Showing papers in "Nature Reviews Genetics in 2005"
TL;DR: Genome-wide association studies will soon become possible, and could open new frontiers in the understanding and treatment of disease, however, the execution and analysis of such studies will require great care.
Abstract: Genetic factors strongly affect susceptibility to common diseases and also influence disease-related quantitative traits. Identifying the relevant genes has been difficult, in part because each causal gene only makes a small contribution to overall heritability. Genetic association studies offer a potentially powerful approach for mapping causal genes with modest effects, but are limited because only a small number of genes can be studied at a time. Genome-wide association studies will soon become possible, and could open new frontiers in our understanding and treatment of disease. However, the execution and analysis of such studies will require great care.
2,912 citations
TL;DR: A large number of human diseases have been found to be associated with aberrant DNA methylation and the study of these diseases has provided new and fundamental insights into the roles that DNAmethylation and other epigenetic modifications have in development and normal cellular homeostasis.
Abstract: DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the roles that DNA methylation and other epigenetic modifications have in development and normal cellular homeostasis.
2,589 citations
TL;DR: Stochasticity in gene expression can provide the flexibility needed by cells to adapt to fluctuating environments or respond to sudden stresses, and a mechanism by which population heterogeneity can be established during cellular differentiation and development.
Abstract: Genetically identical cells exposed to the same environmental conditions can show significant variation in molecular content and marked differences in phenotypic characteristics. This variability is linked to stochasticity in gene expression, which is generally viewed as having detrimental effects on cellular function with potential implications for disease. However, stochasticity in gene expression can also be advantageous. It can provide the flexibility needed by cells to adapt to fluctuating environments or respond to sudden stresses, and a mechanism by which population heterogeneity can be established during cellular differentiation and development.
2,381 citations
TL;DR: The advantages and challenges of polyploidy, and its evolutionary potential, are considered.
Abstract: Polyploids — organisms that have multiple sets of chromosomes — are common in certain plant and animal taxa, and can be surprisingly stable. The evidence that has emerged from genome analyses also indicates that many other eukaryotic genomes have a polyploid ancestry, suggesting that both humans and most other eukaryotes have either benefited from or endured polyploidy. Studies of polyploids soon after their formation have revealed genetic and epigenetic interactions between redundant genes. These interactions can be related to the phenotypes and evolutionary fates of polyploids. Here, I consider the advantages and challenges of polyploidy, and its evolutionary potential.
1,882 citations
TL;DR: Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease.
Abstract: Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.
1,572 citations
TL;DR: This review explores the advances that have been made and the areas in which future progress is likely in understanding basic mitochondrial genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer.
Abstract: The human mitochondrial genome is extremely small compared with the nuclear genome, and mitochondrial genetics presents unique clinical and experimental challenges. Despite the diminutive size of the mitochondrial genome, mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic mitochondrial genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely.
1,525 citations
TL;DR: Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems.
Abstract: The organization of biological activities into daily cycles is universal in organisms as diverse as cyanobacteria, fungi, algae, plants, flies, birds and man. Comparisons of circadian clocks in unicellular and multicellular organisms using molecular genetics and genomics have provided new insights into the mechanisms and complexity of clock systems. Whereas unicellular organisms require stand-alone clocks that can generate 24-hour rhythms for diverse processes, organisms with differentiated tissues can partition clock function to generate and coordinate different rhythms. In both cases, the temporal coordination of a multi-oscillator system is essential for producing robust circadian rhythms of gene expression and biological activity.
1,316 citations
TL;DR: The main factors — including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases — that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci are outlined.
Abstract: To fully understand the allelic variation that underlies common diseases, complete genome sequencing for many individuals with and without disease is required. This is still not technically feasible. However, recently it has become possible to carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies. Here, we outline the main factors - including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases - that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci.
1,204 citations
TL;DR: This work has demonstrated the power of the phylogenomics approach, which has the potential to provide answers to several fundamental evolutionary questions, but challenges for the future have also been revealed.
Abstract: As more complete genomes are sequenced, phylogenetic analysis is entering a new era — that of phylogenomics. One branch of this expanding field aims to reconstruct the evolutionary history of organisms on the basis of the analysis of their genomes. Recent studies have demonstrated the power of this approach, which has the potential to provide answers to several fundamental evolutionary questions. However, challenges for the future have also been revealed. The very nature of the evolutionary history of organisms and the limitations of current phylogenetic reconstruction methods mean that part of the tree of life might prove difficult, if not impossible, to resolve with confidence.
1,165 citations
TL;DR: A protocol for estimating error rates is proposed and it is recommended that these measures be systemically reported to attest the reliability of published genotyping studies.
Abstract: Although genotyping errors affect most data and can markedly influence the biological conclusions of a study, they are too often neglected. Errors have various causes, but their occurrence and effect can be limited by considering these causes in the production and analysis of the data. Procedures that have been developed for dealing with errors in linkage studies, forensic analyses and non-invasive genotyping should be applied more broadly to any genetic study. We propose a protocol for estimating error rates and recommend that these measures be systemically reported to attest the reliability of published genotyping studies.
1,143 citations
TL;DR: The history of adaptation theory is surveyed, focusing on the rise and fall of various views over the past century and the reasons for the slow development of a mature theory of adaptation.
Abstract: Theoretical studies of adaptation have exploded over the past decade. This work has been inspired by recent, surprising findings in the experimental study of adaptation. For example, morphological evolution sometimes involves a modest number of genetic changes, with some individual changes having a large effect on the phenotype or fitness. Here I survey the history of adaptation theory, focusing on the rise and fall of various views over the past century and the reasons for the slow development of a mature theory of adaptation. I also discuss the challenges that face contemporary theories of adaptation.
TL;DR: The recent identification of a second source of myocardial cells that make an important contribution to the cardiac chambers has modified the classical view of heart formation.
Abstract: Cardiogenesis is an exquisitely sensitive process. Any perturbation in the cells that contribute to the building of the heart leads to cardiac malformations, which frequently result in the death of the embryo. Previously, the myocardium was thought to be derived from a single source of cells. However, the recent identification of a second source of myocardial cells that make an important contribution to the cardiac chambers has modified the classical view of heart formation. It also has an important influence on the interpretation of mutant phenotypes in the mouse, with consequences for the classification and prognosis of human congenital heart defects.
TL;DR: Suggestions are made for improvements in the study of study design, sample size and genotyping technology, which influence the analysis and interpretation of observed gene–environment interactions.
Abstract: Studies of gene-environment interactions aim to describe how genetic and environmental factors jointly influence the risk of developing a human disease. Gene-environment interactions can be described by using several models, which take into account the various ways in which genetic effects can be modified by environmental exposures, the number of levels of these exposures and the model on which the genetic effects are based. Choice of study design, sample size and genotyping technology influence the analysis and interpretation of observed gene-environment interactions. Current systems for reporting epidemiological studies make it difficult to assess whether the observed interactions are reproducible, so suggestions are made for improvements in this area.
TL;DR: The addictions are common chronic psychiatric diseases that today are prevented and treated using relatively untargeted and only partially effective methods, but future understanding of addictions will be enhanced by the identification of genes that have a role in altered substance-specific vulnerabilities such as variation in drug metabolism or drug receptors.
Abstract: The addictions are common chronic psychiatric diseases that today are prevented and treated using relatively untargeted and only partially effective methods. The addictions are moderately to highly heritable, which is paradoxical because these disorders require use; a choice that is itself modulated by both genes and environment. The addictions are interrelated and related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioural control and the anxiety or stress response. Our future understanding of addictions will be enhanced by the identification of genes that have a role in altered substance-specific vulnerabilities such as variation in drug metabolism or drug receptors and a role in shared vulnerabilities such as variation in reward or stress resiliency.
TL;DR: Experimental advances towards explaining the mechanisms of repeat instability have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.
Abstract: Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.
TL;DR: These studies have not only highlighted the basic understanding of host–parasite interactions, but also provide key insights into the diversity, regulation and evolution of RNA-silencing pathways.
Abstract: In eukaryotes, small RNA molecules engage in sequence-specific interactions to inhibit gene expression by RNA silencing. This process fulfils fundamental regulatory roles, as well as antiviral functions, through the activities of microRNAs and small interfering RNAs. As a counter-defence mechanism, viruses have evolved various anti-silencing strategies that are being progressively unravelled. These studies have not only highlighted our basic understanding of host-parasite interactions, but also provide key insights into the diversity, regulation and evolution of RNA-silencing pathways.
TL;DR: Experiments in Arabidopsis thaliana have begun to address crucial questions about how DNA methylation is established and maintained, and one cardinal insight has been the discovery thatDNA methylation can be guided by small RNAs produced through RNA-interference pathways.
Abstract: DNA methylation has two essential roles in plants and animals - defending the genome against transposons and regulating gene expression. Recent experiments in Arabidopsis thaliana have begun to address crucial questions about how DNA methylation is established and maintained. One cardinal insight has been the discovery that DNA methylation can be guided by small RNAs produced through RNA-interference pathways. Plants and mammals use a similar suite of DNA methyltransferases to propagate DNA methylation, but plants have also developed a glycosylase-based mechanism for removing DNA methylation, and there are hints that similar processes function in other organisms.
TL;DR: An expanding collection of sequences that are directly regulated by Hox proteins provides information on the specificity of target-gene activation, which might allow the successful prediction of novel Hox-response genes.
Abstract: With their power to shape animal morphology, few genes have captured the imagination of biologists as the evolutionarily conserved members of the Hox clusters have done. Recent research has provided new insight into how Hox proteins cause morphological diversity at the organismal and evolutionary levels. Furthermore, an expanding collection of sequences that are directly regulated by Hox proteins provides information on the specificity of target-gene activation, which might allow the successful prediction of novel Hox-response genes. Finally, the recent discovery of microRNA genes within the Hox gene clusters indicates yet another level of control by Hox genes in development and evolution.
TL;DR: RNA interference (RNAi) is an evolutionarily conserved mechanism that uses short antisense RNAs that are generated by 'dicing' dsRNA precursors to target corresponding mRNAs for cleavage as discussed by the authors.
Abstract: RNA interference (RNAi) is an evolutionarily conserved mechanism that uses short antisense RNAs that are generated by 'dicing' dsRNA precursors to target corresponding mRNAs for cleavage. However, recent developments have revealed that there is also extensive involvement of RNAi-related processes in regulation at the genome level. dsRNA and proteins of the RNAi machinery can direct epigenetic alterations to homologous DNA sequences to induce transcriptional gene silencing or, in extreme cases, DNA elimination. Furthermore, in some organisms RNAi silences unpaired DNA regions during meiosis. These mechanisms facilitate the directed silencing of specific genomic regions.
TL;DR: In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.
Abstract: The list of developmental and degenerative diseases that are caused by expansion of unstable repeats continues to grow, and is now approaching 20 disorders. The pathogenic mechanisms that underlie these disorders involve either loss of protein function or gain of function at the protein or RNA level. Common themes have emerged within and between these different classes of disease; for example, among disorders that are caused by gain-of-function mechanisms, altered protein conformations are central to pathogenesis, leading to changes in protein activity or abundance. In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.
TL;DR: A personal account of the work that led to the generation of gene targeting which now lies at the centre of functional genomic analysis.
Abstract: Gene targeting in mouse embryonic stem cells has become the 'gold standard' for determining gene function in mammals. Since its inception, this technology has revolutionized the study of mammalian biology and human medicine. Here I provide a personal account of the work that led to the generation of gene targeting which now lies at the centre of functional genomic analysis.
TL;DR: This work reviews the literature on biophysics as it relates to molecular evolution and advances a biophysical model of protein evolution that helps to understand phenomena that range from the dynamics of molecular adaptation to the clock-like rate ofprotein evolution.
Abstract: Proteins are finicky molecules; they are barely stable and are prone to aggregate, but they must function in a crowded environment that is full of degradative enzymes bent on their destruction. It is no surprise that many common diseases are due to missense mutations that affect protein stability and aggregation. Here we review the literature on biophysics as it relates to molecular evolution, focusing on how protein stability and aggregation affect organismal fitness. We then advance a biophysical model of protein evolution that helps us to understand phenomena that range from the dynamics of molecular adaptation to the clock-like rate of protein evolution.
TL;DR: Recent advances indicate that efficient, long-term gene expression can be achieved by non-viral means and integration of DNA can be targeted to specific genomic sites without deleterious consequences.
Abstract: The potential dangers of using viruses to deliver and integrate DNA into host cells in gene therapy have been poignantly highlighted in recent clinical trials. Safer, non-viral gene delivery approaches have been largely ignored in the past because of their inefficient delivery and the resulting transient transgene expression. However, recent advances indicate that efficient, long-term gene expression can be achieved by non-viral means. In particular, integration of DNA can be targeted to specific genomic sites without deleterious consequences and it is possible to maintain transgenes as small episomal plasmids or artificial chromosomes. The application of these approaches to human gene therapy is gradually becoming a reality.
TL;DR: In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase the understanding of the regulation of energy balance in humans.
Abstract: Obesity is an important cause of morbidity and mortality in developed countries, and is also becoming increasingly prevalent in the developing world. Although environmental factors are important, there is considerable evidence that genes also have a significant role in its pathogenesis. The identification of genes that are involved in monogenic, syndromic and polygenic obesity has greatly increased our knowledge of the mechanisms that underlie this condition. In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase our understanding of the regulation of energy balance in humans.
TL;DR: Drosophila melanogaster is emerging as one of the most effective tools for analyzing the function of human disease genes, including those responsible for developmental and neurological disorders, cancer, cardiovascular disease, metabolic and storage diseases, and genes required for the function the visual, auditory and immune systems.
Abstract: Drosophila melanogaster is emerging as one of the most effective tools for analyzing the function of human disease genes, including those responsible for developmental and neurological disorders, cancer, cardiovascular disease, metabolic and storage diseases, and genes required for the function of the visual, auditory and immune systems. Flies have several experimental advantages, including their rapid life cycle and the large numbers of individuals that can be generated, which make them ideal for sophisticated genetic screens, and in future should aid the analysis of complex multigenic disorders. The general principles by which D. melanogaster can be used to understand human disease, together with several specific examples, are considered in this review.
TL;DR: The remarkable recent progress in research into the genetic and molecular causes of mental retardation, its promise for understanding neural function, learning and memory, and the implications of this research for health care are reviewed.
Abstract: Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care.
TL;DR: The transcriptional regulatory cascades that control early patterning events during flower formation, the dynamics of the gene-regulatory interactions, and the complex combinatorial mechanisms that create a distinct final floral architecture and form are revealed.
Abstract: An afternoon stroll through an English garden reveals the breathtaking beauty and enormous diversity of flowering plants. The extreme variation of flower morphologies, combined with the relative simplicity of floral structures and the wealth of floral mutants available, has made the flower an excellent model for studying developmental cell-fate specification, morphogenesis and tissue patterning. Recent molecular genetic studies have begun to reveal the transcriptional regulatory cascades that control early patterning events during flower formation, the dynamics of the gene-regulatory interactions, and the complex combinatorial mechanisms that create a distinct final floral architecture and form.
TL;DR: The fruit fly Drosophila melanogaster has only 18 nuclear-receptor genes, far fewer than any other genetic model organism and representing all 6 subfamilies of vertebrate receptors as discussed by the authors.
Abstract: Nuclear receptors are ancient ligand-regulated transcription factors that control key metabolic and developmental pathways. The fruitfly Drosophila melanogaster has only 18 nuclear-receptor genes - far fewer than any other genetic model organism and representing all 6 subfamilies of vertebrate receptors. These unique attributes establish the fly as an ideal system for studying the regulation and function of nuclear receptors during development. Here, we review recent breakthroughs in our understanding of D. melanogaster nuclear receptors, and interpret these results in light of findings from their evolutionarily conserved vertebrate homologues.
TL;DR: New resources, such as chromosome substitution strains and the proposed Collaborative Cross, together with new analytical tools, including probabilistic ancestral haplotype reconstruction in outbred mice, Yin–Yang crosses and in silico analysis of sequence variants in many inbred strains, could make QTL cloning tractable.
Abstract: Over the past 15 years, more than 2,000 quantitative trait loci (QTLs) have been identified in crosses between inbred strains of mice and rats, but less than 1% have been characterized at a molecular level. However, new resources, such as chromosome substitution strains and the proposed Collaborative Cross, together with new analytical tools, including probabilistic ancestral haplotype reconstruction in outbred mice, Yin-Yang crosses and in silico analysis of sequence variants in many inbred strains, could make QTL cloning tractable. We review the potential of these strategies to identify genes that underlie QTLs in rodents.
TL;DR: In this paper, the authors showcase definitive evidence for the prion hypothesis and discuss examples in which prion-encoded heritable information has been harnessed during evolution to confer selective advantages.
Abstract: Changes in protein conformation drive most biological processes, but none have seized the imagination of scientists and the public alike as have the self-replicating conformations of prions. Prions transmit lethal neurodegenerative diseases by means of the food chain. However, self-replicating protein conformations can also constitute molecular memories that transmit genetic information. Here, we showcase definitive evidence for the prion hypothesis and discuss examples in which prion-encoded heritable information has been harnessed during evolution to confer selective advantages. We then describe situations in which prion-enciphered events might have essential roles in long-term memory formation, transcriptional memory and genome-wide expression patterns.