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Showing papers in "Nature Reviews Genetics in 2001"


Journal ArticleDOI
TL;DR: The study of imprinting provides new insights into epigenetic gene modification during development, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother.
Abstract: Genomic imprinting affects several dozen mammalian genes and results in the expression of those genes from only one of the two parental chromosomes. This is brought about by epigenetic instructions--imprints--that are laid down in the parental germ cells. Imprinting is a particularly important genetic mechanism in mammals, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother. Consistent with this view is the fact that imprinted genes tend to affect growth in the womb and behaviour after birth. Aberrant imprinting disturbs development and is the cause of various disease syndromes. The study of imprinting also provides new insights into epigenetic gene modification during development.

2,212 citations


Journal ArticleDOI
TL;DR: Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans, but recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuPLoidy.
Abstract: Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.

2,200 citations


Journal ArticleDOI
TL;DR: The emerging view is that chromosomes are compartmentalized into discrete territories and the location of a gene within a chromosome territory seems to influence its access to the machinery responsible for specific nuclear functions, such as transcription and splicing.
Abstract: The expression of genes is regulated at many levels. Perhaps the area in which least is known is how nuclear organization influences gene expression. Studies of higher-order chromatin arrangements and their dynamic interactions with other nuclear components have been boosted by recent technical advances. The emerging view is that chromosomes are compartmentalized into discrete territories. The location of a gene within a chromosome territory seems to influence its access to the machinery responsible for specific nuclear functions, such as transcription and splicing. This view is consistent with a topological model for gene regulation.

2,126 citations


Journal ArticleDOI
TL;DR: With the discovery of massive numbers of genetic markers and the development of better tools for genotyping, association studies will inevitably proliferate and now is the time to consider critically the design of such studies to avoid the mistakes of the past and to maximize their potential to identify new components of disease.
Abstract: Assessing the association between DNA variants and disease has been used widely to identify regions of the genome and candidate genes that contribute to disease. However, there are numerous examples of associations that cannot be replicated, which has led to skepticism about the utility of the approach for common conditions. With the discovery of massive numbers of genetic markers and the development of better tools for genotyping, association studies will inevitably proliferate. Now is the time to consider critically the design of such studies, to avoid the mistakes of the past and to maximize their potential to identify new components of disease.

1,499 citations


Journal ArticleDOI
TL;DR: The management and analysis of the millions of data points that result from microarray experiments has received less attention as discussed by the authors, but the methods that are used to analyse the data can have a profound influence on the interpretation of the results.
Abstract: Microarray experiments are providing unprecedented quantities of genome-wide data on gene-expression patterns. Although this technique has been enthusiastically developed and applied in many biological contexts, the management and analysis of the millions of data points that result from these experiments has received less attention. Sophisticated computational tools are available, but the methods that are used to analyse the data can have a profound influence on the interpretation of the results. A basic understanding of these computational tools is therefore required for optimal experimental design and meaningful data analysis.

1,400 citations


Journal ArticleDOI
TL;DR: Non-coding RNAs seem to be particularly abundant in roles that require highly specific nucleic acid recognition without complex catalysis, such as in directing post-transcriptional regulation of gene expression or in guiding RNA modifications.
Abstract: Non-coding RNA (ncRNA) genes produce functional RNA molecules rather than encoding proteins. However, almost all means of gene identification assume that genes encode proteins, so even in the era of complete genome sequences, ncRNA genes have been effectively invisible. Recently, several different systematic screens have identified a surprisingly large number of new ncRNA genes. Non-coding RNAs seem to be particularly abundant in roles that require highly specific nucleic acid recognition without complex catalysis, such as in directing post-transcriptional regulation of gene expression or in guiding RNA modifications.

1,315 citations


Journal ArticleDOI
TL;DR: Interactions between both double-stranded break-repair pathways and other cellular processes, such as cell-cycle regulation and replication, are being unveiled.
Abstract: Genome stability is of primary importance for the survival and proper functioning of all organisms. Double-stranded breaks in DNA are important threats to genome integrity because they can result in chromosomal aberrations that can affect, simultaneously, many genes, and lead to cell malfunctioning and cell death. These detrimental consequences are counteracted by two mechanistically distinct pathways of double-stranded break repair: homologous recombination and non-homologous end-joining. Recently, unexpected links between these double-stranded break-repair systems, and several human genome instability and cancer predisposition syndromes, have emerged. Now, interactions between both double-stranded break-repair pathways and other cellular processes, such as cell-cycle regulation and replication, are being unveiled.

1,230 citations


Journal ArticleDOI
TL;DR: Current studies of mouse mutants with disrupted placental development indicate that signalling interactions between the placental trophoblast and embryonic cells have a key role in placental morphogenesis, which should provide novel insights into human placental function.
Abstract: The placenta is the first organ to form during mammalian embryogenesis. Problems in its formation and function underlie many aspects of early pregnancy loss and pregnancy complications in humans. Because the placenta is critical for survival, it is very sensitive to genetic disruption, as reflected by the ever-increasing list of targeted mouse mutations that cause placental defects. Recent studies of mouse mutants with disrupted placental development indicate that signalling interactions between the placental trophoblast and embryonic cells have a key role in placental morphogenesis. Furthering our understanding of mouse trophoblast development should provide novel insights into human placental function.

1,226 citations


Journal ArticleDOI
TL;DR: The circadian clock is a widespread cellular mechanism that underlies diverse rhythmic functions in organisms from bacteria and fungi, to plants and animals, and the weight of evidence favours their independent evolutionary origins in different kingdoms.
Abstract: The circadian clock is a widespread cellular mechanism that underlies diverse rhythmic functions in organisms from bacteria and fungi, to plants and animals. Intense genetic analysis during recent years has uncovered many of the components and molecular mechanisms comprising these clocks. Although autoregulatory genetic networks are a consistent feature in the design of all clocks, the weight of evidence favours their independent evolutionary origins in different kingdoms.

1,105 citations


Journal ArticleDOI
TL;DR: The hope that single nucleotide polymorphisms will allow genes that underlie complex disease to be identified, together with progress in identifying large sets ofSNPs, are the driving forces behind intense efforts to establish the technology for large-scale analysis of SNPs.
Abstract: Understanding the relationship between genetic variation and biological function on a genomic scale is expected to provide fundamental new insights into the biology, evolution and pathophysiology of humans and other species. The hope that single nucleotide polymorphisms (SNPs) will allow genes that underlie complex disease to be identified, together with progress in identifying large sets of SNPs, are the driving forces behind intense efforts to establish the technology for large-scale analysis of SNPs. New genotyping methods that are high throughput, accurate and cheap are urgently needed for gaining full access to the abundant genetic variation of organisms.

1,094 citations


Journal ArticleDOI
TL;DR: The power of RNA interference, the process by which double-stranded RNA induces the silencing of homologous endogenous genes, is slowly becoming clear, and might help to develop an effortless tool to probe gene function in cells and animals.
Abstract: Imagine being able to knock out your favourite gene with only a day's work. Not just in one model system, but in virtually any organism: plants, flies, mice or cultured cells. This sort of experimental dream might one day become reality as we learn to harness the power of RNA interference, the process by which double-stranded RNA induces the silencing of homologous endogenous genes. How this phenomenon works is slowly becoming clear, and might help us to develop an effortless tool to probe gene function in cells and animals.

Journal ArticleDOI
TL;DR: Here, I review binary systems used to analyse complex and multi-staged biological processes, such as embryogenesis and cancer, with unprecedented precision and discuss certain studies that exemplify the advantages and limitations of each system.
Abstract: One of the most powerful tools that the molecular biology revolution has given us is the ability to turn genes on and off at our discretion. In the mouse, this has been accomplished by using binary systems in which gene expression is dependent on the interaction of two components, resulting in either transcriptional transactivation or DNA recombination. During recent years, these systems have been used to analyse complex and multi-staged biological processes, such as embryogenesis and cancer, with unprecedented precision. Here, I review these systems and discuss certain studies that exemplify the advantages and limitations of each system.

Journal ArticleDOI
TL;DR: This unprecedented increase in food grain production resulted from the creation of genetically improved crop varieties, combined with the application of improved agronomic practices, which has been named the 'green revolution'.
Abstract: The origin of agriculture led to the domestication of many plant species and to the exploitation of natural resources. It took almost 10,000 years for food grain production to reach 1 billion tons, in 1960, and only 40 years to reach 2 billion tons, in 2000. This unprecedented increase, which has been named the 'green revolution', resulted from the creation of genetically improved crop varieties, combined with the application of improved agronomic practices.

Journal ArticleDOI
TL;DR: The identification of chromosomal abnormalities and Mendelian syndromes among individuals with autism, in conjunction with data from genome screens and candidate-gene studies, has helped to refine the view of the complex genetics that underlies autism spectrum conditions.
Abstract: Since autism was first recognized as a disorder in 1943, speculation about its aetiology has ranged from biological to psychological and back again. After twin studies during the 1970s and 1980s yielded unequivocal evidence for a genetic component, aetiological research in autism began to focus primarily on uncovering the genetic mechanisms involved. The identification of chromosomal abnormalities and Mendelian syndromes among individuals with autism, in conjunction with data from genome screens and candidate-gene studies, has helped to refine the view of the complex genetics that underlies autism spectrum conditions.

Journal ArticleDOI
TL;DR: Recombineering facilitates many kinds of genomic experiment that have otherwise been difficult to carry out, and should enhance functional genomic studies by providing better mouse models and a more refined genetic analysis of the mouse genome.
Abstract: Highly efficient phage-based Escherichia coli homologous recombination systems have recently been developed that enable genomic DNA in bacterial artificial chromosomes to be modified and subcloned, without the need for restriction enzymes or DNA ligases. This new form of chromosome engineering, termed recombinogenic engineering or recombineering, is efficient and greatly decreases the time it takes to create transgenic mouse models by traditional means. Recombineering also facilitates many kinds of genomic experiment that have otherwise been difficult to carry out, and should enhance functional genomic studies by providing better mouse models and a more refined genetic analysis of the mouse genome.

Journal ArticleDOI
TL;DR: Sequence-level studies on model organisms whose genomes show clearer evidence of ancient polyploidy are invaluable because they indicate what the evolutionary products of genome duplication can look like.
Abstract: Thirty years after Susumu Ohno proposed that vertebrate genomes are degenerate polyploids, the extent to which genome duplication contributed to the evolution of the vertebrate genome, if at all, is still uncertain. Sequence-level studies on model organisms whose genomes show clearer evidence of ancient polyploidy are invaluable because they indicate what the evolutionary products of genome duplication can look like. The greatest mystery is the molecular basis of diploidization, the evolutionary process by which a polyploid genome turns into a diploid one.

Journal ArticleDOI
TL;DR: The mitochondrial oxidative phosphorylation system is the final biochemical pathway in the production of ATP and improvements in this arena have profited from progress in various genome projects, as well as improvements in the ability to create relevant animal models.
Abstract: The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway in the production of ATP. The OXPHOS system consists of five multiprotein complexes, the individual subunits of which are encoded either by the mitochondrial or by the nuclear genome. Defects in the OXPHOS system result in devastating, mainly multisystem, diseases, and recent years have seen the description of the underlying genetic mutations in mitochondrial and nuclear genes. Advances in this arena have profited from progress in various genome projects, as well as improvements in our ability to create relevant animal models.

Journal ArticleDOI
TL;DR: It is argued that exotic libraries, which consist of marker-defined genomic regions taken from wild species and introgressed onto the background of elite crop lines, provide plant breeders with an important opportunity to improve the agricultural performance of modern crop varieties.
Abstract: Naturally occurring variation among wild relatives of cultivated crops is an under-exploited resource in plant breeding. Here, I argue that exotic libraries, which consist of marker-defined genomic regions taken from wild species and introgressed onto the background of elite crop lines, provide plant breeders with an important opportunity to improve the agricultural performance of modern crop varieties. These libraries can also act as reagents for the discovery and characterization of genes that underlie traits of agricultural value.

Journal ArticleDOI
TL;DR: In many sexually dimorphic species, a mechanism is required to ensure equivalent levels of gene expression from the sex chromosomes, and in mammals, such dosage compensation is achieved by X-chromosome inactivation, a process that presents a unique medley of biological puzzles.
Abstract: In many sexually dimorphic species, a mechanism is required to ensure equivalent levels of gene expression from the sex chromosomes. In mammals, such dosage compensation is achieved by X-chromosome inactivation, a process that presents a unique medley of biological puzzles: how to silence one but not the other X chromosome in the same nucleus; how to count the number of X's and keep only one active; how to choose which X chromosome is inactivated; and how to establish this silent state rapidly and efficiently during early development. The key to most of these puzzles lies in a unique locus, the X-inactivation centre and a remarkable RNA — Xist — that it encodes.

Journal ArticleDOI
TL;DR: Studies in fruitflies and in mammals reveal that the defensive strategies of invertebrates and vertebrates are highly conserved at the molecular level, which raises the exciting prospects of an increased understanding of innate immunity.
Abstract: The immune system provides protection from a wide range of pathogens. One component of immunity, the phylogenetically ancient innate immune response, fights infections from the moment of first contact and is the fundamental defensive weapon of multicellular organisms. The Toll family of receptors has a crucial role in immune defence. Studies in fruitflies and in mammals reveal that the defensive strategies of invertebrates and vertebrates are highly conserved at the molecular level, which raises the exciting prospects of an increased understanding of innate immunity.

Journal ArticleDOI
TL;DR: Findings in the β-thalassaemias highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved.
Abstract: The remarkable phenotypic diversity of the beta-thalassaemias reflects the heterogeneity of mutations at the beta-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype-genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype-genotype relationships in designing approaches to gene therapy.

Journal ArticleDOI
TL;DR: The implications of the underlying logic of genetic networks are difficult to deduce through experimental techniques alone, and successful approaches will probably involve the union of new experiments and computational modelling techniques.
Abstract: Remarkable progress in genomic research is leading to a complete map of the building blocks of biology Knowledge of this map is, in turn, setting the stage for a fundamental description of cellular function at the DNA level Such a description will entail an understanding of gene regulation, in which proteins often regulate their own production or that of other proteins in a complex web of interactions The implications of the underlying logic of genetic networks are difficult to deduce through experimental techniques alone, and successful approaches will probably involve the union of new experiments and computational modelling techniques

Journal ArticleDOI
TL;DR: Understanding the molecular and cellular basis by which modifier genes exert their influence will provide insights into developmental and physiological pathways that are critical to fundamental biological processes, as well as into novel targets for therapeutic interventions in human diseases.
Abstract: An emerging theme of studies with spontaneous, engineered and induced mutant mice is that phenotypes often depend on genetic background, implying that genetic modifiers have a role in guiding the functional consequences of genetic variation. Understanding the molecular and cellular basis by which modifier genes exert their influence will provide insights into developmental and physiological pathways that are critical to fundamental biological processes, as well as into novel targets for therapeutic interventions in human diseases.

Journal ArticleDOI
TL;DR: The recent cloning of most of the FA-associated genes, and the characterization of their protein products, has provided tantalizing clues as to the molecular basis of this disease.
Abstract: The past few years have witnessed a considerable expansion in our understanding of the pathways that maintain chromosome stability in dividing cells through the identification of genes that are mutated in certain human chromosome instability disorders. Cells that are derived from patients with Fanconi anaemia (FA) show spontaneous chromosomal instability and mutagen hypersensitivity, but FA poses a unique challenge as the nature of the DNA-damage-response pathway thought to be affected by the disease has long been a mystery. However, the recent cloning of most of the FA-associated genes, and the characterization of their protein products, has provided tantalizing clues as to the molecular basis of this disease.

Journal ArticleDOI
TL;DR: The authors showed that the distribution of recombination events in eukaryotic genomes might reflect global features of chromosome structure, such as distribution of modified nucleosomes, which can hinder the ability of geneticists to identify genes by map-based techniques.
Abstract: Meiotic recombination events are distributed unevenly throughout eukaryotic genomes This inhomogeneity leads to distortions of genetic maps that can hinder the ability of geneticists to identify genes by map-based techniques Various lines of evidence, particularly from studies of yeast, indicate that the distribution of recombination events might reflect, at least in part, global features of chromosome structure, such as the distribution of modified nucleosomes

Journal ArticleDOI
TL;DR: The complete sequence of the Arabidopsis thaliana genome provides a framework for exploring the 'big bang' of R genes that occurred and how R genes evolved in plants from their associations with microorganisms, and for improving strategies for more sustainable deployment of disease resistance in crops.
Abstract: Plant pathology was born after the nineteenth-century potato famine, and since then insightful genetic experiments have contributed to the great progress in our understanding of disease control. Our current view of plant resistance focuses on numerous polymorphic resistance loci, which contain genes known as R genes. The complete sequence of the Arabidopsis thaliana genome provides a framework for exploring the 'big bang' of R genes that occurred and how R genes evolved in plants from their associations with microorganisms, and for improving strategies for more sustainable deployment of disease resistance in crops.

Journal ArticleDOI
TL;DR: Modelling experiments in mice are helping to delineate the molecular aetiology of glioblastoma multiforme and are providing systems to identify and test novel and rational therapeutic strategies.
Abstract: Glioblastoma multiforme is the most malignant of the primary brain tumours and is almost always fatal. The treatment strategies for this disease have not changed appreciably for many years and most are based on a limited understanding of the biology of the disease. However, in the past decade, characteristic genetic alterations have been identified in gliomas that might underlie the initiation or progression of the disease. Recent modelling experiments in mice are helping to delineate the molecular aetiology of this disease and are providing systems to identify and test novel and rational therapeutic strategies.

Journal ArticleDOI
TL;DR: Developments in genetics have allowed a more systematic study of the impact that the human genome and infectious disease have on each other, and have confirmed heritability of susceptibility to several infectious diseases.
Abstract: Before Robert Koch's work in the late nineteenth century, diseases such as tuberculosis and leprosy were widely believed to be inherited disorders. Heritability of susceptibility to several infectious diseases has been confirmed by studies in the twentieth century. Infectious diseases, old and new, continue to be an important cause of mortality worldwide. A greater understanding of disease processes is needed if more effective therapies and more useful vaccines are to be produced. As part of this effort, developments in genetics have allowed a more systematic study of the impact that the human genome and infectious disease have on each other.

Journal ArticleDOI
TL;DR: Behavioural genetics research is at the forefront of behavioural genetics research, and the fruitfly Drosophila melanogaster has provided important insights into the molecular, cellular and evolutionary bases of behaviour.
Abstract: Genes are understandably crucial to physiology, morphology and biochemistry, but the idea of genes contributing to individual differences in behaviour once seemed outrageous. Nevertheless, some scientists have aspired to understand the relationship between genes and behaviour, and their research has become increasingly informative and productive over the past several decades. At the forefront of behavioural genetics research is the fruitfly Drosophila melanogaster, which has provided us with important insights into the molecular, cellular and evolutionary bases of behaviour.

Journal ArticleDOI
TL;DR: Inventive genetic screens in zebrafish are revealing new genetic pathways that control vertebrate development, disease and behaviour, and provide a powerful system by which to dissect vertebrate gene function and gene networks.
Abstract: Inventive genetic screens in zebrafish are revealing new genetic pathways that control vertebrate development, disease and behaviour. By exploiting the versatility of zebrafish, biological processes that had been previously obscured can be visualized and many of the responsible genes can be isolated. Coupled with gene knockdown and overexpression technologies, and small-molecule-induced phenotypes, genetic screens in zebrafish provide a powerful system by which to dissect vertebrate gene function and gene networks.