Showing papers in "Nature Reviews Genetics in 2008"
TL;DR: This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of micro RNA function.
Abstract: MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.
4,973 citations
University of Oxford1, Wellcome Trust Centre for Human Genetics2, University of Michigan3, Fred Hutchinson Cancer Research Center4, Duke University5, University of Ottawa6, Foundation for Research & Technology – Hellas7, Tufts University8, Broad Institute9, Harvard University10, Boston Children's Hospital11
TL;DR: This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
Abstract: The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
2,908 citations
TL;DR: The conventional view that DNA methylation functions predominantly to irreversibly silence transcription is being challenged and not only is promoter methylation often highly dynamic during development, but many organisms also seem to targetDNA methylation specifically to the bodies of active genes.
Abstract: The genomes of many animals, plants and fungi are tagged by methylation of DNA cytosine. To understand the biological significance of this epigenetic mark it is essential to know where in the genome it is located. New techniques are making it easier to map DNA methylation patterns on a large scale and the results have already provided surprises. In particular, the conventional view that DNA methylation functions predominantly to irreversibly silence transcription is being challenged. Not only is promoter methylation often highly dynamic during development, but many organisms also seem to target DNA methylation specifically to the bodies of active genes.
2,809 citations
TL;DR: Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
Abstract: Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
1,747 citations
TL;DR: This work has shown that despite continuous misunderstandings and controversies over its use and application, heritability remains key to the response to selection in evolutionary biology and agriculture, and to the prediction of disease risk in medicine.
Abstract: Heritability allows a comparison of the relative importance of genes and environment to the variation of traits within and across populations. The concept of heritability and its definition as an estimable, dimensionless population parameter was introduced by Sewall Wright and Ronald Fisher nearly a century ago. Despite continuous misunderstandings and controversies over its use and application, heritability remains key to the response to selection in evolutionary biology and agriculture, and to the prediction of disease risk in medicine. Recent reports of substantial heritability for gene expression and new estimation methods using marker data highlight the relevance of heritability in the genomics era.
1,716 citations
TL;DR: Together, these studies set the scene for applying the knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
Abstract: Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
1,392 citations
TL;DR: There is a renewed appreciation both for the importance of studying gene interactions and for addressing these questions in a unified, quantitative manner with the advent of high-throughput functional genomics.
Abstract: Epistasis, or interactions between genes, has long been recognized as fundamentally important to understanding the structure and function of genetic pathways and the evolutionary dynamics of complex genetic systems. With the advent of high-throughput functional genomics and the emergence of systems approaches to biology, as well as a new-found ability to pursue the genetic basis of evolution down to specific molecular changes, there is a renewed appreciation both for the importance of studying gene interactions and for addressing these questions in a unified, quantitative manner.
1,387 citations
Journal Article•
TL;DR: In this paper, the authors show that global repression of miRNA maturation promotes cellular transformation and tumorigenesis in cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery.
Abstract: MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in proliferation, differentiation and apoptosis 1,2 , processes commonly altered during tumorigenesis. Recent work has shown a global decrease of mature miRNA expression in human cancers 3 . However, it is unclear whether this global repression of miRNAs reflects the undifferentiated state of tumors or causally contributes to the transformed phenotype. Here we show that global repression of miRNA maturation promotes cellular transformation and tumorigenesis. Cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery showed a substantial decrease in steady-state miRNA levels and a more pronounced transformed phenotype. In animals, miRNA processing-impaired cells formed tumors with accelerated kinetics. These tumors were more invasive than control tumors, suggesting that global miRNA loss enhances tumorigenesis. Furthermore, conditional deletion of Dicer1 enhanced tumor development in a K-Ras-induced mouse model of lung cancer. Overall, these studies indicate that abrogation of global miRNA processing promotes tumorigenesis.
1,324 citations
TL;DR: It is shown that the high rate of nucleotide substitution in RNA viruses is matched by some DNA viruses, suggesting that evolutionary rates in viruses are explained by diverse aspects of viral biology, such as genomic architecture and replication speed, and not simply by polymerase fidelity.
Abstract: Understanding the factors that determine the rate at which genomes generate and fix mutations provides important insights into key evolutionary mechanisms. We review our current knowledge of the rates of mutation and substitution, as well as their determinants, in RNA viruses, DNA viruses and retroviruses. We show that the high rate of nucleotide substitution in RNA viruses is matched by some DNA viruses, suggesting that evolutionary rates in viruses are explained by diverse aspects of viral biology, such as genomic architecture and replication speed, and not simply by polymerase fidelity.
1,321 citations
TL;DR: The linkage disequilibrium process, the nonrandom association of alleles at different loci, and the population genetic processes that affect it are reviewed.
Abstract: Linkage disequilibrium — the nonrandom association of alleles at different loci — is a sensitive indicator of the population genetic forces that structure a genome. Because of the explosive growth of methods for assessing genetic variation at a fine scale, evolutionary biologists and human geneticists are increasingly exploiting linkage disequilibrium in order to understand past evolutionary and demographic events, to map genes that are associated with quantitative characters and inherited diseases, and to understand the joint evolution of linked sets of genes. This article introduces linkage disequilibrium, reviews the population genetic processes that affect it and describes some of its uses. At present, linkage disequilibrium is used much more extensively in the study of humans than in non-humans, but that is changing as technological advances make extensive genomic studies feasible in other species.
1,194 citations
Journal Article•
TL;DR: It is shown here that Myc regulates a much broader set of miRNAs than previously anticipated, and extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.
Abstract: The c-Myc oncogenic transcription factor (Myc) is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. Through the analysis of human and mouse models of B cell lymphoma, we show here that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of activation of Myc is widespread repression of miRNA expression. Chromatin immunoprecipitation reveals that much of this repression is likely to be a direct result of Myc binding to miRNA promoters. We further show that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.
TL;DR: The number of well-supported cases of transfer from both prokaryotes and eukaryotes, many with significant functional implications, is now expanding rapidly and major recent trends include the important role of HGT in adaptation to certain specialized niches and the highly variable impact of H GT in different lineages.
Abstract: Horizontal gene transfer (HGT; also known as lateral gene transfer) has had an important role in eukaryotic genome evolution, but its importance is often overshadowed by the greater prevalence and our more advanced understanding of gene transfer in prokaryotes. Recurrent endosymbioses and the generally poor sampling of most nuclear genes from diverse lineages have also complicated the search for transferred genes. Nevertheless, the number of well-supported cases of transfer from both prokaryotes and eukaryotes, many with significant functional implications, is now expanding rapidly. Major recent trends include the important role of HGT in adaptation to certain specialized niches and the highly variable impact of HGT in different lineages.
TL;DR: Earlier models are revisited and expanded and it is proposed that genomic repeats, and in particular transposable elements, have been a rich source of material for the assembly and tinkering of eukaryotic gene regulatory systems.
Abstract: The control and coordination of eukaryotic gene expression rely on transcriptional and post-transcriptional regulatory networks. Although progress has been made in mapping the components and deciphering the function of these networks, the mechanisms by which such intricate circuits originate and evolve remain poorly understood. Here I revisit and expand earlier models and propose that genomic repeats, and in particular transposable elements, have been a rich source of material for the assembly and tinkering of eukaryotic gene regulatory systems.
TL;DR: Genomic data suggest that different gene classes tend to be retained after single-gene and whole-genome duplications, and in many cases the 'new' function of one copy is a secondary property that was always present, but that has been co-opted to a primary role after the duplication.
Abstract: Gene duplication provides raw material for functional innovation. Recent advances have shed light on two fundamental questions regarding gene duplication: which genes tend to undergo duplication? And how does natural selection subsequently act on them? Genomic data suggest that different gene classes tend to be retained after single-gene and whole-genome duplications. We also know that functional differences between duplicate genes can originate in several different ways, including mutations that directly impart new functions, subdivision of ancestral functions and selection for changes in gene dosage. Interestingly, in many cases the 'new' function of one copy is a secondary property that was always present, but that has been co-opted to a primary role after the duplication.
TL;DR: A productive future for DNA vaccine technology is suggested as more optimized constructs, better trial designs and improved platforms are being brought into the clinic.
Abstract: Since the discovery, over a decade and a half ago, that genetically engineered DNA can be delivered in vaccine form and elicit an immune response, there has been much progress in understanding the basic biology of this platform. A large amount of data has been generated in preclinical model systems, and more sustained cellular responses and more consistent antibody responses are being observed in the clinic. Four DNA vaccine products have recently been approved, all in the area of veterinary medicine. These results suggest a productive future for this technology as more optimized constructs, better trial designs and improved platforms are being brought into the clinic.
TL;DR: The molecular mechanisms and organization of the DNA-repair pathways that remove single-strand breaks are reviewed and the connection between defects in these pathways and hereditary neurodegenerative disease are discussed.
Abstract: Hereditary defects in the repair of DNA damage are implicated in a variety of diseases, many of which are typified by neurological dysfunction and/or increased genetic instability and cancer. Of the different types of DNA damage that arise in cells, single-strand breaks (SSBs) are the most common, arising at a frequency of tens of thousands per cell per day from direct attack by intracellular metabolites and from spontaneous DNA decay. Here, the molecular mechanisms and organization of the DNA-repair pathways that remove SSBs are reviewed and the connection between defects in these pathways and hereditary neurodegenerative disease are discussed.
TL;DR: A range of recent studies give fascinating insight into cellular strategies for keeping gene expression in tune with physiological needs dictated by the environment, promoting adaptation to both short- and long-term environmental changes.
Abstract: Organisms are constantly exposed to a wide range of environmental changes, including both short-term changes during their lifetime and longer-term changes across generations. Stress-related gene expression programmes, characterized by distinct transcriptional mechanisms and high levels of noise in their expression patterns, need to be balanced with growth-related gene expression programmes. A range of recent studies give fascinating insight into cellular strategies for keeping gene expression in tune with physiological needs dictated by the environment, promoting adaptation to both short- and long-term environmental changes. Not only do organisms show great resilience to external challenges, but emerging data suggest that they also exploit these challenges to fuel phenotypic variation and evolutionary innovation.
TL;DR: The relationship that exists between cell-cycle progression and the self-renewal versus commitment cell-fate decision in embryonic and adult stem cells is deconstructed.
Abstract: The regulation of stem cell self-renewal must balance the regenerative needs of tissues that persist throughout life with the potential for cell overgrowth, transformation and cancer. Here, we attempt to deconstruct the relationship that exists between cell-cycle progression and the self-renewal versus commitment cell-fate decision in embryonic and adult stem cells. Recent genetic studies in mice have provided insights into the regulation of the cell cycle in stem cells, including its potential modulation by the stem cell niche. Although the dynamics of the embryonic and adult stem cell cycles are profoundly dissimilar, we suggest that shared principles underlie the governance of this important decision point in diverse stem cell types.
TL;DR: It is shown that epigenetic modifiers have key roles in germ-cell development itself and contributes to the gene-expression programme that is required for germ- cell development, regulation of meiosis and genomic integrity.
Abstract: The epigenetic profile of germ cells, which is defined by modifications of DNA and chromatin, changes dynamically during their development. Many of the changes are associated with the acquisition of the capacity to support post-fertilization development. Our knowledge of this aspect has greatly increased- for example, insights into how the re-establishment of parental imprints is regulated. In addition, an emerging theme from recent studies is that epigenetic modifiers have key roles in germ-cell development itself--for example, epigenetics contributes to the gene-expression programme that is required for germ-cell development, regulation of meiosis and genomic integrity. Understanding epigenetic regulation in germ cells has implications for reproductive engineering technologies and human health.
TL;DR: Emergent themes are now beginning to illustrate how microRNAs have been incorporated into diverse settings, including potent inhibition of individual key targets, fine-tuning of target activity, the coordinated regulation of target batteries, and the reversibility of some aspects of microRNA-mediated repression.
Abstract: Regulation of gene activity by microRNAs is critical to myriad aspects of eukaryotic development and physiology. Amidst an extensive regulatory web that is predicted to involve thousands of transcripts, emergent themes are now beginning to illustrate how microRNAs have been incorporated into diverse settings. These include potent inhibition of individual key targets, fine-tuning of target activity, the coordinated regulation of target batteries, and the reversibility of some aspects of microRNA-mediated repression. Such themes may reflect some of the inherent advantages of exploiting microRNA control in biological circuits, and provide insight into the consequences of microRNA dysfunction in disease.
TL;DR: The causes and consequences of instability are reviewed with the aim of providing a mechanistic perspective on the origin of genomic instability.
Abstract: Genomic instability in the form of mutations and chromosome rearrangements is usually associated with pathological disorders, and yet it is also crucial for evolution. Two types of elements have a key role in instability leading to rearrangements: those that act in trans to prevent instability--among them are replication, repair and S-phase checkpoint factors--and those that act in cis--chromosomal hotspots of instability such as fragile sites and highly transcribed DNA sequences. Taking these elements as a guide, we review the causes and consequences of instability with the aim of providing a mechanistic perspective on the origin of genomic instability.
TL;DR: Results suggest that the coordinated synthesis of replication- dependent and variant histone mRNAs is achieved by signals that affect formation of the 3′ end of the replication-dependent histonemRNAs.
Abstract: The canonical histone proteins are encoded by replication-dependent genes and must rapidly reach high levels of expression during S phase. In metazoans the genes that encode these proteins produce mRNAs that, instead of being polyadenylated, contain a unique 3' end structure. By contrast, the synthesis of the variant, replication-independent histones, which are encoded by polyadenylated mRNAs, persists outside of S phase. Accurate positioning of both histone types in chromatin is essential for proper transcriptional regulation, the demarcation of heterochromatic boundaries and the epigenetic inheritance of gene expression patterns. Recent results suggest that the coordinated synthesis of replication-dependent and variant histone mRNAs is achieved by signals that affect formation of the 3' end of the replication-dependent histone mRNAs.
TL;DR: Retinoic acid has complex and pleiotropic functions during vertebrate development and some of these functions could be maintained throughout the life of an organism to regulate cell-lineage decisions and/or the differentiation of stem cell populations, highlighting possibilities for regenerative medicine.
Abstract: Retinoic acid (RA) has complex and pleiotropic functions during vertebrate development. Recent work in several species has increased our understanding of the roles of RA as a signalling molecule. These functions rely on a tight control of RA distribution within embryonic tissues through the combined action of synthesizing and metabolizing enzymes, possibly leading to diffusion gradients. Also important is the switching of nuclear receptors from a transcriptionally repressing state to an activating state. In addition, cross-talk with other key embryonic signals, especially fibroblast growth factors (FGFs) and sonic hedgehog (SHH), is being uncovered. Some of these functions could be maintained throughout the life of an organism to regulate cell-lineage decisions and/or the differentiation of stem cell populations, highlighting possibilities for regenerative medicine.
TL;DR: Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.
Abstract: Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.
TL;DR: Recent advances in elucidating the intracellular signalling pathways that coordinate gene expression between organelles and the nucleus are reviewed, with a focus on photosynthetic plants.
Abstract: Following the acquisition of chloroplasts and mitochondria by eukaryotic cells during endosymbiotic evolution, most of the genes in these organelles were either lost or transferred to the nucleus. Encoding organelle-destined proteins in the nucleus allows for host control of the organelle. In return, organelles send signals to the nucleus to coordinate nuclear and organellar activities. In photosynthetic eukaryotes, additional interactions exist between mitochondria and chloroplasts. Here we review recent advances in elucidating the intracellular signalling pathways that coordinate gene expression between organelles and the nucleus, with a focus on photosynthetic plants.
TL;DR: New models for how centromeric chromatin is established and propagated are proposed for the establishment and maintenance of centromere identity and kinetochore assembly.
Abstract: The assembly of just a single kinetochore at the centromere of each sister chromatid is essential for accurate chromosome segregation during cell division. Surprisingly, despite their vital function, centromeres show considerable plasticity with respect to their chromosomal locations and activity. The establishment and maintenance of centromeric chromatin, and therefore the location of kinetochores, is epigenetically regulated. The histone H3 variant CENP-A is the key determinant of centromere identity and kinetochore assembly. Recent studies have identified many factors that affect CENP-A localization, but their precise roles in this process are unknown. We build on these advances and on new information about the timing of CENP-A assembly during the cell cycle to propose new models for how centromeric chromatin is established and propagated.
TL;DR: It seems that mutation by gene duplication and inactivation has important roles in both the adaptive and non-adaptive evolution of chemosensation.
Abstract: Chemosensory receptors are essential for the survival of organisms that range from bacteria to mammals. Recent studies have shown that the numbers of functional chemosensory receptor genes and pseudogenes vary enormously among the genomes of different animal species. Although much of the variation can be explained by the adaptation of organisms to different environments, it has become clear that a substantial portion is generated by genomic drift, a random process of gene duplication and deletion. Genomic drift also generates a substantial amount of copy-number variation in chemosensory receptor genes within species. It seems that mutation by gene duplication and inactivation has important roles in both the adaptive and non-adaptive evolution of chemosensation.
TL;DR: Genetically engineering plants to produce cellulases and hemicellulases, and to reduce the need for pretreatment processes through lignin modification, are promising paths to solving the problem of low-cost biofuel supply.
Abstract: Biofuels provide a potential route to avoiding the global political instability and environmental issues that arise from reliance on petroleum. Currently, most biofuel is in the form of ethanol generated from starch or sugar, but this can meet only a limited fraction of global fuel requirements. Conversion of cellulosic biomass, which is both abundant and renewable, is a promising alternative. However, the cellulases and pretreatment processes involved are very expensive. Genetically engineering plants to produce cellulases and hemicellulases, and to reduce the need for pretreatment processes through lignin modification, are promising paths to solving this problem, together with other strategies, such as increasing plant polysaccharide content and overall biomass.
Journal Article•
TL;DR: The miR-34 activation can recapitulate elements of p53 activity, including induction of cell-cycle arrest and promotion of apoptosis, and loss of miR34 can impair p53-mediated cell death as discussed by the authors.
Abstract: | Several recent studies have found a conserved microRNA (miRNA) family, the miR-34s, to be direct transcriptional targets of p53. miR-34 activation can recapitulate elements of p53 activity, including induction of cell-cycle arrest and promotion of apoptosis, and loss of miR-34 can impair p53-mediated cell death. These data reinforce the growing awareness that non-coding RNAs are key players in tumour development by placing miRNAs in a central role in a well-known tumour-suppressor network.
TL;DR: The concept of evolvability, and the increasing theoretical and empirical literature that refers to it, may constitute one of several pillars on which an extended evolutionary synthesis will take shape during the next few years, although much work remains to be done on how evolVability comes about.
Abstract: The ability to evolve — evolvability — is important in determining the course of evolution. But does evolvability itself evolve, and how should we even agree on a definition of evolvability?