Showing papers in "Nature Reviews Genetics in 2002"
TL;DR: This review discusses patterns of DNA methylation and chromatin structure in neoplasia and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.
Abstract: Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.
5,492 citations
TL;DR: As the splicing mechanisms that depend on exonic signals are elucidated, new therapeutic approaches to treating certain genetic diseases can begin to be explored.
Abstract: Point mutations in the coding regions of genes are commonly assumed to exert their effects by altering single amino acids in the encoded proteins. However, there is increasing evidence that many human disease genes harbour exonic mutations that affect pre-mRNA splicing. Nonsense, missense and even translationally silent mutations can inactivate genes by inducing the splicing machinery to skip the mutant exons. Similarly, coding-region single-nucleotide polymorphisms might cause phenotypic variability by influencing splicing accuracy or efficiency. As the splicing mechanisms that depend on exonic signals are elucidated, new therapeutic approaches to treating certain genetic diseases can begin to be explored.
2,218 citations
TL;DR: The regulation of higher-order chromatin structures by DNA methylation and histone modification is crucial for genome reprogramming during early embryogenesis and gametogenesis, and for tissue-specific gene expression and global gene silencing.
Abstract: The developmental programme of embryogenesis is controlled by both genetic and epigenetic mechanisms. An emerging theme from recent studies is that the regulation of higher-order chromatin structures by DNA methylation and histone modification is crucial for genome reprogramming during early embryogenesis and gametogenesis, and for tissue-specific gene expression and global gene silencing. Disruptions to chromatin modification can lead to the dysregulation of developmental processes, such as X-chromosome inactivation and genomic imprinting, and to various diseases. Understanding the process of epigenetic reprogramming in development is important for studies of cloning and the clinical application of stem-cell therapy.
1,894 citations
TL;DR: This work has shown that the use of siRNAs to silence genes in vertebrate cells was only reported a year ago, and the emerging literature indicates that most vertebrate genes can be studied with this technology.
Abstract: Among the 3 billion base pairs of the human genome, there are approximately 30,000-40,000 protein-coding genes, but the function of at least half of them remains unknown. A new tool - short interfering RNAs (siRNAs) - has now been developed for systematically deciphering the functions and interactions of these thousands of genes. siRNAs are an intermediate of RNA interference, the process by which double-stranded RNA silences homologous genes. Although the use of siRNAs to silence genes in vertebrate cells was only reported a year ago, the emerging literature indicates that most vertebrate genes can be studied with this technology.
1,620 citations
TL;DR: During the past 65 million years, Alu elements have propagated to more than one million copies in primate genomes, which has resulted in the generation of a series of Alu subfamilies of different ages.
Abstract: During the past 65 million years, Alu elements have propagated to more than one million copies in primate genomes, which has resulted in the generation of a series of Alu subfamilies of different ages. Alu elements affect the genome in several ways, causing insertion mutations, recombination between elements, gene conversion and alterations in gene expression. Alu-insertion polymorphisms are a boon for the study of human population genetics and primate comparative genomics because they are neutral genetic markers of identical descent with known ancestral states.
1,415 citations
TL;DR: Sequence comparisons and functional studies are beginning to show the extent to which the rapid divergence of reproductive proteins is involved in the speciation process.
Abstract: Many genes that mediate sexual reproduction, such as those involved in gamete recognition, diverge rapidly, often as a result of adaptive evolution This widespread phenomenon might have important consequences, such as the establishment of barriers to fertilization that might lead to speciation Sequence comparisons and functional studies are beginning to show the extent to which the rapid divergence of reproductive proteins is involved in the speciation process
1,247 citations
TL;DR: The integration of phylogenetic, ecological and population-genetic studies have provided new insights into the selective mechanisms that are responsible for major evolutionary transitions between reproductive modes.
Abstract: Charles Darwin recognized that flowering plants have an unrivalled diversity of sexual systems. Determining the ecological and genetic factors that govern sexual diversification in plants is today a central problem in evolutionary biology. The integration of phylogenetic, ecological and population-genetic studies have provided new insights into the selective mechanisms that are responsible for major evolutionary transitions between reproductive modes.
1,103 citations
TL;DR: This review draws on empirical studies in humans and Drosophila, as well as simulation studies, to assess the current state of knowledge about patterns of LD, and consider the implications for the use of LD as a mapping tool.
Abstract: Particular alleles at neighbouring loci tend to be co-inherited. For tightly linked loci, this might lead to associations between alleles in the population — a property known as linkage disequilibrium (LD). LD has recently become the focus of intense study in the hope that it might facilitate the mapping of complex disease loci through whole-genome association studies. This approach depends crucially on the patterns of LD in the human genome. In this review, we draw on empirical studies in humans and Drosophila, as well as simulation studies, to assess the current state of knowledge about patterns of LD, and consider the implications for the use of LD as a mapping tool.
1,053 citations
TL;DR: An overview of the current resources for twin research is provided to obtain insights into the genetic epidemiology of complex traits and diseases, to study the interaction of genotype with sex, age and lifestyle factors, and the causes of co-morbidity between traits and disease.
Abstract: Twin studies have been a valuable source of information about the genetic basis of complex traits. To maximize the potential of twin studies, large, worldwide registers of data on twins and their relatives have been established. Here, we provide an overview of the current resources for twin research. These can be used to obtain insights into the genetic epidemiology of complex traits and diseases, to study the interaction of genotype with sex, age and lifestyle factors, and to study the causes of co-morbidity between traits and diseases. Because of their design, these registers offer unique opportunities for selected sampling for quantitative trait loci linkage and association studies.
1,043 citations
TL;DR: The candidate-gene approach has been criticised because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms as discussed by the authors, and these challenges have led to pessimism about the candidate gene approach and about the genetic analysis of complex diseases in general.
Abstract: Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These challenges have led to pessimism about the candidate-gene approach and about the genetic analysis of complex diseases in general. We believe that these criticisms can be usefully countered with an appeal to the principles of epidemiological investigation.
1,041 citations
TL;DR: The recent availability of large quantities of genomic sequence has led to a shift from the genetic characterization of single elements to genome-wide analysis of enormous transposable-element populations, particularly in plants.
Abstract: Transposable elements are the single largest component of the genetic material of most eukaryotes. The recent availability of large quantities of genomic sequence has led to a shift from the genetic characterization of single elements to genome-wide analysis of enormous transposable-element populations. Nowhere is this shift more evident than in plants, in which transposable elements were first discovered and where they are still actively reshaping genomes.
TL;DR: Cell size and mitotic index (MI) in two nearly isogenic tomato lines in which either a largeor small-fruit fw2.2 allele was present were analysed, indicating that an extended period of cell division might underlie larger fruit size in this line.
Abstract: Fruit weight and size are agriculturally important traits, but little is known of their genetic and molecular bases. Many genetic studies on these traits have been done in the tomato, owing to the disparity in size between the fruits of wild and domesticated tomatoes (see picture). Quantitative trait loci (QTL) mapping studies in this plant have identified nearly 30 tomato QTL that affect fruit weight and size. One such QTL is fw2.2, which accounts for ~30% of the difference in fruit weight between wild and domesticated tomatoes. Earlier studies have strongly indicated that altered gene regulation underlies the effects of the largeand small-fruit alleles of fw2.2 on fruit weight. It has long been believed that such mutations, especially when they affect the timing of development (‘heterochronic’ mutations), might be a natural force of evolutionary change in plants. In a detailed study of fw2.2, Steven Tanksley’s group now provide the first experimental evidence to support this theory. Because previous studies in plants and Drosophila have shown that both cell division and expansion are essential factors that determine organ and fruit size, Cong et al. analysed cell size and mitotic index (MI) in two nearly isogenic tomato lines in which either a largeor small-fruit fw2.2 allele was present. Differences in MI were found between the fruits of these two lines, but not in cell size. In the small-fruit fw2.2 line (TA1144), a rapid but brief rise in MI occurs immediately after fertilization. By contrast, a more gradual and sustained rise in MI occurs in the large-fruit allele line (TA1143), indicating that an extended period of cell division might underlie larger fruit size in this line. Next, the authors found that the fw2.2 alleles differ in the timing of their peak expression by around one week. This difference in expression timing inversely correlated with changes in mitotic activity during early fruit development, indicating that fw2.2 might negatively regulate cell division. Moreover, by ~12 days post-fertilization, fw2.2 levels in TA1144 were more than double those in TA1143. However, only subtle differences in expression patterns were evident between the two lines.
TL;DR: This paper focuses on microarray experiments, which are used to quantify and compare gene expression on a large scale and can be costly in terms of equipment, consumables and time.
Abstract: Microarray experiments are used to quantify and compare gene expression on a large scale. As with all large-scale experiments, they can be costly in terms of equipment, consumables and time. Therefore, careful design is particularly important if the resulting experiment is to be maximally informative, given the effort and the resources. What then are the issues that need to be addressed when planning microarray experiments? Which features of an experiment have the most impact on the accuracy and precision of the resulting measurements? How do we balance the different components of experimental design to reach a decision? For example, should we replicate, and if so, how?
TL;DR: The phylogeny and timescale of life are becoming better understood as the analysis of genomic data from model organisms continues to grow and the emphasis on historical patterns is helping to bridge barriers among organism-based research communities.
Abstract: The phylogeny and timescale of life are becoming better understood as the analysis of genomic data from model organisms continues to grow. As a result, discoveries are being made about the early history of life and the origin and development of complex multicellular life. This emerging comparative framework and the emphasis on historical patterns is helping to bridge barriers among organism-based research communities.
TL;DR: The lessons learnt from this evolution of QTL methodology might also be generally relevant to other types of functional genomics approach that are aimed at the dissection of complex phenotypes, such as microarray assessment of gene expression.
Abstract: Simple statistical methods for the study of quantitative trait loci (QTL), such as analysis of variance, have given way to methods that involve several markers and high-resolution genetic maps. As a result, the mapping community has been provided with statistical and computational tools that have much greater power than ever before for studying and locating multiple and interacting QTL. Apart from their immediate practical applications, the lessons learnt from this evolution of QTL methodology might also be generally relevant to other types of functional genomics approach that are aimed at the dissection of complex phenotypes, such as microarray assessment of gene expression.
TL;DR: By combining genetic engineering with cell-biological studies and with human genome data analyses, skin biologists are discovering the mechanisms that underlie the development and differentiation of the epidermis and hair follicles of the skin.
Abstract: At the surface of the skin, the epidermis serves as the armour for the body. Scientists are now closer than ever to understanding how the epidermis accomplishes this extraordinary feat, and is able to survive and replenish itself under the harshest conditions that face any tissue. By combining genetic engineering with cell-biological studies and with human genome data analyses, skin biologists are discovering the mechanisms that underlie the development and differentiation of the epidermis and hair follicles of the skin. This explosion of knowledge paves the way for new discoveries into the genetic bases of human skin disorders and for developing new therapeutics.
TL;DR: A personal perspective on the history of zebrafish research is provided, from the assembly of the first genetic and embryological tools through to sequencing of the genome.
Abstract: The understanding of vertebrate development has advanced considerably in recent years, primarily due to the study of a few model organisms. The zebrafish, the newest of these models, has risen to prominence because both genetic and experimental embryological methods can be easily applied to this animal. The combination of approaches has proven powerful, yielding insights into the formation and function of individual tissues, organ systems and neural networks, and into human disease mechanisms. Here, we provide a personal perspective on the history of zebrafish research, from the assembly of the first genetic and embryological tools through to sequencing of the genome.
TL;DR: The key to understanding the evolutionary significance of QTL is to understand the nature of inherited variation, not in the immediate mechanistic sense of how genes influence phenotype, but, rather, to know what evolutionary forces maintain genetic variability.
Abstract: Until recently, it was impracticable to identify the genes that are responsible for variation in continuous traits, or to directly observe the effects of their different alleles. Now, the abundance of genetic markers has made it possible to identify quantitative trait loci (QTL)--the regions of a chromosome or, ideally, individual sequence variants that are responsible for trait variation. What kind of QTL do we expect to find and what can our observations of QTL tell us about how organisms evolve? The key to understanding the evolutionary significance of QTL is to understand the nature of inherited variation, not in the immediate mechanistic sense of how genes influence phenotype, but, rather, to know what evolutionary forces maintain genetic variability.
TL;DR: This work considers both the theoretical framework and the experimental evidence to explain the preservation of duplicated genes.
Abstract: Many genes are members of large families that have arisen during evolution through gene duplication events. Our increasing understanding of gene organization at the scale of whole genomes is revealing further evidence for the extensive retention of genes that arise during duplication events of various types. Duplication is thought to be an important means of providing a substrate on which evolution can work. An understanding of gene duplication and its resolution is crucial for revealing mechanisms of genetic redundancy. Here, we consider both the theoretical framework and the experimental evidence to explain the preservation of duplicated genes.
TL;DR: A better understanding of the genetic differences between wild grasses and domesticated crops adds important facets to the continuing debate on the origin of Western agriculture and the societies to which it gave rise.
Abstract: About 12,000 years ago, humans began the transition from hunter-gathering to a sedentary, agriculture-based society. From its origins in the Near East, farming expanded throughout Europe, Asia and Africa, together with various domesticated plants and animals. Where, how and why agriculture originated is still debated. But newer findings, on the basis of genome-wide measures of genetic similarity, have traced the origins of some domesticated cereals to wild populations of naturally occurring grasses that persist in the Near East. A better understanding of the genetic differences between wild grasses and domesticated crops adds important facets to the continuing debate on the origin of Western agriculture and the societies to which it gave rise.
TL;DR: Improvements in genotyping technologies have led to the increased use of genetic polymorphism for inference about population phenomena, such as migration and selection, which presents a challenge in analysis of polymorphism data.
Abstract: Improvements in genotyping technologies have led to the increased use of genetic polymorphism for inference about population phenomena, such as migration and selection. Such inference presents a challenge, because polymorphism data reflect a unique, complex, non-repeatable evolutionary history. Traditional analysis methods do not take this into account. A stochastic process known as the 'coalescent' presents a coherent statistical framework for analysis of genetic polymorphisms.
TL;DR: This article showed that a large body of theoretical work has shown that sexual reproduction and recombination should only evolve under a restricted set of conditions, and that this discrepancy might result from the fact that previous models have ignored important complexities that face natural populations, such as genetic drift and the spatial structure of populations.
Abstract: Sexual reproduction and recombination are ubiquitous. However, a large body of theoretical work has shown that these processes should only evolve under a restricted set of conditions. New studies indicate that this discrepancy might result from the fact that previous models have ignored important complexities that face natural populations, such as genetic drift and the spatial structure of populations.
TL;DR: The genes and genetic markers that are being discovered can be used to enhance the genetic improvement of breeding stock through marker-assisted selection.
Abstract: Substantial advances have been made in the genetic improvement of agriculturally important animal and plant populations through artificial selection on quantitative traits. Most of this selection has been on the basis of observable phenotype, without knowledge of the genetic architecture of the selected characteristics. However, continuing molecular genetic analysis of traits in animal and plant populations is leading to a better understanding of quantitative trait genetics. The genes and genetic markers that are being discovered can be used to enhance the genetic improvement of breeding stock through marker-assisted selection.
TL;DR: In this paper, the authors introduce the use of fish as model genetic systems to study gene function in the context of vertebrate development, using the Zebrafish as a model vertebrate and its Far Eastern cousin Medaka as an important model fish.
Abstract: Genome sequencing has yielded a plethora of new genes the function of which can be unravelled through comparative genomic approaches. Increasingly, developmental biologists are turning to fish as model genetic systems because they are amenable to studies of gene function. Zebrafish has already secured its place as a model vertebrate and now its Far Eastern cousin--medaka--is emerging as an important model fish, because of recent additions to the genetic toolkit available for this organism. Already, the popularity of medaka among developmental biologists has led to important insights into vertebrate development.
TL;DR: The ingenious approaches that have been devised to circumvent traditional screens now make it possible to screen for almost any phenotype in any cell at any stage of development.
Abstract: The success of Drosophila melanogaster as a model organism is largely due to the power of forward genetic screens to identify the genes that are involved in a biological process. Traditional screens, such as the Nobel-prize-winning screen for embryonic-patterning mutants, can only identify the earliest phenotype of a mutation. This review describes the ingenious approaches that have been devised to circumvent this problem: modifier screens, for example, have been invaluable for elucidating signal-transduction pathways, whereas clonal screens now make it possible to screen for almost any phenotype in any cell at any stage of development.
TL;DR: Three main issues that should be resolved to advance the understanding of postcopulatory sexual selection are identified: to determine the genetic basis of different male fertility traits and female traits that mediate sperm selection, and establish the coevolutionary trajectory of sexes.
Abstract: The female reproductive tract is where competition between the sperm of different males takes place, aided and abetted by the female herself Intense postcopulatory sexual selection fosters inter-sexual conflict and drives rapid evolutionary change to generate a startling diversity of morphological, behavioural and physiological adaptations We identify three main issues that should be resolved to advance our understanding of postcopulatory sexual selection We need to determine the genetic basis of different male fertility traits and female traits that mediate sperm selection; identify the genes or genomic regions that control these traits; and establish the coevolutionary trajectory of sexes
TL;DR: Recent developments in quantitative genotyping assays and in the design and analysis of pooling studies are discussed.
Abstract: DNA pooling is a practical way to reduce the cost of large-scale association studies to identify susceptibility loci for common diseases. Pooling allows allele frequencies in groups of individuals to be measured using far fewer PCR reactions and genotyping assays than are used when genotyping individuals. Here, we discuss recent developments in quantitative genotyping assays and in the design and analysis of pooling studies. Sophisticated pooling designs are being developed that can take account of hidden population stratification, confounders and inter-loci interactions, and that allow the analysis of haplotypes.
TL;DR: An explosion of information is generated about the intriguing biology of this pathogen and about its mechanisms of virulence, which reveal the extent of similarities and differences between C. albicans and its benign relative, Saccharomyces cerevisiae.
Abstract: Candida albicans is an opportunistic fungal pathogen that is found in the normal gastrointestinal flora of most healthy humans. However, in immunocompromised patients, blood-stream infections often cause death, despite the use of anti-fungal therapies. The recent completion of the C. albicans genome sequence, the availability of whole-genome microarrays and the development of tools for rapid molecular-genetic manipulations of the C. albicans genome are generating an explosion of information about the intriguing biology of this pathogen and about its mechanisms of virulence. They also reveal the extent of similarities and differences between C. albicans and its benign relative, Saccharomyces cerevisiae.
TL;DR: In this paper, the molecular basis of left-right asymmetry was a mystery, but studies indicate that Nodal and the Lefty proteins, transforming growth factor-beta-related molecules, have a central role in generating asymmetric signals.
Abstract: The generation of morphological, such as left-right, asymmetry during development is an integral part of the establishment of a body plan. Until recently, the molecular basis of left-right asymmetry was a mystery, but studies indicate that Nodal and the Lefty proteins, transforming growth factor-beta-related molecules, have a central role in generating asymmetric signals. Although the initial mechanism of symmetry breaking remains unknown, developmental biologists are beginning to analyse the pathway that leads to left-right asymmetry establishment and maintenance.
TL;DR: The heightened interest in stem-cell biology, along with the successful application of molecular, cellular and genomic approaches in planarians, is re-establishing these fascinating organisms as models for studying regeneration and developmental plasticity.
Abstract: Freshwater planarians were a classic model for studying the problems of development and regeneration. However, as attention shifted towards animals with more rigid developmental processes, the planarians, with their notoriously plastic ontogeny, declined in significance as a model system. This trend was exacerbated with the introduction of genetic and molecular approaches, which did not work well in planarians. More recently, the heightened interest in stem-cell biology, along with the successful application of molecular, cellular and genomic approaches in planarians, is re-establishing these fascinating organisms as models for studying regeneration and developmental plasticity.