement? These are related questions that have haunted molecular diagnostics companies and services, coloring scientific, clinical, and business decisions. Can the profusion of whole-genome analysis methods proceed without fear of patent infringement liability?Whole-genome sequencing is proceeding (...) apace. Academic centers have been performing whole-genome and -exome sequencing in research for at least five years, and academic clinical laboratories with national reach have been doing sequencing for clinical applications for almost as long. Companies have also been offering WGS and WES as a clinical service for a few years now. So far as we know, no one has been sued for infringement of “gene patents” for performing WGS. (shrink)

We address Turkheimer’s argument that genome-wide association studies of behaviors and psychiatric traits will fail to produce coherent explanations. We distinguish two major sources of potential i...

In this article we examine the “phenotype” concept in light of recent technological advances in Genome-Wide Association Studies . By observing the technology and its presuppositions, we put forward the thesis that at least in this case genotype and phenotype are effectively coidentifled one by means of the other. We suggest that the coidentiflcation of genotype-phenotype couples in expression-based GWAS also indicates a conceptual dependence, which we call “co-deñnition.” We note that viewing these terms as codeflned runs against (...) possible expectations, viz., that genotypes and phenotypes could ultimately be expressed independently from one another. In addition, the co-definition of genotypes and phenotypes in this context emphasizes the correlative character of both genotypes and phenotypes in GWAS. (shrink)

A recent analysis of the genomes of Darwin's finches revealed extensive interspecies allele sharing throughout the history of the radiation and identified a key locus responsible for morphological evolution in this group. The radiation of Darwin's finches on the Galápagos archipelago has long been regarded as an iconic study system for field ecology and evolutionary biology. Coupled with an extensive history of field work, these latest findings affirm the increasing acceptance of introgressive hybridization, or gene flow between species, as a (...) significant contributor to adaptive evolution. Here, we review and discuss these findings in relation to both classical work on Darwin's finches and contemporary work showing similar evolutionary signatures in other biological systems. The continued unification of genomic data with field biology promises to further elucidate the molecular basis of adaptation in Darwin's finches and well beyond. (shrink)

Recent years have witnessed an explosion of the single-cell biochemical toolbox including chromosome conformation capture -based methods that provide novel insights into chromatin spatial organization in individual cells. The observations made with these techniques revealed that topologically associating domains emerge from cell population averages and do not exist as static structures in individual cells. Stochastic nature of the genome folding is likely to be biologically relevant and may reflect the ability of chromatin fibers to adopt a number of alternative (...) configurations, some of which could be transiently stabilized and serve regulatory purposes. Single-cell Hi-C approaches provide an opportunity to analyze chromatin folding in rare cell types such as stem cells, tumor progenitors, oocytes, and totipotent cells, contributing to a deeper understanding of basic mechanisms in development and disease. Here, we review key findings of single-cell Hi-C and discuss possible biological reasons and consequences of the inferred dynamic chromatin spatial organization. Single-cell Hi-C expands the molecular biology toolbox for studies of chromatin structure in individual cells. This technique allows one to analyze cell-to-cell variability in TAD and loop structure, and to capture chromosome conformation in rare cell types such as oocytes, totipotent cells, and tumor progenitors. (shrink)

Recent years have witnessed an explosion of the single-cell biochemical toolbox including chromosome conformation capture -based methods that provide novel insights into chromatin spatial organization in individual cells. The observations made with these techniques revealed that topologically associating domains emerge from cell population averages and do not exist as static structures in individual cells. Stochastic nature of the genome folding is likely to be biologically relevant and may reflect the ability of chromatin fibers to adopt a number of alternative (...) configurations, some of which could be transiently stabilized and serve regulatory purposes. Single-cell Hi-C approaches provide an opportunity to analyze chromatin folding in rare cell types such as stem cells, tumor progenitors, oocytes, and totipotent cells, contributing to a deeper understanding of basic mechanisms in development and disease. Here, we review key findings of single-cell Hi-C and discuss possible biological reasons and consequences of the inferred dynamic chromatin spatial organization. Single-cell Hi-C expands the molecular biology toolbox for studies of chromatin structure in individual cells. This technique allows one to analyze cell-to-cell variability in TAD and loop structure, and to capture chromosome conformation in rare cell types such as oocytes, totipotent cells, and tumor progenitors. (shrink)

Numerous groups race to discover the gene biomarker whose alteration alone is indicative of a particular disease in all humans. Biomarkers are selected from the most frequently altered genes in large population cohorts. However, thousands of other genes are simultaneously affected, and, in each person, the same disease results from a unique, never-repeatable combination of gene alterations. Therefore, our Genomic Fabric Paradigm (GFP) switches the focus from the alteration of one particular gene to the overall change in selected groups of (...) functionally related genes. Biomarkers are of little therapeutic value, their high alterability indicating low protection by the homeostatic mechanisms as for minor players. Instead of these most alterable genes in all patients, GFP identifies in each patient the genes whose highly protected expression governs major functional pathways by controlling the expression of numerous other genes. Smart manipulation of such (commander) genes would have the maximum therapeutic benefit not for everybody but for the treated person. The genomic fabric is defined as the transcriptome associated with the most interconnected and stably expressed network of genes responsible for a particular functional pathway. The fabric exhibits specificity with respect to race/strain, sex, age, tissue/cell type, and lifestyle and environmental factors. It remodels during development, progression of a disease, and in response to external stimuli. GFP is powered by mathematically advanced analytical tools whose application is illustrated by reprocessing data from previously published gene expression experiments. (shrink)

Nuclear bodies contribute to non‐random organization of the human genome and nuclear function. Using a major prototypical nuclear body, the Cajal body, as an example, we suggest that these structures assemble at specific gene loci located across the genome as a result of high transcriptional activity. Subsequently, target genes are physically clustered in close proximity in Cajal body‐containing cells. However, Cajal bodies are observed in only a limited number of human cell types, including neuronal and cancer cells. Ultimately, (...) Cajal body depletion perturbs splicing kinetics by reducing target small nuclear RNA (snRNA) transcription and limiting the levels of spliceosomal snRNPs, including their modification and turnover following each round of RNA splicing. As such, Cajal bodies are capable of shaping the chromatin interaction landscape and the transcriptome by influencing spliceosome kinetics. Future studies should concentrate on characterizing the direct influence of Cajal bodies upon snRNA gene transcriptional dynamics.Also see the video abstract here. (shrink)

Transcriptome sequencing has identified more than a thousand potentially imprinted genes in the mouse brain. This comes as a revelation to someone who cut his teeth on the identification of imprinted genes when only a handful was known. Genomic imprinting, an epigenetic mechanism that determines expression of alleles according to sex of transmitting parent, was discovered over 25 years ago in mice but remains an enigmatic phenomenon. Why do these genes disobey the normal Mendelian logic of inheritance, do they function (...) in specific processes, and how is their imprinting conferred? Next generation sequencing technologies are providing an unprecedented opportunity to survey the whole genome for imprinted genes and are beginning to reveal that imprinting may be more pervasive than we had come to believe. Such advances should lay the foundation for a definitive account of imprinting, but may also challenge accepted views on what it means to be imprinted.Editor's suggested further reading in BioEssays RNA as the substrate for epigenome‐environment interactions Abstract. (shrink)

There is increasing evidence that dynamic changes to chromatin, chromosomes and nuclear architecture are regulated by RNA signalling. Although the precise molecular mechanisms are not well understood, they appear to involve the differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. A significant fraction of the genome-wide transcription of non-protein coding RNAs may be involved in this process, comprising a previously hidden layer of intermediary genetic (...) information that underpins developmental ontogeny and the differences between species, ecotypes and individuals. It is also evident that RNA editing is a primary means by which hardwired genetic information in animals can be altered by environmental signals, especially in the brain, indicating a dynamic RNA-mediated interplay between the transcriptome, the environment and the epigenome. Moreover, RNA-directed regulatory processes may also transfer epigenetic information not only within cells but also between cells and organ systems, as well as across generations. (shrink)

Sponges are important but often‐neglected organisms. The absence of classical animal traits (nerves, digestive tract, and muscles) makes sponges challenging for non‐specialists to work with and has delayed getting high quality genomic data compared to other invertebrates. Yet analyses of sponge genomes and transcriptomes currently available have radically changed our understanding of animal evolution. Sponges are of prime evolutionary importance as one of the best candidates to form the sister group of all other animals, and genomic data are essential to (...) understand the mechanisms that control animal evolution and diversity. Here we review the most significant outcomes of current genomic and transcriptomic analyses of sponges, and discuss limitations and future directions of sponge transcriptomic and genomic studies. (shrink)

Endogenous retrovirsuses (ERVs) have long been known to influence gene expression in plants in important ways, but what of their roles in mammals? Our relatively sparse knowledge in that area was recently increased with the finding that ERVs can influence the expression of mammalian resident genes by disrupting transcriptional termination. For many mammalian biologists, retrotransposition is considered unimportant except when it disrupts the reading frame of a gene, but this view continues to be challenged. It has been known for some (...) time that integration into an intron can create novel transcripts and integration upstream of a gene can alter the expression of the transcript, in many cases producing phenotypic consequences and disease. The new findings on transcriptional termination extend the opportunities for retrotransposons to play a role in human disease. (shrink)

The ontogeny of the vertebrate retina has been a topic of interest to developmental biologists and human geneticists for many decades. Understanding the unfolding of the genetic program that transforms a field of progenitors cells into a functionally complex and multi‐layered sensory organ is a formidable challenge. Although classical genetic studies succeeded in identifying the key regulators of retina specification, understanding the architecture of their gene network and predicting their behavior are still a distant hope. The emergence of next‐generation sequencing (...) platforms revolutionized the field unlocking the access to genome‐wide datasets. Emerging techniques such as RNA‐seq, ChIP‐seq, ATAC‐seq, or single cell RNA‐seq are used to characterize eye developmental programs. These studies provide valuable information on the transcriptional and cis‐regulatory profiles of precursors and differentiated cells, outlining the trajectories that connect each intermediate state. Here, recent systems biology efforts are reviewed to understand the genetic programs shaping the vertebrate retina. (shrink)

The Plasmodium falciparum genome‐sequencing project has provided malariologists with vast amounts of new information pertinent to a multitude of cellular processes that previously were only guessed about. In exploring this morass of predicted genes and proteins, there is now a danger of simply re‐inventing the cell. Fortunately, new global transcriptional analyses reassure malariologists that they are not dealing with just “any old cell.” The informative papers on the plasmodial transcriptome by Le Roch et al. (2003)1 and Bozdech et al. (...) (2003)2 discussed below forge a bridge between the genomics and proteomics of P. falciparum. They are likely to act as a fulcrum upon which much future research will turn: for example, the study of regulation and feed‐back loops. BioEssays 26:339–342, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

As genomic science has evolved, so have policy and practice debates about how to describe and evaluate the ways in which genomic information is treated for individuals, institutions, and society. The term genetic exceptionalism, describing the concept that genetic information is special or unique, and specifically different from other kinds of medical information, has been utilized widely, but often counterproductively in these debates. We offer genomic contextualism as a new term to frame the characteristics of genomic science in the debates. (...) Using stasis theory to draw out the important connection between definitional issues and resulting policies, we argue that the framework of genomic contextualism is better suited to evaluating genomics and its policy-relevant features to arrive at more productive discussion and resolve policy debates. (shrink)

CRISPR is widely considered to be a disruptive technology. However, when it comes to the most controversial topic, germline genome editing (GGE), there is no consensus on whether this technology has any substantial advantages over existing procedures such as embryo selection after in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD). Answering this question, however, is crucial for evaluating whether the pursuit of further research and development on GGE is justified. This paper explores the question from both a clinical (...) and a moral viewpoint, namely whether GGE has any advantages over existing technologies of selective reproduction and whether GGE could complement or even replace them. In a first step, I review an argument of extended applicability. The paper confirms that there are some scenarios in which only germline intervention allows couples to have (biologically related) healthy offspring, because selection will not avoid disease. In a second step, I examine possible moral arguments in favour of genetic modification, namely that GGE could save some embryos and that GGE would provide certain benefits for a future person that PGD does not. Both arguments for GGE have limitations. With regard to the extended applicability of GGE, however, a weak case in favour of GGE should still be made. (shrink)

The prospect of using genome technologies to modify the human germline has raised profound moral disagreement but also emphasizes the need for wide-ranging discussion and a well-informed policy response. The Hinxton Group brought together scientists, ethicists, policymakers, and journal editors for an international, interdisciplinary meeting on this subject. This consensus statement formulated by the group calls for support of genome editing research and the development of a scientific roadmap for safety and efficacy; recognizes the ethical challenges involved (...) in clinical reproductive applications of genome editing but, importantly, rejects the idea that human reproductive germline modification is necessarily morally unacceptable; and highlights the importance of meaningful engagement in discussions of genome editing and the development of regulation and oversight mechanisms to govern future uses of such technologies. (shrink)

Genome editing in livestock could potentially be used in ways that help resolve some of the most urgent and serious global problems pertaining to livestock, including animal suffering, pollution, antimicrobial resistance, and the spread of infectious disease. But despite this potential, some may object to pursuing it, not because genome editing is wrong in and of itself, but because it is the wrong kind of solution to the problems it addresses: it is merely a ‘technological fix’ to a (...) complex societal problem. Yet though this objection might have wide intuitive appeal, it is often not clear what, exactly, the moral problem is supposed to be. The aim of this paper is to formulate and shed some light on the ‘technological fix objection’ to genome editing in livestock. I suggest that three concerns may underlie it, make implicit assumptions underlying the concerns explicit, and cast some doubt on several of these assumptions, at least as they apply to the use of genome editing to produce pigs resistant to the Porcine Reproductive and Respiratory Syndrome and hornless dairy cattle. I then suggest that the third, and most important, concern could be framed as a concern about complicity in factory farming. I suggest ways to evaluate this concern, and to reduce or offset any complicity in factory farming. Thinking of genome editing’s contribution to factory farming in terms of complicity, may, I suggest, tie it more explicitly and strongly to the wider obligations that come with pursuing it, including the cessation of factory farming, thereby addressing the concern that technological fixes focus only on a narrow problem. (shrink)

Genomic research can reveal ‘unsolicited’ or ‘incidental’ findings that are of potential health or reproductive significance to participants. It is widely thought that researchers have a moral obligation, grounded in the duty of easy rescue, to return certain kinds of unsolicited findings to research participants. It is less widely thought that researchers have a moral obligation to actively look for health-related findings. This paper examines whether there is a moral obligation, grounded in the duty of easy rescue, to actively hunt (...) for genomic secondary findings. We begin by showing how the duty to disclose individual research findings can be grounded in the duty of easy rescue. Next, we describe a parallel moral duty, also grounded in the duty of easy rescue, to actively hunt for such information. We then consider six possible objections to our argument, each of which we find unsuccessful. Some of these objections provide reason to limit the scope of the duty to look for secondary findings, but none provide reason to reject this duty outright. We argue that under a certain range of circumstances, researchers are morally required to hunt for these kinds of secondary findings. Although these circumstances may not currently obtain, genomic researchers will likely acquire an obligation to hunt for secondary findings as the field of genomics continues to evolve. (shrink)

The largest transcriptome reported so far comprises 60,770 mouse full‐length cDNA clones, and is an effective reference data set for comparative transcriptomics. The number of mouse cDNAs identified greatly exceeds the number of genes predicted from the sequenced human and mouse genomes. This is largely because of extensive alternative splicing and the presence of many non‐coding RNAs (ncRNAs), which are difficult to predict from genomic sequences. Notably, ncRNAs are a major component of the transcriptomes of higher organisms, and many (...) sense–antisense pairs have been identified. The ncRNAs function in a range of regulatory mechanisms for gene expression and other biological processes. They might also have contributed to the increased functional diversification of genomes during evolution. In this review, we discuss aspects of the transcriptome of various organisms in relation to the mouse data, in order to shed light on the regulatory mechanisms and physiological significance of these abundant RNAs. BioEssays 26:833–843, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

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

Evidence for recombination suppression has been identified in linkage studies of several unstable DNA diseases. Also sex‐specific changes in recombination frequency have been detected at the loci of Huntington's disease and myotonic dystrophy. It can be hypothesized that meiotic recombination is regulated by genome‐wide genomic imprinting and that changes in meiotic recombination imply the presence of the genomic imprinting defect. If aberrant recombination at the locus of trinucleotide repeat expansion is verified, new theoretical and experimental opportunities will arise (...) in studies on the role of genomic imprinting in the unstable DNA diseases. (shrink)

Madole & Harden argue that the Mendelian reshuffling of genes and genomes is analogous to randomised controlled trials. We are not convinced by their arguments. First, their recipe for meeting the demands on randomised experiments is inherently inconsistent. Second, disequilibrium across chromosomes conflicts with their assumption of statistical independence. Third, the genome-wide association study (GWAS) method has many pitfalls, including low repeatability.

A recent single cell mRNA sequencing study by Dueck et al. compares neuronal transcriptomes to the transcriptomes of adipocytes and cardiomyocytes. Single cell ‘omic approaches such as those used by the authors are at the leading edge of molecular and biophysical measurement. Many groups are currently employing single cell sequencing approaches to understand cellular heterogeneity in cancer and during normal development. These single cell approaches also are beginning to address long‐standing questions regarding nervous system diversity. Beyond an innate interest in (...) cataloging cell type diversity in the brain, single cell neuronal diversity has important implications for neurotypic neural circuit function and for neurological disease. Herein, we review the authors’ methods and findings, which most notably include evidence of unique expression profiles in some single neurons. (shrink)

Health care is transitioning from genetics to genomics, in which single-gene testing for diagnosis is being replaced by multi-gene panels, genome-wide sequencing, and other multi-genic tests for disease diagnosis, prediction, prognosis, and treatment. This health care transition is spurring a new set of increased or novel liability risks for health care providers and test laboratories. This article describes this transition in both medical care and liability, and addresses 11 areas of potential increased or novel liability risk, offering recommendations (...) to both health care and legal actors to address and manage those liability risks. (shrink)

Broad genome-wide testing is increasingly finding its way to the public through the online direct-to-consumer marketing of so-called personal genome tests. Personal genome tests estimate genetic susceptibilities to multiple diseases and other phenotypic traits simultaneously. Providers commonly make use of Terms of Service agreements rather than informed consent procedures. However, to protect consumers from the potential physical, psychological and social harms associated with personal genome testing and to promote autonomous decision-making with regard to the testing (...) offer, we argue that current practices of information provision are insufficient and that there is a place – and a need – for informed consent in personal genome testing, also when it is offered commercially. The increasing quantity, complexity and diversity of most testing offers, however, pose challenges for information provision and informed consent. Both specific and generic models for informed consent fail to meet its moral aims when applied to personal genome testing. Consumers should be enabled to know the limitations, risks and implications of personal genome testing and should be given control over the genetic information they do or do not wish to obtain. We present the outline of a new model for informed consent which can meet both the norm of providing sufficient information and the norm of providing understandable information. The model can be used for personal genome testing, but will also be applicable to other, future forms of broad genetic testing or screening in commercial and clinical settings. (shrink)

The discovery and ongoing investigation of microRNAs suggest important conceptual and methodological lessons for philosophers and historians of biology. This paper provides an account of miRNA research and the shift from viewing these tiny regulatory entities as minor curiosities to seeing them as major players in the post-transcriptional regulation of genes. Conceptually, the study of miRNAs is part of a broader change in understandings of genetic regulation, in which simple switch-like mechanisms were reinterpreted as aspects of complex cellular and (...) class='Hi'>genome-wide processes. Among them are the activities of small RNAs, previously regarded as non-functional. Methodologically, the miRNA story suggests new ways of characterizing biological research that should prove helpful to philosophers of science who seek to develop more pluralistic, pragmatic models of scientific inquiry. miRNA research displays iterative movements between multiple modes of investigation that include not only the proposal and testing of hypotheses but also exploratory, technology-oriented and question-driven modes of research. As an exemplary story of scientific discovery and development, the miRNA case illustrates transitions from genetics to genomics and systems biology, and it shows how diverse configurations of research practice are related to major scientific advances. (shrink)

BackgroundGenome-wide association studies (GWAS) provide a powerful means of identifying genetic variants that play a role in common diseases. Such studies present important ethical challenges. An increasing number of GWAS is taking place in lower income countries and there is a pressing need to identify the particular ethical challenges arising in such contexts. In this paper, we draw upon the experiences of the MalariaGEN Consortium to identify specific ethical issues raised by such research in Africa, Asia and Oceania.DiscussionWe explore (...) ethical issues in three key areas: protecting the interests of research participants, regulation of international collaborative genomics research and protecting the interests of scientists in low income countries. With regard to participants, important challenges are raised about community consultation and consent. Genomics research raises ethical and governance issues about sample export and ownership, about the use of archived samples and about the complexity of reviewing such large international projects. In the context of protecting the interests of researchers in low income countries, we discuss aspects of data sharing and capacity building that need to be considered for sustainable and mutually beneficial collaborations.SummaryMany ethical issues are raised when genomics research is conducted on populations that are characterised by lower average income and literacy levels, such as the populations included in MalariaGEN. It is important that such issues are appropriately addressed in such research. Our experience suggests that the ethical issues in genomics research can best be identified, analysed and addressed where ethics is embedded in the design and implementation of such research projects. (shrink)

The variation in genome size and basic chromosome number was analyzed in the wide range of angiosperm plants. A divergence of monocots vs. dicots (eudicots) genome size distributions was revealed. A similar divergence was found for annual vs. perennial dicots. The divergence of monocots vs. dicots genome size distributions holds at different taxonomic levels and is more pronounced for species with larger genomes. Using nested analysis of variance, it was shown that putative constraints on genome (...) size variation are not only stronger in dicots as compared to monocots but in the former they start to operate already at the family level, whereas in the latter they do so only at the order level. At the same time, variation in basic chromosome number is constrained at the order level in both groups. Higher basic chromosome numbers were found in perennial plants as compared to the annual ones, which can be explained by their need for a higher genetic recombination as compensation for the longer life-cycles. A negative correlation was found between genome size and basic chromosome number, which can be explained as a trade-off between different recombination mechanisms. (shrink)

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

Whole genome sequencing is quickly becoming more affordable and accessible, with the prospect of personal genome sequencing for under $1,000 now widely said to be in sight. The ethical issues raised by the use of this technology in the research context have received some significant attention, but little has been written on its use in the clinical context, and most of this analysis has been futuristic forecasting. This is problematic, given the speed with which whole genome sequencing (...) technology is likely to be incorporated into clinical care. This paper explores one particular subset of these issues: the implications of adopting this technology in the prenatal context without a good understanding of when and how it is useful. Prenatal whole genome sequencing differs from current prenatal genetic testing practice in a number of ethically relevant ways. Most notably, whole genome sequencing would radically increase the volume and scope of available prenatal genetic data. The wealth of new data could enhance reproductive decision‐making, promoting parents' freedom to make well‐informed reproductive decisions. We argue, however, that there is potential for prenatal whole genome sequencing to alter clinical practice in undesirable ways, especially in the short term. We are concerned that the technology could (1) change the norms and expectations of pregnancy in ways that complicate parental autonomy and informed decision‐making, (2) exacerbate the deleterious role that genetic determinism plays in child rearing, and (3) undermine children's future autonomy by removing the option of not knowing their genetic information without appropriate justification. (shrink)

Everyone in biology keeps predicting that the next few years will bring answers to some of the major open questions in evolutionary biology, but there seems to be disagreement on what, exactly, those questions are. Enthusiasts of the various “-omics” (genomics, proteomics, transcriptomics, metabolomics, and even phenomics) believe, as Michael Lynch puts it in the final chapter of The Origins of Genome Architecture, that “we can be confident of two things: the basic theoretical machinery for understanding the evolutionary (...) process is well established, and we will soon be effectively unlimited by the availability of information at the DNA level.”. (shrink)

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

Genes are functional cell segments of DNA within an organism, as well as basic physical units of biological inheritance, which have consequences for human dignity and public interest. Genes and genetic material (DNA strands of nucleotides, genetically altered plants and animals e.g., see Appendix B) are patentable. In the US and around the globe, governments grant genetic patents for new, non-obvious, and useful gene inventions. A wide range of interest groups such as religious leaders, scientists, biotech pharmaceuticals, medical practitioners, (...) health care providers, venture capitalists, medical patients and persons have interests in defining what is subject to patents. Yet, it is at least questionable that genetic inventions, and the ownership of discoveries of gene mutations leading to possible diseases, should be subject to influence by interest groups. Although some genes (cDNA) are currently legally patentable, the question in this examination is whether gene patents should be legally and morally justified. In this work I examine whether gene patents should legally and morally be justified, given the principles of biomedical ethics such as human Beneficence /Autonomy and Justice. I argue that gene patenting is not justifiable, and I consider what can be done to create a system that delivers access to genetic information in the current genetic Intellectual Patent system. This interdisciplinary work is more complex than whether bio-science researchers and corporate entities should hold gene patents, or differentiating the legal question of whether genes are an invention or a discovery in the human genome. Mere responses to these questions would not ultimately solve the genetic justice problem. The justification for genetic appropriation is more complexity, since it is grounded in axiological claims about human dignity and public interest set in an ever changing biomedical/biogenetic technology. To address this complexity, I will draw upon the ideas of “the capability approach” to genetic justice found in the work of Nussbaum and Sen. This work is an interdisciplinary examination of the proper appropriation of natural genetic material and its impact on human dignity. It is argued that genetic material and information should be accessible to all, via heath care, for example. We must look to new ways to achieve genetic justice that promote human flourishing as a public good. (shrink)

In the future, the Human Genome Project could eventually open the way to perhaps the determination of the complete wiling diagram of the human brain. This kind of progress may move neuroscience forward into the next level of understanding of human neurophysiology, development and behavior. The next crucial step would be to know, exactly what are the function of this genes, and why its lack or alteration causes a certain disease. Although, genomic has in some way contributed to almost (...) every aspects of neurobiology, the results are both significant and troubling.One of the areas, where HGP will contribute to neuroscience is the mapping of qualitative or complex traits. Complex traits like appearence, intelligence and personality are likely to be affected by hundreds or thousands of different genes, rather than one or a few. On the other hand, the complex organisms are not just the simple result of the sum of their genes, nor do genes alone build the different part of organism or influence behaviour by themselves. In spite of the wide variety of misunderstanding, misinterpretation or possible misusing of these new genetic information, this sort of research may eventually lead to useful practical medical results for humans. This information can contribute to work out therapies to treat learning and memory disorders, neurological disorders like Alzheimer's disease, afflicting more and more people in an increasingly ageing population. Genetics believe, there are 3000 to 4000 hereditary diseases. Gene therapy could one day cure some of them, but only when all the details of their genetic basis are known. Biomedicine in the next century will probably have a completely new role in society based on the beginnings inherent in the HGP.There is a general agreement, that modern neuroscience raises important ethical concerns that not have been adequately addressed either by scientists themselves or by the bioethics community. Some scientists interpreted the rapid progress in neuroscience as additional conformation for a materialist account of human nature, resulting in an attack on traditional belief systems. There is a clear tension between the widely held believes and the intellectual views of many scientists. (shrink)