Showing papers in "Nature Reviews Genetics in 2003"
TL;DR: With the development of a leukaemia-like syndrome in two patients cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.
Abstract: Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.
2,451 citations
TL;DR: The past five years have witnessed important insights into osteoclast formation and function and many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis.
Abstract: Osteoclasts are the principal, if not exclusive, bone-resorbing cells, and their activity has a profound impact on skeletal health. So, disorders of skeletal insufficiency, such as osteoporosis, typically represent enhanced osteoclastic bone resorption relative to bone formation. Prevention of pathological bone loss therefore depends on an appreciation of the mechanisms by which osteoclasts differentiate from their precursors and degrade the skeleton. The past five years have witnessed important insights into osteoclast formation and function. Many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis.
1,548 citations
TL;DR: In this article, the authors examined the dynamics of evolutionary adaptation, the genetic bases of adaptation, tradeoffs and the environmental specificity of adaptation and the origin and evolutionary consequences of mutators.
Abstract: Microorganisms have been mutating and evolving on Earth for billions of years. Now, a field of research has developed around the idea of using microorganisms to study evolution in action. Controlled and replicated experiments are using viruses, bacteria and yeast to investigate how their genomes and phenotypic properties evolve over hundreds and even thousands of generations. Here, we examine the dynamics of evolutionary adaptation, the genetic bases of adaptation, tradeoffs and the environmental specificity of adaptation, the origin and evolutionary consequences of mutators, and the process of drift decay in very small populations.
1,359 citations
TL;DR: The most useful contribution of the genomics model to population genetics will be improving inferences about population demography and evolutionary history.
Abstract: Population genomics has the potential to improve studies of evolutionary genetics, molecular ecology and conservation biology, by facilitating the identification of adaptive molecular variation and by improving the estimation of important parameters such as population size, migration rates and phylogenetic relationships. There has been much excitement in the recent literature about the identification of adaptive molecular variation using the population-genomic approach. However, the most useful contribution of the genomics model to population genetics will be improving inferences about population demography and evolutionary history.
1,276 citations
TL;DR: Molecular farming in plants has already proven to be a successful way of producing a range of technical proteins and the first plant-derived recombinant pharmaceutical proteins are now approaching commercial approval, and many more are expected to follow.
Abstract: Imagine a world in which any protein, either naturally occurring or designed by man, could be produced safely, inexpensively and in almost unlimited quantities using only simple nutrients, water and sunlight. This could one day become reality as we learn to harness the power of plants for the production of recombinant proteins on an agricultural scale. Molecular farming in plants has already proven to be a successful way of producing a range of technical proteins. The first plant-derived recombinant pharmaceutical proteins are now approaching commercial approval, and many more are expected to follow.
957 citations
TL;DR: The availability of the near-complete chromosome sequence, plus many new polymorphisms, a highly resolved phylogeny and insights into its mutation processes, now provide new avenues for investigating human evolution.
Abstract: Until recently, the Y chromosome seemed to fulfil the role of juvenile delinquent among human chromosomes — rich in junk, poor in useful attributes, reluctant to socialize with its neighbours and with an inescapable tendency to degenerate. The availability of the near-complete chromosome sequence, plus many new polymorphisms, a highly resolved phylogeny and insights into its mutation processes, now provide new avenues for investigating human evolution. Y-chromosome research is growing up.
917 citations
TL;DR: The availability of the human and mouse genome sequences has allowed the identification and comparison of their respective degradomes — the complete repertoire of proteases that are produced by these organisms.
Abstract: The availability of the human and mouse genome sequences has allowed the identification and comparison of their respective degradomes--the complete repertoire of proteases that are produced by these organisms. Because of the essential roles of proteolytic enzymes in the control of cell behaviour, survival and death, degradome analysis provides a useful framework for the global exploration of these protease-mediated functions in normal and pathological conditions.
907 citations
TL;DR: The study of ancient genes has highlighted the antiquity and general importance of some mechanisms of gene origination, and recent observations of young genes at early stages in their evolution have unveiled unexpected molecular and evolutionary processes.
Abstract: Genome data have revealed great variation in the numbers of genes in different organisms, which indicates that there is a fundamental process of genome evolution: the origin of new genes. However, there has been little opportunity to explore how genes with new functions originate and evolve. The study of ancient genes has highlighted the antiquity and general importance of some mechanisms of gene origination, and recent observations of young genes at early stages in their evolution have unveiled unexpected molecular and evolutionary processes.
877 citations
TL;DR: Recent developments in LD are reviewed, including the recently proposed 'haplotype-block' model of LD, which can provide insights into the biology of recombination and human demographic history.
Abstract: There is great interest in the patterns and extent of linkage disequilibrium (LD) in humans and other species. Characterizing LD is of central importance for gene-mapping studies and can provide insights into the biology of recombination and human demographic history. Here, we review recent developments in this field, including the recently proposed 'haplotype-block' model of LD. We describe some of the recent data in detail and compare the observed patterns to those seen in simulations.
706 citations
TL;DR: More than 80 mutant mouse genes disrupt neurulation and allow an in-depth analysis of the underlying developmental mechanisms, including the planar cell-polarity pathway and the sonic hedgehog signalling pathway that regulates neural plate bending.
Abstract: More than 80 mutant mouse genes disrupt neurulation and allow an in-depth analysis of the underlying developmental mechanisms. Although many of the genetic mutants have been studied in only rudimentary detail, several molecular pathways can already be identified as crucial for normal neurulation. These include the planar cell-polarity pathway, which is required for the initiation of neural tube closure, and the sonic hedgehog signalling pathway that regulates neural plate bending. Mutant mice also offer an opportunity to unravel the mechanisms by which folic acid prevents neural tube defects, and to develop new therapies for folate-resistant defects.
676 citations
TL;DR: The ability of the new approaches to address previously intractable questions is making phylogenetic analysis an essential tool in an increasing number of areas of genetic research.
Abstract: The construction of evolutionary trees is now a standard part of exploratory sequence analysis. Bayesian methods for estimating trees have recently been proposed as a faster method of incorporating the power of complex statistical models into the process. Researchers who rely on comparative analyses need to understand the theoretical and practical motivations that underlie these new techniques, and how they differ from previous methods. The ability of the new approaches to address previously intractable questions is making phylogenetic analysis an essential tool in an increasing number of areas of genetic research.
TL;DR: Applied wisely, nutrigenomics will allow effective dietary-intervention strategies to recover normal homeostasis and to prevent diet-related diseases.
Abstract: Nutrigenomics is the application of high-throughput genomics tools in nutrition research. Applied wisely, it will promote an increased understanding of how nutrition influences metabolic pathways and homeostatic control, how this regulation is disturbed in the early phase of a diet-related disease and to what extent individual sensitizing genotypes contribute to such diseases. Ultimately, nutrigenomics will allow effective dietary-intervention strategies to recover normal homeostasis and to prevent diet-related diseases.
TL;DR: The discovery of the molecular clock provided an insight into the mechanisms of molecular evolution, and created one of the most useful new tools in biology, which provides a method for testing a wide range of biological hypotheses.
Abstract: The discovery of the molecular clock — a relatively constant rate of molecular evolution — provided an insight into the mechanisms of molecular evolution, and created one of the most useful new tools in biology. The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral. Theory predicts several sources of variation in the rate of molecular evolution. However, even an approximate clock allows time estimates of events in evolutionary history, which provides a method for testing a wide range of biological hypotheses ranging from the origins of the animal kingdom to the emergence of new viral epidemics.
TL;DR: Although the early embryo is rife with translational control, controlling mRNA activity is also important in other developmental processes, such as stem-cell proliferation, sex determination, neurogenesis and erythropoiesis.
Abstract: Many crucial decisions, such as the location and timing of cell division, cell-fate determination, and embryonic axes establishment, are made in the early embryo, a time in development when there is often little or no transcription. For this reason, the control of variation in gene expression in the early embryo often relies on post-transcriptional control of maternal genes. Although the early embryo is rife with translational control, controlling mRNA activity is also important in other developmental processes, such as stem-cell proliferation, sex determination, neurogenesis and erythropoiesis.
TL;DR: By comparing mitochondrial and nuclear DNA sequences of modern breeds with their potential wild and domestic ancestors, new insights are gained into the timing and location of domestication events that produced the farm animals of today.
Abstract: A series of recent genetic studies has revealed the remarkably complex picture of domestication in both New World and Old World livestock. By comparing mitochondrial and nuclear DNA sequences of modern breeds with their potential wild and domestic ancestors, we have gained new insights into the timing and location of domestication events that produced the farm animals of today. The real surprise has been the high number of domestication events and the diverse locations in which they took place — factors which could radically change our approach to conserving livestock biodiversity resources in the future.
TL;DR: The realization that both blood vessels and nerves use common genetic pathways should not only form links between vascular biology and neuroscience, but also promises to accelerate the discovery of new mechanistic insights and therapeutic opportunities.
Abstract: Both blood vessels and nerves are vital channels to and from tissues. Recent genetic insights show that they have much more in common than was originally anticipated. They use similar signals and principles to differentiate, grow and navigate towards their targets. Moreover, the vascular and nervous systems cross-talk and, when dysregulated, this contributes to medically important diseases. The realization that both systems use common genetic pathways should not only form links between vascular biology and neuroscience, but also promises to accelerate the discovery of new mechanistic insights and therapeutic opportunities.
TL;DR: The most recent data show that some classes of proteins bound to Z-DNA with high affinity and great specificity participate in the pathology of poxviruses.
Abstract: Biologists were puzzled by the discovery of left-handed Z-DNA because it seemed unnecessary. Z-DNA was stabilized by the negative supercoiling generated by transcription, which indicated a transient localized conformational change. Few laboratories worked on the biology of Z-DNA. However, the discovery that certain classes of proteins bound to Z-DNA with high affinity and great specificity indicated a biological role. The most recent data show that some of these proteins participate in the pathology of poxviruses.
TL;DR: Three hypotheses claim to have found a countervailing selective advantage of parent-specific expression, proposed to have evolved because it enhances evolvability in a changing environment, protects females against the ravages of invasive trophoblast, or because natural selection acts differently on genes of maternal and paternal origin in interactions among kin.
Abstract: Parent-specific gene expression (genomic imprinting) is an evolutionary puzzle because it forgoes an important advantage of diploidy--protection against the effects of deleterious recessive mutations. Three hypotheses claim to have found a countervailing selective advantage of parent-specific expression. Imprinting is proposed to have evolved because it enhances evolvability in a changing environment, protects females against the ravages of invasive trophoblast, or because natural selection acts differently on genes of maternal and paternal origin in interactions among kin. The last hypothesis has received the most extensive theoretical development and seems the best supported by the properties of known imprinted genes. However, the hypothesis is yet to provide a compelling explanation for many examples of imprinting.
TL;DR: Signs of natural selection left in the authors' genome can be used to identify genes that might underlie variation in disease resistance or drug metabolism, but these signatures are confounded by population history and by variation in local recombination rates.
Abstract: During their dispersal from Africa, our ancestors were exposed to new environments and diseases Those who were better adapted to local conditions passed on their genes, including those conferring these benefits, with greater frequency This process of natural selection left signatures in our genome that can be used to identify genes that might underlie variation in disease resistance or drug metabolism These signatures are, however, confounded by population history and by variation in local recombination rates Although this complexity makes finding adaptive polymorphisms a challenge, recent discoveries are instructing us how and where to look for the signatures of selection
TL;DR: Looking at how these pathways evolved might provide insights into how a few signalling pathways can generate so much cellular and morphological diversity during the development of individual organisms and the evolution of animal body plans.
Abstract: Despite the bewildering number of cell types and patterns found in the animal kingdom, only a few signalling pathways are required to generate them. Most cell‐cell interactions during embryonic development involve the Hedgehog, Wnt, transforming growth factor-β, receptor tyrosine kinase, Notch, JAK/STAT and nuclear hormone pathways. Looking at how these pathways evolved might provide insights into how a few signalling pathways can generate so much cellular and morphological diversity during the development of individual organisms and the evolution of animal body plans.
TL;DR: It is discussed here that RNA-induced gene silencing approaches are also likely to be effective for investigating plant gene function in a high-throughput, genome-wide manner.
Abstract: The nucleotide sequences of several animal, plant and bacterial genomes are now known, but the functions of many of the proteins that they are predicted to encode remain unclear. RNA interference is a gene-silencing technology that is being used successfully to investigate gene function in several organisms - for example, Caenorhabditis elegans. We discuss here that RNA-induced gene silencing approaches are also likely to be effective for investigating plant gene function in a high-throughput, genome-wide manner.
King's College London1, University of Texas MD Anderson Cancer Center2, Pasteur Institute3, Monell Chemical Senses Center4, Oregon Health & Science University5, University of Colorado Boulder6, Drexel University7, Pennsylvania State University8, Wadsworth Center9, Leibniz Association10, Health Canada11, University of Tennessee Health Science Center12, Washington University in St. Louis13, University of Memphis14, University of Massachusetts Medical School15, Hebrew University of Jerusalem16, University of Groningen17, Roswell Park Cancer Institute18, Purdue University19, University of California, Davis20, University of Oxford21, University of Texas Southwestern Medical Center22, International Livestock Research Institute23, Max Planck Society24, University of Alabama at Birmingham25, National Institutes of Health26, Charité27, RWTH Aachen University28, University of California, Los Angeles29, McGill University30, Royal Melbourne Hospital31, Rutgers University32, Stanford University33, Columbia University34, Princeton University35, University of Nebraska–Lincoln36, Harvard University37, University of Toronto38, Vanderbilt University39, Northwestern University40, Shriners Hospitals for Children41, University of Colorado Denver42, Thomas Jefferson University43, University of Vermont44, University of North Carolina at Chapel Hill45, Southern Illinois University Carbondale46, Medical Research Council47, New York University48, University of Kentucky49
TL;DR: This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits.
Abstract: This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?
TL;DR: Future advances will necessitate the re-engineering of scientific attitudes, training and institutions, to achieve extensive multidisciplinarity.
Abstract: A unique combination of disciplines is emerging--evolutionary and ecological functional genomics--which focuses on the genes that affect ecological success and evolutionary fitness in natural environments and populations. Already this approach has provided new insights that were not available from its disciplinary components in isolation. However, future advances will necessitate the re-engineering of scientific attitudes, training and institutions, to achieve extensive multidisciplinarity.
TL;DR: Transgenes engineered into annual crops could be unintentionally introduced into the genomes of their free-living wild relatives and have negative ecological consequences.
Abstract: Transgenes engineered into annual crops could be unintentionally introduced into the genomes of their free-living wild relatives. The fear is that these transgenes might persist in the environment and have negative ecological consequences. Are some crops or transgenic traits of more concern than others? Are there natural genetic barriers to minimize gene escape? Can the genetic transformation process be exploited to produce new barriers to gene flow? Questions abound, but luckily so do answers.
TL;DR: The molecules and signalling pathways that induce myogenic determination in the embryo might be manipulated or mimicked to direct the differentiation of adult stem cells either in vivo or ex vivo.
Abstract: Skeletal muscle has an intrinsic capacity for regeneration following injury or exercise. The presence of adult stem cells in various tissues with myogenic potential provides new opportunities for cell-based therapies to treat muscle disease. Recent studies have shown a conserved transcriptional hierarchy that regulates the myogenic differentiation of both embryonic and adult stem cells. Importantly, the molecules and signalling pathways that induce myogenic determination in the embryo might be manipulated or mimicked to direct the differentiation of adult stem cells either in vivo or ex vivo.
TL;DR: In this article, the authors used population-genetic methods to obtain an accurate measure of how recombination rates vary across the genome, which has implications for understanding the molecular basis of recombination, its evolutionary significance and the distribution of linkage disequilibrium.
Abstract: Obtaining an accurate measure of how recombination rates vary across the genome has implications for understanding the molecular basis of recombination, its evolutionary significance and the distribution of linkage disequilibrium in natural populations. Although measuring the recombination rate is experimentally challenging, good estimates can be obtained by applying population-genetic methods to DNA sequences taken from natural populations. Statistical methods are now providing insights into the nature and scale of variation in the recombination rate, particularly in humans. Such knowledge will become increasingly important owing to the growing use of population-genetic methods in biomedical research.
TL;DR: The emerging genetic pathways that regulate female reproductive-tract formation in mammals and that are implicated in congenital abnormalities of this organ system are reviewed and it is shown that these pathways might be conserved between invertebrates and mammals.
Abstract: The female reproductive tract receives the oocytes for fertilization, supports the development of the fetus and provides the passage for birth. Although abnormalities of this organ system can result in infertility and even death, until recently relatively little was known about the genetic processes that underlie its development. By drawing primarily on mouse mutagenesis studies and the analysis of human mutations we review the emerging genetic pathways that regulate female reproductive-tract formation in mammals and that are implicated in congenital abnormalities of this organ system. We also show that these pathways might be conserved between invertebrates and mammals.
TL;DR: Biological databases have been invaluable for managing these data and for making them accessible, but, although they are architecturally similar, so far their integration has proved problematic.
Abstract: Recent years have seen an explosion in the amount of available biological data. More and more genomes are being sequenced and annotated, and protein and gene interaction data are accumulating. Biological databases have been invaluable for managing these data and for making them accessible. Depending on the data that they contain, the databases fulfil different functions. But, although they are architecturally similar, so far their integration has proved problematic.
TL;DR: It seems increasingly likely that investment in Pharmacogenetics might be the most effective strategy for rapidly delivering the public health benefits that are promised by the Human Genome Project and related endeavours.
Abstract: Most people in the developed world will sooner or later be given prescription drugs to treat common diseases or to reduce the risk of getting them. Almost everyone who takes medicines will, at some stage, encounter those that do not work as well as they do in other people or even that cause an adverse reaction. Pharmacogenetics seeks to reduce the variation in how people respond to medicines by tailoring therapy to individual genetic make-up. It seems increasingly likely that investment in this field might be the most effective strategy for rapidly delivering the public health benefits that are promised by the Human Genome Project and related endeavours.
TL;DR: New statistical methods are outlined that capture the simultaneous effects of multiple gene loci and thereby achieve a more global view of gene action and interaction than is possible by traditional gene-by-gene analysis.
Abstract: Statistical analysis methods for gene mapping originated in counting recombinant and non-recombinant offspring, but have now progressed to sophisticated approaches for the mapping of complex trait genes. Here, we outline new statistical methods that capture the simultaneous effects of multiple gene loci and thereby achieve a more global view of gene action and interaction than is possible by traditional gene-by-gene analysis. We aim to show that the work of statisticians goes far beyond the running of computer programs.