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1.  DNA vaccines: ready for prime time? 
Nature reviews. Genetics  2008;9(10):776-788.
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.
PMCID: PMC4317294  PMID: 18781156
2.  The rise of regulatory RNA 
Nature reviews. Genetics  2014;15(6):423-437.
Discoveries over the last decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also in the regulation of genome organization and gene expression, which is increasingly elaborated in complex organisms. Regulatory RNAs appear to operate at many levels, but in particular to play an important role in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here we survey the emergence of the previously unsuspected world of regulatory RNAs from an historical perspective.
PMCID: PMC4314111  PMID: 24776770
3.  Expanding the computational toolbox for mining cancer genomes 
Nature reviews. Genetics  2014;15(8):556-570.
High-throughput DNA sequencing has revolutionized cancer genomics with numerous discoveries relevant to cancer diagnosis and treatment. The latest sequencing and analysis methods have successfully identified somatic alterations including single nucleotide variants (SNVs), insertions and deletions (indels), structural aberrations, and gene fusions. Additional computational techniques have proved useful to define those mutations, genes, and molecular networks that drive diverse cancer phenotypes as well as determine clonal architectures in tumour samples. Collectively, these tools have advanced the study of genomic, transcriptomic, epigenomic alterations and their association to clinical properties. Here, we review cancer genomics software and the insights that have been gained from their application.
PMCID: PMC4168012  PMID: 25001846
4.  Coupling mRNA processing with transcription in time and space 
Nature reviews. Genetics  2014;15(3):163-175.
Maturation of mRNA precursors often occurs simultaneously with their synthesis by RNA polymerase II (Pol II). The co-transcriptional nature of mRNA processing has permitted the evolution of coupling mechanisms that coordinate transcription with mRNA capping, splicing, editing and 3′ end formation. Recent experiments using sophisticated new methods for analysis of nascent RNA have provided important insights into the relative amount of co-transcriptional and post-transcriptional processing, the relationship between mRNA elongation and processing, and the role of the Pol II carboxy-terminal domain (CTD) in regulating these processes.
PMCID: PMC4304646  PMID: 24514444
6.  High-resolution network biology: connecting sequence with function 
Nature reviews. Genetics  2013;14(12):865-879.
Proteins are not monolithic entities; rather, they can contain multiple domains that mediate distinct interactions, and their functionality can be regulated through post-translational modifications at multiple distinct sites. Traditionally, network biology has ignored such properties of proteins and has instead examined either the physical interactions of whole proteins or the consequences of removing entire genes. In this Review, we discuss experimental and computational methods to increase the resolution of protein– protein, genetic and drug–gene interaction studies to the domain and residue levels. Such work will be crucial for using interaction networks to connect sequence and structural information, and to understand the biological consequences of disease-associated mutations, which will hopefully lead to more effective therapeutic strategies.
PMCID: PMC4023809  PMID: 24197012
7.  X chromosome regulation: diverse patterns in development, tissues and disease 
Nature reviews. Genetics  2014;15(6):367-378.
Genes on the mammalian X chromosome are present in one copy in males and two copies in females. The complex mechanisms that regulate the X chromosome lead to evolutionary and physiological variability in gene expression between species, the sexes, individuals, developmental stages, tissues and cell types. In early development, delayed and incomplete X chromosome inactivation (XCI) in some species causes variability in gene expression. Additional diversity stems from escape from XCI and from mosaicism or XCI skewing in females. This causes sex-specific differences that manifest as differential gene expression and associated phenotypes. Furthermore, the complexity and diversity of X dosage regulation affect the severity of diseases caused by X-linked mutations.
PMCID: PMC4117651  PMID: 24733023
8.  Genome dynamics during experimental evolution 
Nature reviews. Genetics  2013;14(12):827-839.
Evolutionary changes in organismal traits may occur gradually or suddenly. Until recently, however, there has been little direct information about how phenotypic changes are related to the rate and nature of underlying changes in genotype. Technological advances enabling whole-genome and whole-population sequencing coupled with experiments that watch evolution in action have brought new precision and insights to studies of mutation rates and genome evolution. Here, we discuss the evolutionary forces and ecological processes that govern genome dynamics in various laboratory systems in the context of relevant population genetic theory, and we relate these findings to evolution in natural populations.
PMCID: PMC4239992  PMID: 24166031
9.  New genes as drivers of phenotypic evolution 
Nature reviews. Genetics  2013;14(9):645-660.
During the course of evolution, genomes acquire novel genetic elements as sources of functional and phenotypic diversity, including new genes that originated in recent evolution. In the past few years, substantial progress has been made in understanding the evolution and phenotypic effects of new genes. In particular, an emerging picture is that new genes, despite being present in the genomes of only a subset of species, can rapidly evolve indispensable roles in fundamental biological processes, including development, reproduction, brain function and behaviour. The molecular underpinnings of how new genes can develop these roles are starting to be characterized. These recent discoveries yield fresh insights into our broad understanding of biological diversity at refined resolution.
PMCID: PMC4236023  PMID: 23949544
10.  Comparative primate genomics: emerging patterns of genome content and dynamics 
Nature reviews. Genetics  2014;15(5):347-359.
Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for several primates, with analyses of several others underway. Whole genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other nonhuman primates provide valuable insight into genetic similarities and differences among species used as models for disease-related research. This review summarizes current knowledge regarding primate genome content and dynamics and offers a series of goals for the near future.
PMCID: PMC4113315  PMID: 24709753
11.  RNA interference (RNAi) in the Nucleus: roles for small RNA in transcription, epigenetics and beyond 
Nature reviews. Genetics  2013;14(2):100-112.
A growing number of functions are emerging for RNAi in the nucleus, in addition to well-characterized roles in post-transcriptional gene silencing in the cytoplasm. Epigenetic modifications directed by small RNA have been shown to cause transcriptional repression in plants, fungi, and animals. Additionally growing evidence indicates that RNAi regulates transcription through interaction with transcriptional machinery. Nuclear small RNAs include small interfering RNA (siRNA) and PIWI-interacting RNA (piRNA) and are implicated in nuclear processes such as transposon regulation, heterochromatin formation, developmental gene regulation and genome stability.
PMCID: PMC4205957  PMID: 23329111
12.  Dynamics, mechanisms, and functional implications of transcription factor binding evolution in metazoans 
Nature reviews. Genetics  2014;15(4):221-233.
Transcription factor binding differences can contribute to organismal evolution by altering downstream gene expression programmes. Recent genome-wide studies in Drosophila and mammals have revealed common quantitative and combinatorial properties of in vivo DNA-binding, as well as significant differences in the rate and mechanisms of metazoan transcription factor binding evolution. Here, we review the recently-discovered, rapid re-wiring of in vivo transcription factor binding between related metazoan species and summarize general principles underlying the observed patterns of evolution. We then consider what might explain genome evolution differences between metazoan phyla, and outline the conceptual and technological challenges facing the field.
PMCID: PMC4175440  PMID: 24590227
13.  Routes for breaching and protecting genetic privacy 
Nature reviews. Genetics  2014;15(6):409-421.
We are entering an era of ubiquitous genetic information for research, clinical care and personal curiosity. Sharing these datasets is vital for progress in biomedical research. However, one growing concern is the ability to protect the genetic privacy of the data originators. Here, we present an overview of genetic privacy breaching strategies. We outline the principles of each technique, point to the underlying assumptions, and assess its technological complexity and maturation. We then review potential mitigation methods for privacy-preserving dissemination of sensitive data and highlight different cases that are relevant to genetic applications.
PMCID: PMC4151119  PMID: 24805122
14.  Spatiotemporal signalling in plant development 
Nature reviews. Genetics  2013;14(9):10.1038/nrg3541.
Plants, being sessile organisms, need to respond to changing environments, and as a result they have evolved unique signalling mechanisms that allow rapid communication between different parts of the plant. The signalling mechanisms that direct plant development include long-range effectors, such as phytohormones, and molecules with a local intra-organ range, such as peptides, transcription factors and some small RNAs. In this Review, we highlight recent advances in understanding plant signalling mechanisms and discuss how different classes of signalling networks can integrate with gene regulatory networks and contribute to plant development. In some cases, we also address the evolutionary context of mechanisms and discuss possible links between the lifestyle of plants and selection for different signalling mechanisms.
PMCID: PMC3870141  PMID: 23949543
15.  Adult-specific functions of animal microRNAs 
Nature reviews. Genetics  2013;14(8):535-548.
microRNAs (miRNAs) are ~22 nucleotide (nt) RNAs that coordinate vast regulatory networks in animals, and thereby influence myriad processes. This review examines evidence that miRNAs play continuous roles in adults, in ways that are separable from developmental control. Adult-specific activities for miRNAs have been described in a variety of stem cell populations, in the context of neural function and cardiovascular biology, in metabolism and physiology, and during cancer. In addition to reviewing recent results, we also discuss methods for studying miRNA activities specifically in adults and evaluate their relative strengths and weaknesses. A fuller understanding of continuous functions of miRNAs in adults has bearing on efforts and opportunities to manipulate miRNAs for therapeutic purposes.
PMCID: PMC4136762  PMID: 23817310
17.  Y chromosome evolution: emerging insights into processes of Y chromosome degeneration 
Nature reviews. Genetics  2013;14(2):113-124.
The human Y chromosome is intriguing not only because it harbours the master-switch gene determining gender but also because of its unusual evolutionary trajectory. Previously an autosome, Y chromosome evolution has been characterized by massive gene decay. Recent whole-genome and transcriptome analyses of Y chromosomes in humans and other primates, in Drosophila species as well as in plants have shed light on the current gene content of the Y, its origins and its long-term fate. Comparative analysis of young and old Y chromosomes have given further insights into the evolutionary and molecular forces triggering Y degeneration and its evolutionary destiny.
PMCID: PMC4120474  PMID: 23329112
18.  Chromatin modifiers: regulators of cellular differentiation 
Nature reviews. Genetics  2013;15(2):93-106.
Cellular differentiation, by definition, is epigenetic. Genome-wide profiling of pluripotent cells and differentiated cells suggests global chromatin remodeling during differentiation, resulting in progressive transition from a relatively open chromatin configuration to a more compact state. Genetic studies in mouse models demonstrate major roles for a variety of histone modifiers and chromatin remodelers in key developmental transitions, such as the segregation of embryonic and extraembryonic lineages in blastocyst stage embryos, the formation of the three germ layers during gastrulation, and differentiation of adult stem cells. Furthermore, rather than merely stabilizing the gene expression changes driven by developmental transcription factors, evidence is emerging that chromatin regulators have multifaceted roles in cell fate decisions.
PMCID: PMC3999985  PMID: 24366184
19.  Sequencing studies in human genetics: design and interpretation 
Nature reviews. Genetics  2013;14(7):460-470.
Next-gene ration sequencing is becoming the primary discovery tool in human genetics. There have been many clear successes in identifying genes that are responsible for Mendelian diseases, and sequencing approaches are now poised to identify the mutations that cause undiagnosed childhood genetic diseases and those that predispose individuals to more common complex diseases. There are, however, growing concerns that the complexity and magnitude of complete sequence data could lead to an explosion of weakly justified claims of association between genetic variants and disease. Here, we provide an overview of the basic workflow in next-generation sequencing studies and emphasize, where possible, measures and considerations that facilitate accurate inferences from human sequencing studies.
PMCID: PMC4117319  PMID: 23752795
20.  Genetic Architectures of Psychiatric Disorders: The Emerging Picture and Its Implications 
Nature reviews. Genetics  2012;13(8):537-551.
Psychiatric disorders are among the most intractable enigmas in medicine. In the past five years, there has been unprecedented progress on the genetics of many of these conditions. In this review, we discuss the genetics of nine cardinal psychiatric disorders (Alzheimer’s disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence, and schizophrenia). Empirical approaches have yielded new hypotheses about etiology, and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.
PMCID: PMC4110909  PMID: 22777127
psychiatric disorders; genetics; structural variation; copy number variation; genome-wide association; meta-analysis; sequencing
21.  Genome structural variation discovery and genotyping 
Nature reviews. Genetics  2011;12(5):363-376.
Comparisons of human genomes show that more base pairs are altered as a result of structural variation — including copy number variation — than as a result of point mutations. Here we review advances and challenges in the discovery and genotyping of structural variation. The recent application of massively parallel sequencing methods has complemented microarray-based methods and has led to an exponential increase in the discovery of smaller structural-variation events. Some global discovery biases remain, but the integration of experimental and computational approaches is proving fruitful for accurate characterization of the copy, content and structure of variable regions. We argue that the long-term goal should be routine, cost-effective and high quality de novo assembly of human genomes to comprehensively assess all classes of structural variation.
PMCID: PMC4108431  PMID: 21358748
22.  Pleiotropy in complex traits: challenges and strategies 
Nature reviews. Genetics  2013;14(7):483-495.
Genome-wide association studies have identified many variants that each affects multiple traits, particularly across autoimmune diseases, cancers and neuropsychiatric disorders, suggesting that pleiotropic effects on human complex traits may be widespread. However, systematic detection of such effects is challenging and requires new methodologies and frameworks for interpreting cross-phenotype results. In this Review, we discuss the evidence for pleiotropy in contemporary genetic mapping studies, new and established analytical approaches to identifying pleiotropic effects, sources of spurious cross-phenotype effects and study design considerations. We also outline the molecular and clinical implications of such findings and discuss future directions of research.
PMCID: PMC4104202  PMID: 23752797
23.  The Role of Replicates for Error Mitigation in Next-Generation Sequencing 
Nature reviews. Genetics  2013;15(1):56-62.
Advances in next-generation technologies have rapidly improved sequencing fidelity and significantly decreased sequencing error rates. However, with billions of nucleotides in a human genome, even low experimental error rates yield many errors in variant calls. Erroneous variants can mimic true somatic and rare variants, thus requiring costly confirmatory experiments to minimize the number of false positives. Here we discuss sources of experimental error in next-generation sequencing and how replicates can be used to abate them.
PMCID: PMC4103745  PMID: 24322726
24.  Pitfalls of predicting complex traits from SNPs 
Nature reviews. Genetics  2013;14(7):507-515.
The success of genome-wide association studies has led to increasing interest in making predictions of complex trait phenotypes including disease from genotype data. Rigorous assessment of the value of predictors is critical before implementation. Here we discuss some of the limitations and pitfalls of prediction analysis and show how naïve implementations can lead to severe bias and misinterpretation of results.
PMCID: PMC4096801  PMID: 23774735
25.  Evolution of genetic and genomic features unique to the human lineage 
Nature reviews. Genetics  2012;13(12):853-866.
Given the unprecedented tools now available for rapidly comparing genomes, the identification and study of genetic and genomic changes unique to our species has accelerated, and we are entering a golden age of human evolutionary genomics. Here we provide an overview of these efforts, highlighting important recent discoveries, examples of the different types of human-specific genomic and genetic changes identified, and salient trends such as the localization of evolutionary adaptive changes to complex loci that are highly enriched for disease associations. Lastly, we discuss the remaining challenges, such as the incomplete nature of current genome sequence assemblies, and difficulties in linking human-specific genomic changes to human-specific phenotypic traits.
PMCID: PMC4097811  PMID: 23154808

Results 1-25 (171)