Showing papers in "Nature Reviews Genetics in 2006"
TL;DR: In light of the recent advances in understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, the exciting therapeutic opportunities for targeting this pathway to treat these diseases are discussed.
Abstract: Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.
2,935 citations
TL;DR: This work suggests that non-neoplastic but epigenetically disrupted stem/progenitor cells might be a crucial target for cancer risk assessment and chemoprevention.
Abstract: Cancer is widely perceived as a heterogeneous group of disorders with markedly different biological properties, which are caused by a series of clonally selected genetic changes in key tumour-suppressor genes and oncogenes. However, recent data suggest that cancer has a fundamentally common basis that is grounded in a polyclonal epigenetic disruption of stem/progenitor cells, mediated by 'tumour-progenitor genes'. Furthermore, tumour cell heterogeneity is due in part to epigenetic variation in progenitor cells, and epigenetic plasticity together with genetic lesions drives tumour progression. This crucial early role for epigenetic alterations in cancer is in addition to epigenetic alterations that can substitute for genetic variation later in tumour progression. Therefore, non-neoplastic but epigenetically disrupted stem/progenitor cells might be a crucial target for cancer risk assessment and chemoprevention.
1,806 citations
TL;DR: Rapidly accumulating evidence indicates that structural variants can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.
Abstract: The first wave of information from the analysis of the human genome revealed SNPs to be the main source of genetic and phenotypic human variation. However, the advent of genome-scanning technologies has now uncovered an unexpectedly large extent of what we term 'structural variation' in the human genome. This comprises microscopic and, more commonly, submicroscopic variants, which include deletions, duplications and large-scale copy-number variants - collectively termed copy-number variants or copy-number polymorphisms - as well as insertions, inversions and translocations. Rapidly accumulating evidence indicates that structural variants can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.
1,804 citations
TL;DR: An overview of statistical approaches to population association studies, including preliminary analyses (Hardy–Weinberg equilibrium testing, inference of phase and missing data, and SNP tagging), and single-SNP and multipoint tests for association.
Abstract: Although genetic association studies have been with us for many years, even for the simplest analyses there is little consensus on the most appropriate statistical procedures. Here I give an overview of statistical approaches to population association studies, including preliminary analyses (Hardy-Weinberg equilibrium testing, inference of phase and missing data, and SNP tagging), and single-SNP and multipoint tests for association. My goal is to outline the key methods with a brief discussion of problems (population structure and multiple testing), avenues for solutions and some ongoing developments.
1,429 citations
TL;DR: In just a few years, microarrays have gone from obscurity to being almost ubiquitous in biological research, and points of consensus are emerging about the general approaches that warrant use and elaboration.
Abstract: In just a few years, microarrays have gone from obscurity to being almost ubiquitous in biological research. At the same time, the statistical methodology for microarray analysis has progressed from simple visual assessments of results to a weekly deluge of papers that describe purportedly novel algorithms for analysing changes in gene expression. Although the many procedures that are available might be bewildering to biologists who wish to apply them, statistical geneticists are recognizing commonalities among the different methods. Many are special cases of more general models, and points of consensus are emerging about the general approaches that warrant use and elaboration.
1,349 citations
TL;DR: A better understanding of periimplantation biology could alleviate female infertility and help to develop novel contraceptives and the future challenges of the field are highlighted.
Abstract: Implantation involves an intricate discourse between the embryo and uterus and is a gateway to further embryonic development. Synchronizing embryonic development until the blastocyst stage with the uterine differentiation that takes place to produce the receptive state is crucial to successful implantation, and therefore to pregnancy outcome. Although implantation involves the interplay of numerous signalling molecules, the hierarchical instructions that coordinate the embryo-uterine dialogue are not well understood. This review highlights our knowledge about the molecular development of preimplantation and implantation and the future challenges of the field. A better understanding of periimplantation biology could alleviate female infertility and help to develop novel contraceptives.
1,152 citations
TL;DR: The evolutionary relationship between Jumonji C (JmjC)-domain-containing proteins is analysed and their cellular functions in relation to their potential enzymatic activities are discussed.
Abstract: Histone methylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity. Enzymes that directly remove methyl marks from histones have recently been identified, revealing a new level of plasticity within this epigenetic modification system. Here we analyse the evolutionary relationship between Jumonji C (JmjC)-domain-containing proteins and discuss their cellular functions in relation to their potential enzymatic activities.
1,149 citations
TL;DR: The line between these two components is blurred by inherited epigenetic variation, which is potentially sensitive to environmental inputs.
Abstract: A growing body of evidence indicates that epigenetic states can be influenced by the environment. Considering that erasure of epigenetic marks between generations is not universal among multicellular organisms, what are the potential implications of inherited epigenetic variation for current theories of inheritance and evolutionary change? Phenotypic variation is traditionally parsed into components that are directed by genetic and environmental variation. The line between these two components is blurred by inherited epigenetic variation, which is potentially sensitive to environmental inputs. Chromatin and DNA methylation-based mechanisms mediate a semi-independent epigenetic inheritance system at the interface between genetic control and the environment. Should the existence of inherited epigenetic variation alter our thinking about evolutionary change?
1,071 citations
TL;DR: This framework could allow us to understand, for the first time, the genetic basis of ecosystem processes, and the effect of such phenomena as climate change and introduced transgenic organisms on entire communities.
Abstract: Can heritable traits in a single species affect an entire ecosystem? Recent studies show that such traits in a common tree have predictable effects on community structure and ecosystem processes. Because these 'community and ecosystem phenotypes' have a genetic basis and are heritable, we can begin to apply the principles of population and quantitative genetics to place the study of complex communities and ecosystems within an evolutionary framework. This framework could allow us to understand, for the first time, the genetic basis of ecosystem processes, and the effect of such phenomena as climate change and introduced transgenic organisms on entire communities.
1,034 citations
TL;DR: New evidence indicates that even some synonymous mutations are subject to constraint, often because they affect splicing and/or mRNA stability, which has implications for understanding disease, optimizing transgene design, detecting positive selection and estimating the mutation rate.
Abstract: Although the assumption of the neutral theory of molecular evolution - that some classes of mutation have too small an effect on fitness to be affected by natural selection - seems intuitively reasonable, over the past few decades the theory has been in retreat. At least in species with large populations, even synonymous mutations in exons are not neutral. By contrast, in mammals, neutrality of these mutations is still commonly assumed. However, new evidence indicates that even some synonymous mutations are subject to constraint, often because they affect splicing and/or mRNA stability. This has implications for understanding disease, optimizing transgene design, detecting positive selection and estimating the mutation rate.
819 citations
TL;DR: A flurry of recent papers has clarified the key regulatory signals and brought us to the point where the authors can begin to give a coherent account, for at least one tissue, of how these signals collaborate to organize the architecture and behaviour of a stem-cell system.
Abstract: The lining of the intestine is renewed at an extraordinary rate, outpacing all other tissues in the vertebrate body. The renewal process is neatly organized in space, so that the whole production line, from the ever-youthful stem cells to their dying, terminally differentiated progeny, is laid out to view in histological sections. A flurry of recent papers has clarified the key regulatory signals and brought us to the point where we can begin to give a coherent account, for at least one tissue, of how these signals collaborate to organize the architecture and behaviour of a stem-cell system.
TL;DR: Genetic insights provide the rationale for new strategies for prevention or therapy, and have led to animal models of disease in which these strategies can be tested.
Abstract: Parkinson disease is a complex, multifactorial neurodegenerative disease. Although a heritable basis was originally thought unlikely, recent studies have implicated several genes in its pathogenesis, and molecular findings now allow accurate diagnosis and challenge past criteria for defining Parkinson disease. Most importantly, genetic insights provide the rationale for new strategies for prevention or therapy, and have led to animal models of disease in which these strategies can be tested. Neuroprotective therapies can now be designed to slow or halt disease progression in affected subjects and asymptomatic carriers.
TL;DR: A new field of genetic analysis of global gene expression has emerged in recent years, driven by the realization that traditional techniques of linkage and association analysis can be applied to thousands of transcript levels measured by microarrays.
Abstract: A new field of genetic analysis of global gene expression has emerged in recent years, driven by the realization that traditional techniques of linkage and association analysis can be applied to thousands of transcript levels measured by microarrays. Genetic dissection of transcript abundance has shed light on the architecture of quantitative traits, provided a new approach for connecting DNA sequence variation with phenotypic variation, and improved our understanding of transcriptional regulation and regulatory variation.
TL;DR: New insights suggest that the mechanisms of action of both enhancer blockers and barriers might not be unique to these types of element, but instead are adaptations of other gene-regulatory mechanisms.
Abstract: Insulators are DNA sequence elements that prevent inappropriate interactions between adjacent chromatin domains. One type of insulator establishes domains that separate enhancers and promoters to block their interaction, whereas a second type creates a barrier against the spread of heterochromatin. Recent studies have provided important advances in our understanding of the modes of action of both types of insulator. These new insights also suggest that the mechanisms of action of both enhancer blockers and barriers might not be unique to these types of element, but instead are adaptations of other gene-regulatory mechanisms.
TL;DR: This work states that literature mining is also becoming useful for both hypothesis generation and biological discovery, however, the latter will require the integration of literature and high-throughput data, which should encourage close collaborations between biologists and computational linguists.
Abstract: For the average biologist, hands-on literature mining currently means a keyword search in PubMed. However, methods for extracting biomedical facts from the scientific literature have improved considerably, and the associated tools will probably soon be used in many laboratories to automatically annotate and analyse the growing number of system-wide experimental data sets. Owing to the increasing body of text and the open-access policies of many journals, literature mining is also becoming useful for both hypothesis generation and biological discovery. However, the latter will require the integration of literature and high-throughput data, which should encourage close collaborations between biologists and computational linguists.
TL;DR: Understanding of the molecular basis that underlies the diverse clinical features of human disorders with pleiotropic clinical features is enhancing the understanding of the damage-response mechanisms and their role in development, and might ultimately facilitate treatment.
Abstract: The efficient repair of DNA double-strand breaks is crucial in safeguarding the genomic integrity of organisms. Responses to double-strand breaks include complex signal-transduction, cell-cycle-checkpoint and repair pathways. Defects in these pathways lead to several human disorders with pleiotropic clinical features. Dissection of the molecular basis that underlies the diverse clinical features is enhancing our understanding of the damage-response mechanisms and their role in development, and might ultimately facilitate treatment.
TL;DR: DNA microarrays have become synonymous with this kind of study and are the obvious platform to achieve this aim, and new areas of application, such as genome-wide epigenetic analysis and on-chip synthesis, continue to emerge.
Abstract: Understanding complex functional mechanisms requires the global and parallel analysis of different cellular processes. DNA microarrays have become synonymous with this kind of study and, in many cases, are the obvious platform to achieve this aim. They have already made important contributions, most notably to gene-expression studies, although the true potential of this technology is far greater. Whereas some assays, such as transcript profiling and genotyping, are becoming routine, others are still in the early phases of development, and new areas of application, such as genome-wide epigenetic analysis and on-chip synthesis, continue to emerge.
TL;DR: Patterns of intron-position correspondence between widely diverged eukaryotic species have provided insights into the origins of the vast differences in intron number between eukARYotic species, and studies of specific cases of introns loss and gain have led to progress in understanding the underlying molecular mechanisms and the forces that control intron evolution.
Abstract: The origins and importance of spliceosomal introns comprise one of the longest-abiding mysteries of molecular evolution. Considerable debate remains over several aspects of the evolution of spliceosomal introns, including the timing of intron origin and proliferation, the mechanisms by which introns are lost and gained, and the forces that have shaped intron evolution. Recent important progress has been made in each of these areas. Patterns of intron-position correspondence between widely diverged eukaryotic species have provided insights into the origins of the vast differences in intron number between eukaryotic species, and studies of specific cases of intron loss and gain have led to progress in understanding the underlying molecular mechanisms and the forces that control intron evolution.
TL;DR: Exciting new findings suggest that SDs have not only created novel primate gene families, but might have also influenced current human genic and phenotypic variation on a previously unappreciated scale.
Abstract: Compared with other mammals, the genomes of humans and other primates show an enrichment of large, interspersed segmental duplications (SDs) with high levels of sequence identity. Recent evidence has begun to shed light on the origin of primate SDs, pointing to a complex interplay of mechanisms and indicating that distinct waves of duplication took place during primate evolution. There is also evidence for a strong association between duplication, genomic instability and large-scale chromosomal rearrangements. Exciting new findings suggest that SDs have not only created novel primate gene families, but might have also influenced current human genic and phenotypic variation on a previously unappreciated scale. A growing number of examples link natural human genetic variation of these regions to susceptibility to common disease.
TL;DR: The status of a much-needed coherent view that integrates studies on protein evolution with biochemistry and functional and structural genomics is discussed.
Abstract: Why do proteins evolve at different rates? Advances in systems biology and genomics have facilitated a move from studying individual proteins to characterizing global cellular factors. Systematic surveys indicate that protein evolution is not determined exclusively by selection on protein structure and function, but is also affected by the genomic position of the encoding genes, their expression patterns, their position in biological networks and possibly their robustness to mistranslation. Recent work has allowed insights into the relative importance of these factors. We discuss the status of a much-needed coherent view that integrates studies on protein evolution with biochemistry and functional and structural genomics.
TL;DR: The study of LMNA, its products and the phenotypes that result from its mutation have provided important insights into subjects ranging from transcriptional regulation, the cell biology of the nuclear lamina and mechanisms of ageing.
Abstract: Few genes have generated as much recent interest as LMNA, LMNB1 and LMNB2, which encode the components of the nuclear lamina. Over 180 mutations in these genes are associated with at least 13 known diseases--the laminopathies. In particular, the study of LMNA, its products and the phenotypes that result from its mutation have provided important insights into subjects ranging from transcriptional regulation, the cell biology of the nuclear lamina and mechanisms of ageing. Recent studies have begun the difficult task of correlating the genotypes of laminopathies with their phenotypes, and potential therapeutic strategies using existing drugs, modified oligonucleotides and RNAi are showing real promise for the treatment of these diseases.
TL;DR: A better understanding of these patterns should provide valuable information on the evolution of genes located on the X chromosome and suggest solutions to more general problems in molecular evolution, such as detecting selection and estimating mutational effects on fitness.
Abstract: Although the X chromosome is usually similar to the autosomes in size and cytogenetic appearance, theoretical models predict that its hemizygosity in males may cause unusual patterns of evolution. The sequencing of several genomes has indeed revealed differences between the X chromosome and the autosomes in the rates of gene divergence, patterns of gene expression and rates of gene movement between chromosomes. A better understanding of these patterns should provide valuable information on the evolution of genes located on the X chromosome. It could also suggest solutions to more general problems in molecular evolution, such as detecting selection and estimating mutational effects on fitness.
TL;DR: Large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress in human studies of longevity.
Abstract: Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.
TL;DR: The fact that family-based designs contain both within- and between-family information has substantial benefits in terms of multiple-hypothesis testing, especially in the context of whole-genome association studies.
Abstract: Both population-based and family-based designs are commonly used in genetic association studies to locate genes that underlie complex diseases. The simplest version of the family-based design — the transmission disequilibrium test — is well known, but the numerous extensions that broaden its scope and power are less widely appreciated. Family-based designs have unique advantages over population-based designs, as they are robust against population admixture and stratification, allow both linkage and association to be tested for and offer a solution to the problem of model building. Furthermore, the fact that family-based designs contain both within- and between-family information has substantial benefits in terms of multiple-hypothesis testing, especially in the context of whole-genome association studies.
TL;DR: The key developments that enable highly parallel genomic assays are described and it is suggested that most cancers might be staged by high-resolution molecular profiling rather than by gross cytological analysis.
Abstract: Recent developments in highly parallel genome-wide assays are transforming the study of human health and disease. High-resolution whole-genome association studies of complex diseases are finally being undertaken after much hypothesizing about their merit for finding disease loci. The availability of inexpensive high-density SNP-genotyping arrays has made this feasible. Cancer biology will also be transformed by high-resolution genomic and epigenomic analysis. In the future, most cancers might be staged by high-resolution molecular profiling rather than by gross cytological analysis. Here, we describe the key developments that enable highly parallel genomic assays.
TL;DR: As more glycosylation disorders and patients with these disorders are identified, the functions of the glycome are starting to be revealed.
Abstract: The spectrum of all glycan structures — the glycome — is immense. In humans, its size is orders of magnitude greater than the number of proteins that are encoded by the genome, one percent of which encodes proteins that make, modify, localize or bind sugar chains, which are known as glycans. In the past decade, over 30 genetic diseases have been identified that alter glycan synthesis and structure, and ultimately the function of nearly all organ systems. Many of the causal mutations affect key biosynthetic enzymes, but more recent discoveries point to defects in chaperones and Golgi-trafficking complexes that impair several glycosylation pathways. As more glycosylation disorders and patients with these disorders are identified, the functions of the glycome are starting to be revealed.
TL;DR: This work has begun to delineate differences and similarities in the regenerative capabilities and mechanisms among diverse animal species, and to address some of the key questions about the molecular and cell biology of regeneration.
Abstract: Significant progress has recently been made in our understanding of animal regenerative biology, spurred on by the use of a wider range of model organisms and an increasing ability to use genetic tools in traditional models of regeneration. This progress has begun to delineate differences and similarities in the regenerative capabilities and mechanisms among diverse animal species, and to address some of the key questions about the molecular and cell biology of regeneration. Our expanding knowledge in these areas not only provides insights into animal biology in general, but also has important implications for regenerative medicine and stem-cell biology.
TL;DR: The y- axis label for Figure 1d was incorrect and the correct y-axis label should be .
Abstract: Nature Reviews Genetics 7 55-65 (2006) In this article, the y-axis label for Figure 1d was incorrect. The correct y-axis label should be . The authors apologize for the error.
TL;DR: These studies highlight genes and pathways that also control size in mammals: insects use insulin-like growth factor and Target of rapamycin kinase signalling to coordinate nutrition with cell growth, and steroid and neuropeptide hormones to terminate feeding after a genetically encoded target weight is achieved.
Abstract: Body size affects important fitness variables such as mate selection, predation and tolerance to heat, cold and starvation. It is therefore subject to intense evolutionary selection. Recent genetic and physiological studies in insects are providing predictions as to which gene systems are likely to be targeted in selecting for changes in body size. These studies highlight genes and pathways that also control size in mammals: insects use insulin-like growth factor (IGF) and Target of rapamycin (TOR) kinase signalling to coordinate nutrition with cell growth, and steroid and neuropeptide hormones to terminate feeding after a genetically encoded target weight is achieved. However, we still understand little about how size is actually sensed, or how organ-intrinsic size controls interface with whole-body physiology.
TL;DR: The potential of natural gene drive systems for spreading genes that can block the transmission of insect-borne pathogens are explored and the artificial constructs that could be envisaged for this purpose are discussed.
Abstract: The elegant mechanisms by which naturally occurring selfish genetic elements, such as transposable elements, meiotic drive genes, homing endonuclease genes and Wolbachia, spread at the expense of their hosts provide some of the most fascinating and remarkable subjects in evolutionary genetics These elements also have enormous untapped potential to be used in the control of some of the world's most devastating diseases Effective gene drive systems for spreading genes that can block the transmission of insect-borne pathogens are much needed Here we explore the potential of natural gene drive systems and discuss the artificial constructs that could be envisaged for this purpose