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  • Genetic Screens to Analyze Pattern Formation of Egg and Embryo in Drosophila: A Personal History
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Trudi Schüpbach

    In Drosophila development, the axes of the egg and future embryo are established during oogenesis. To learn about the underlying genetic and molecular pathways that lead to axis formation, I conducted a large-scale genetic screen at the beginning of my independent career. This led to the eventual understanding that both anterior-posterior and dorsal-ventral pattern information is transmitted from the oocyte to the surrounding follicle cells and in turn from the follicle cells back to the oocyte. How I came to conduct this screen and what further insights were gained by studying the mutants isolated in the screen are the topics of this autobiographical article.

    更新日期:2019-12-04
  • Crossover Interference: Shedding Light on the Evolution of Recombination
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Sarah P. Otto, Bret A. Payseur

    Through recombination, genes are freed to evolve more independently of one another, unleashing genetic variance hidden in the linkage disequilibrium that accumulates through selection combined with drift. Yet crossover numbers are evolutionarily constrained, with at least one and not many more than one crossover per bivalent in most taxa. Crossover interference, whereby a crossover reduces the probability of a neighboring crossover, contributes to this homogeneity. The mechanisms by which interference is achieved and crossovers are regulated are a major current subject of inquiry, facilitated by novel methods to visualize crossovers and to pinpoint recombination events. Here, we review patterns of crossover interference and the models built to describe this process. We then discuss the selective forces that have likely shaped interference and the regulation of crossover numbers.

    更新日期:2019-12-04
  • Cell Size Control in Plants
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Marco D'Ario, Robert Sablowski

    The genetic control of the characteristic cell sizes of different species and tissues is a long-standing enigma. Plants are convenient for studying this question in a multicellular context, as their cells do not move and are easily tracked and measured from organ initiation in the meristems to subsequent morphogenesis and differentiation. In this article, we discuss cell size control in plants compared with other organisms. As seen from yeast cells to mammalian cells, size homeostasis is maintained cell autonomously in the shoot meristem. In developing organs, vacuolization contributes to cell size heterogeneity and may resolve conflicts between growth control at the cellular and organ levels. Molecular mechanisms for cell size control have implications for how cell size responds to changes in ploidy, which are particularly important in plant development and evolution. We also discuss comparatively the functional consequences of cell size and their potential repercussions at higher scales, including genome evolution.

    更新日期:2019-12-04
  • Drosophila Myoblast Fusion: Invasion and Resistance for the Ultimate Union
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Donghoon M. Lee, Elizabeth H. Chen

    Cell–cell fusion is indispensable for creating life and building syncytial tissues and organs. Ever since the discovery of cell–cell fusion, how cells join together to form zygotes and multinucleated syncytia has remained a fundamental question in cell and developmental biology. In the past two decades, Drosophila myoblast fusion has been used as a powerful genetic model to unravel mechanisms underlying cell–cell fusion in vivo. Many evolutionarily conserved fusion-promoting factors have been identified and so has a surprising and conserved cellular mechanism. In this review, we revisit key findings in Drosophila myoblast fusion and highlight the critical roles of cellular invasion and resistance in driving cell membrane fusion.

    更新日期:2019-12-04
  • Evolutionary Ecology of Wolbachia Releases for Disease Control
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Perran A. Ross, Michael Turelli, Ary A. Hoffmann

    Wolbachia is an endosymbiotic Alphaproteobacteria that can suppress insect-borne diseases through decreasing host virus transmission (population replacement) or through decreasing host population density (population suppression). We contrast natural Wolbachia infections in insect populations with Wolbachia transinfections in mosquitoes to gain insights into factors potentially affecting the long-term success of Wolbachia releases. Natural Wolbachia infections can spread rapidly, whereas the slow spread of transinfections is governed by deleterious effects on host fitness and demographic factors. Cytoplasmic incompatibility (CI) generated by Wolbachia is central to both population replacement and suppression programs, but CI in nature can be variable and evolve, as can Wolbachia fitness effects and virus blocking. Wolbachia spread is also influenced by environmental factors that decrease Wolbachia titer and reduce maternal Wolbachia transmission frequency. More information is needed on the interactions between Wolbachia and host nuclear/mitochondrial genomes, the interaction between invasion success and local ecological factors, and the long-term stability of Wolbachia-mediated virus blocking.

    更新日期:2019-12-04
  • Genetic Factors in Mammalian Prion Diseases
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Simon Mead, Sarah Lloyd, John Collinge

    Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene (PRNP) and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of PRNP, whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non-PRNP factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.

    更新日期:2019-12-04
  • Light in the Fungal World: From Photoreception to Gene Transcription and Beyond
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Luis M. Corrochano

    Fungi see light of different colors by using photoreceptors such as the White Collar proteins and cryptochromes for blue light, opsins for green light, and phytochromes for red light. Light regulates fungal development, promotes the accumulation of protective pigments and proteins, and regulates tropic growth. The White Collar complex (WCC) is a photoreceptor and a transcription factor that is responsible for regulating transcription after exposure to blue light. In Neurospora crassa, light promotes the interaction of WCCs and their binding to the promoters to activate transcription. In Aspergillus nidulans, the WCC and the phytochrome interact to coordinate gene transcription and other responses, but the contribution of these photoreceptors to fungal photobiology varies across fungal species. Ultimately, the effect of light on fungal biology is the result of the coordinated transcriptional regulation and activation of signal transduction pathways.

    更新日期:2019-12-04
  • Liquid–Liquid Phase Separation in Disease
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Simon Alberti, Dorothee Dormann

    We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ability to develop effective disease treatments. To overcome this limitation, we need new concepts to describe and comprehend the complex mechanisms underlying human diseases. Condensate formation by phase separation emerges as a new principle to explain the organization of living cells. In this review, we present emerging evidence that aberrant forms of condensates are associated with many human diseases, including cancer, neurodegeneration, and infectious diseases. We examine disease mechanisms driven by aberrant condensates, and we point out opportunities for therapeutic interventions. We conclude that phase separation provides a useful new framework to understand and fight some of the most severe human diseases.

    更新日期:2019-12-04
  • Living with Two Genomes: Grafting and Its Implications for Plant Genome-to-Genome Interactions, Phenotypic Variation, and Evolution
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Brandon S. Gaut, Allison J. Miller, Danelle K. Seymour

    Plant genomes interact when genetically distinct individuals join, or are joined, together. Individuals can fuse in three contexts: artificial grafts, natural grafts, and host–parasite interactions. Artificial grafts have been studied for decades and are important platforms for studying the movement of RNA, DNA, and protein. Yet several mysteries about artificial grafts remain, including the factors that contribute to graft incompatibility, the prevalence of genetic and epigenetic modifications caused by exchanges between graft partners, and the long-term effects of these modifications on phenotype. Host–parasite interactions also lead to the exchange of materials, and RNA exchange actively contributes to an ongoing arms race between parasite virulence and host resistance. Little is known about natural grafts except that they can be frequent and may provide opportunities for evolutionary innovation through genome exchange. In this review, we survey our current understanding about these three mechanisms of contact, the genomic interactions that result, and the potential evolutionary implications.

    更新日期:2019-12-04
  • Mechanisms of DNA Uptake by Naturally Competent Bacteria
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    David Dubnau, Melanie Blokesch

    Transformation is a widespread mechanism of horizontal gene transfer in bacteria. DNA uptake to the periplasmic compartment requires a DNA-uptake pilus and the DNA-binding protein ComEA. In the gram-negative bacteria, DNA is first pulled toward the outer membrane by retraction of the pilus and then taken up by binding to periplasmic ComEA, acting as a Brownian ratchet to prevent backward diffusion. A similar mechanism probably operates in the gram-positive bacteria as well, but these systems have been less well characterized. Transport, defined as movement of a single strand of transforming DNA to the cytosol, requires the channel protein ComEC. Although less is understood about this process, it may be driven by proton symport. In this review we also describe various phenomena that are coordinated with the expression of competence for transformation, such as fratricide, the kin-discriminatory killing of neighboring cells, and competence-mediated growth arrest.

    更新日期:2019-12-04
  • The Microbiome and Aging
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Bianca Bana, Filipe Cabreiro

    Aging is a natural process of organismal decay that underpins the development of myriad diseases and disorders. Extensive efforts have been made to understand the biology of aging and its regulation, but most studies focus solely on the host organism. Considering the pivotal role of the microbiota in host health and metabolism, we propose viewing the host and its microbiota as a single biological entity whose aging phenotype is influenced by the complex interplay between host and bacterial genetics. In this review we present how the microbiota changes as the host ages, but also how the intricate relationship between host and indigenous bacteria impacts organismal aging and life span. In addition, we highlight other microbiota-dependent mechanisms that potentially regulate aging, and present experimental animal models for addressing these questions. Importantly, we propose microbiome dysbiosis as an additional hallmark and biomarker of aging.

    更新日期:2019-12-04
  • Microglia in Brain Development, Homeostasis, and Neurodegeneration
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Christopher J. Bohlen, Brad A. Friedman, Borislav Dejanovic, Morgan Sheng

    Advances in human genetics have implicated a growing number of genes in neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease in particular, genome-wide association studies and gene expression studies have emphasized the pathogenic contributions from microglial cells and motivated studies of microglial function/dysfunction. Here, we summarize recent genetic evidence for microglial involvement in neurodegenerative disease with a focus on Alzheimer disease, for which the evidence is most compelling. To provide context for these genetic discoveries, we discuss how microglia influence brain development and homeostasis, how microglial characteristics change in disease, and which microglial activities likely influence the course of neurodegeneration. In all, we aim to synthesize varied aspects of microglial biology and highlight microglia as possible targets for therapeutic interventions in neurodegenerative disease.

    更新日期:2019-12-04
  • Multigenerational Regulation of the Caenorhabditis elegans Chromatin Landscape by Germline Small RNAs
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Natasha E. Weiser, John K. Kim

    In animals, small noncoding RNAs that are expressed in the germline and transmitted to progeny control gene expression to promote fertility. Germline-expressed small RNAs, including endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs), drive the repression of deleterious transcripts such as transposons, repetitive elements, and pseudogenes. Recent studies have highlighted an important role for small RNAs in transgenerational epigenetic inheritance via regulation of heritable chromatin marks; therefore, small RNAs are thought to convey an epigenetic memory of genomic self and nonself elements. Small RNA pathways are highly conserved in metazoans and have been best described for the model organism Caenorhabditis elegans. In this review, we describe the biogenesis, regulation, and function of C. elegans endo-siRNAs and piRNAs, along with recent insights into how these distinct pathways are integrated to collectively regulate germline gene expression, transgenerational epigenetic inheritance, and ultimately, animal fertility.

    更新日期:2019-12-04
  • Natural Viruses of Caenorhabditis Nematodes
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Marie-Anne Félix, David Wang

    Caenorhabditis elegans has long been a laboratory model organism with no known natural pathogens. In the past ten years, however, natural viruses have been isolated from wild-caught C. elegans (Orsay virus) and its relative Caenorhabditis briggsae (Santeuil virus, Le Blanc virus, and Melnik virus). All are RNA positive-sense viruses related to Nodaviridae; they infect intestinal cells and are horizontally transmitted. The Orsay virus capsid structure has been determined and the virus can be reconstituted by transgenesis of the host. Recent use of the Orsay virus has enabled researchers to identify evolutionarily conserved proviral and antiviral genes that function in nematodes and mammals. These pathways include endocytosis through SID-3 and WASP; a uridylyltransferase that destabilizes viral RNAs by uridylation of their 3′ end; ubiquitin protein modifications and turnover; and the RNA interference pathway, which recognizes and degrades viral RNA.

    更新日期:2019-12-04
  • Regulation of Genomic Output and (Pluri)potency in Regeneration
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Elizabeth M. Duncan, Alejandro Sánchez Alvarado

    Regeneration is a remarkable phenomenon that has been the subject of awe and bafflement for hundreds of years. Although regeneration competence is found in highly divergent organisms throughout the animal kingdom, recent advances in tools used for molecular and genomic characterization have uncovered common genes, molecular mechanisms, and genomic features in regenerating animals. In this review we focus on what is known about how genome regulation modulates cellular potency during regeneration. We discuss this regulation in the context of complex tissue regeneration in animals, from Hydra to humans, with reference to ex vivo–cultured cell models of pluripotency when appropriate. We emphasize the importance of a detailed molecular understanding of both the mechanisms that regulate genomic output and the functional assays that assess the biological relevance of such molecular characterizations.

    更新日期:2019-12-04
  • Standard Deviations: The Biological Bases of Transmission Ratio Distortion
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Lila Fishman, Mariah McIntosh

    The rule of Mendelian inheritance is remarkably robust, but deviations from the equal transmission of alternative alleles at a locus [a.k.a. transmission ratio distortion (TRD)] are also commonly observed in genetic mapping populations. Such TRD reveals locus-specific selection acting at some point between the diploid heterozygous parents and progeny genotyping and therefore can provide novel insight into otherwise-hidden genetic and evolutionary processes. Most of the classic selfish genetic elements were discovered through their biasing of transmission, but many unselfish evolutionary and developmental processes can also generate TRD. In this review, we describe methodologies for detecting TRD in mapping populations, detail the arenas and genetic interactions that shape TRD during plant and animal reproduction, and summarize patterns of TRD from across the genetic mapping literature. Finally, we point to new experimental approaches that can accelerate both detection of TRD and characterization of the underlying genetic mechanisms.

    更新日期:2019-12-04
  • The foraging Gene and Its Behavioral Effects: Pleiotropy and Plasticity
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Ina Anreiter, Marla B. Sokolowski

    The Drosophila melanogaster foraging (for) gene is a well-established example of a gene with major effects on behavior and natural variation. This gene is best known for underlying the behavioral strategies of rover and sitter foraging larvae, having been mapped and named for this phenotype. Nevertheless, in the last three decades an extensive array of studies describing for’s role as a modifier of behavior in a wide range of phenotypes, in both Drosophila and other organisms, has emerged. Furthermore, recent work reveals new insights into the genetic and molecular underpinnings of how for affects these phenotypes. In this article, we discuss the history of the for gene and its role in natural variation in behavior, plasticity, and behavioral pleiotropy, with special attention to recent findings on the molecular structure and transcriptional regulation of this gene.

    更新日期:2019-12-04
  • The Arms Race Between KRAB–Zinc Finger Proteins and Endogenous Retroelements and Its Impact on Mammals
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Melania Bruno, Mohamed Mahgoub, Todd S. Macfarlan

    Nearly half of the human genome consists of endogenous retroelements (EREs) and their genetic remnants, a small fraction of which carry the potential to propagate in the host genome, posing a threat to genome integrity and cell/organismal survival. The largest family of transcription factors in tetrapods, the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs), binds to specific EREs and represses their transcription. Since their first appearance over 400 million years ago, KRAB-ZFPs have undergone dramatic expansion and diversification in mammals, correlating with the invasions of new EREs. In this article we review our current understanding of the structure, function, and evolution of KRAB-ZFPs and discuss growing evidence that the arms race between KRAB-ZFPs and the EREs they target is a major driving force for the evolution of new traits in mammals, often accompanied by domestication of EREs themselves.

    更新日期:2019-12-04
  • The Evolution of Sexual Reproduction and the Mating-Type Locus: Links to Pathogenesis of Cryptococcus Human Pathogenic Fungi
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Sheng Sun, Marco A. Coelho, Márcia David-Palma, Shelby J. Priest, Joseph Heitman

    Cryptococcus species utilize a variety of sexual reproduction mechanisms, which generate genetic diversity, purge deleterious mutations, and contribute to their ability to occupy myriad environmental niches and exhibit a range of pathogenic potential. The bisexual and unisexual cycles of pathogenic Cryptococcus species are stimulated by properties associated with their environmental niches and proceed through well-characterized signaling pathways and corresponding morphological changes. Genes governing mating are encoded by the mating-type (MAT) loci and influence pathogenesis, population dynamics, and lineage divergence in Cryptococcus. MAT has undergone significant evolutionary changes within the Cryptococcus genus, including transition from the ancestral tetrapolar state in nonpathogenic species to a bipolar mating system in pathogenic species, as well as several internal reconfigurations. Owing to the variety of established sexual reproduction mechanisms and the robust characterization of the evolution of mating and MAT in this genus, Cryptococcus species provide key insights into the evolution of sexual reproduction.

    更新日期:2019-12-04
  • Organization of Chromosomal DNA by SMC Complexes
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Stanislau Yatskevich, James Rhodes, Kim Nasmyth

    Structural maintenance of chromosomes (SMC) complexes are key organizers of chromosome architecture in all kingdoms of life. Despite seemingly divergent functions, such as chromosome segregation, chromosome maintenance, sister chromatid cohesion, and mitotic chromosome compaction, it appears that these complexes function via highly conserved mechanisms and that they represent a novel class of DNA translocases.

    更新日期:2019-12-04
  • The Power of Human Cancer Genetics as Revealed by Low-Grade Gliomas
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    David T.W. Jones, Pratiti Bandopadhayay, Nada Jabado

    The human brain contains a vast number of cells and shows extraordinary cellular diversity to facilitate the many cognitive and automatic commands governing our bodily functions. This complexity arises partly from large-scale structural variations in the genome, evolutionary processes to increase brain size, function, and cognition. Not surprisingly given recent technical advances, low-grade gliomas (LGGs), which arise from the glia (the most abundant cell type in the brain), have undergone a recent revolution in their classification and therapy, especially in the pediatric setting. Next-generation sequencing has uncovered previously unappreciated diverse LGG entities, unraveling genetic subgroups and multiple molecular alterations and altered pathways, including many amenable to therapeutic targeting. In this article we review these novel entities, in which oncogenic processes show striking age-related neuroanatomical specificity (highlighting their close interplay with development); the opportunities they provide for targeted therapies, some of which are already practiced at the bedside; and the challenges of implementing molecular pathology in the clinic.

    更新日期:2019-12-04
  • Zebrafish Pigment Pattern Formation: Insights into the Development and Evolution of Adult Form
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2019-12-03
    Larissa B. Patterson, David M. Parichy

    Vertebrate pigment patterns are diverse and fascinating adult traits that allow animals to recognize conspecifics, attract mates, and avoid predators. Pigment patterns in fish are among the most amenable traits for studying the cellular basis of adult form, as the cells that produce diverse patterns are readily visible in the skin during development. The genetic basis of pigment pattern development has been most studied in the zebrafish, Danio rerio. Zebrafish adults have alternating dark and light horizontal stripes, resulting from the precise arrangement of three main classes of pigment cells: black melanophores, yellow xanthophores, and iridescent iridophores. The coordination of adult pigment cell lineage specification and differentiation with specific cellular interactions and morphogenetic behaviors is necessary for stripe development. Besides providing a nice example of pattern formation responsible for an adult trait of zebrafish, stripe-forming mechanisms also provide a conceptual framework for posing testable hypotheses about pattern diversification more broadly. Here, we summarize what is known about lineages and molecular interactions required for pattern formation in zebrafish, we review some of what is known about pattern diversification in Danio, and we speculate on how patterns in more distant teleosts may have evolved to produce a stunningly diverse array of patterns in nature.

    更新日期:2019-12-04
  • Power in Numbers: Single-Cell RNA-Seq Strategies to Dissect Complex Tissues
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Kenneth D. Birnbaum

    The growing scale and declining cost of single-cell RNA-sequencing (RNA-seq) now permit a repetition of cell sampling that increases the power to detect rare cell states, reconstruct developmental trajectories, and measure phenotype in new terms such as cellular variance. The characterization of anatomy and developmental dynamics has not had an equivalent breakthrough since groundbreaking advances in live fluorescent microscopy. The new resolution obtained by single-cell RNA-seq is a boon to genetics because the novel description of phenotype offers the opportunity to refine gene function and dissect pleiotropy. In addition, the recent pairing of high-throughput genetic perturbation with single-cell RNA-seq has made practical a scale of genetic screening not previously possible.

    更新日期:2019-11-19
  • Tracing My Roots: How I Became a Plant Biologist
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Frederick M. Ausubel

    My trajectory to becoming a plant biologist was shaped by a complex mix of scientific, political, sociological, and personal factors. I was trained as a microbiologist and molecular biologist in the late 1960s and early 1970s, a time of political upheaval surrounding the Vietnam War. My political activism taught me to be wary of the potential misuses of scientific knowledge and to promote the positive applications of science for the benefit of society. I chose agricultural science for my postdoctoral work. Because I was not trained as a plant biologist, I devised a postdoctoral project that took advantage of my microbiological training, and I explored using genetic technologies to transfer the ability to fix nitrogen from prokaryotic nitrogen-fixing species to the model plant Arabidopsis thaliana with the ultimate goal of engineering crop plants. The invention of recombinant DNA technology greatly facilitated the cloning and manipulation of bacterial nitrogen-fixation (nif) genes, but it also forced me to consider how much genetic engineering of organisms, including human beings, is acceptable. My laboratory has additionally studied host–pathogen interactions using Arabidopsis and the nematode Caenorhabditis elegans as model hosts.

    更新日期:2019-11-18
  • Transgenerational Epigenetic Inheritance
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Ana Bošković, Oliver J. Rando

    Inheritance of genomic DNA underlies the vast majority of biological inheritance, yet it has been clear for decades that additional epigenetic information can be passed on to future generations. Here, we review major model systems for transgenerational epigenetic inheritance via the germline in multicellular organisms. In addition to surveying examples of epivariation that may arise stochastically or in response to unknown stimuli, we also discuss the induction of heritable epigenetic changes by genetic or environmental perturbations. Mechanistically, we discuss the increasingly well-understood molecular pathways responsible for epigenetic inheritance, with a focus on the unusual features of the germline epigenome.

    更新日期:2019-11-18
  • Mechanisms of Neural Crest Migration
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    András Szabó, Roberto Mayor

    Neural crest cells are a transient embryonic cell population that migrate collectively to various locations throughout the embryo to contribute a number of cell types to several organs. After induction, the neural crest delaminates and undergoes an epithelial-to-mesenchymal transition before migrating through intricate yet characteristic paths. The neural crest exhibits a variety of migratory behaviors ranging from sheet-like mass migration in the cephalic regions to chain migration in the trunk. During their journey, neural crest cells rely on a range of signals both from their environment and within the migrating population for navigating through the embryo as a collective. Here we review these interactions and mechanisms, including chemotactic cues of neural crest cells’ migration.

    更新日期:2019-11-18
  • The Hippo Signaling Network and Its Biological Functions
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Jyoti R. Misra, Kenneth D. Irvine

    Hippo signaling is an evolutionarily conserved network that has a central role in regulating cell proliferation and cell fate to control organ growth and regeneration. It promotes activation of the LATS kinases, which control gene expression by inhibiting the activity of the transcriptional coactivator proteins YAP and TAZ in mammals and Yorkie in Drosophila. Diverse upstream inputs, including both biochemical cues and biomechanical cues, regulate Hippo signaling and enable it to have a key role as a sensor of cells’ physical environment and an integrator of growth control signals. Several components of this pathway localize to cell–cell junctions and contribute to regulation of Hippo signaling by cell polarity, cell contacts, and the cytoskeleton. Downregulation of Hippo signaling promotes uncontrolled cell proliferation, impairs differentiation, and is associated with cancer. We review the current understanding of Hippo signaling and highlight progress in the elucidation of its regulatory mechanisms and biological functions.

    更新日期:2019-11-18
  • The Smc5/6 Complex: New and Old Functions of the Enigmatic Long-Distance Relative
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Luis Aragón

    Smc5 and Smc6, together with the kleisin Nse4, form the heart of the enigmatic and poorly understood Smc5/6 complex, which is frequently viewed as a cousin of cohesin and condensin with functions in DNA repair. As novel functions for cohesin and condensin complexes in the organization of long-range chromatin architecture have recently emerged, new unsuspected roles for Smc5/6 have also surfaced. Here, I aim to provide a comprehensive overview of our current knowledge of the Smc5/6 complex, including its long-established function in genome stability, its multiple roles in DNA repair, and its recently discovered connection to the transcription inhibition of hepatitis B virus genomes. In addition, I summarize new research that is beginning to tease out the molecular details of Smc5/6 structure and function, knowledge that will illuminate the nuclear activities of Smc5/6 in the stability and dynamics of eukaryotic genomes.

    更新日期:2019-11-18
  • H3–H4 Histone Chaperone Pathways
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Prerna Grover, Jonathon S. Asa, Eric I. Campos

    Nucleosomes compact and organize genetic material on a structural level. However, they also alter local chromatin accessibility through changes in their position, through the incorporation of histone variants, and through a vast array of histone posttranslational modifications. The dynamic nature of chromatin requires histone chaperones to process, deposit, and evict histones in different tissues and at different times in the cell cycle. This review focuses on the molecular details of canonical and variant H3–H4 histone chaperone pathways that lead to histone deposition on DNA as they are currently understood. Emphasis is placed on the most established pathways beginning with the folding, posttranslational modification, and nuclear import of newly synthesized H3–H4 histones. Next, we review the deposition of replication-coupled H3.1–H4 in S-phase and replication-independent H3.3–H4 via alternative histone chaperone pathways. Highly specialized histone chaperones overseeing the deposition of histone variants are also briefly discussed.

    更新日期:2019-11-18
  • piRNA-Guided Genome Defense: From Biogenesis to Silencing
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Benjamin Czech, Marzia Munafò, Filippo Ciabrelli, Evelyn L. Eastwood, Martin H. Fabry, Emma Kneuss, Gregory J. Hannon

    PIWI-interacting RNAs (piRNAs) and their associated PIWI clade Argonaute proteins constitute the core of the piRNA pathway. In gonadal cells, this conserved pathway is crucial for genome defense, and its main function is to silence transposable elements. This is achieved through posttranscriptional and transcriptional gene silencing. Precursors that give rise to piRNAs require specialized transcription and transport machineries because piRNA biogenesis is a cytoplasmic process. The ping-pong cycle, a posttranscriptional silencing mechanism, combines the cleavage-dependent silencing of transposon RNAs with piRNA production. PIWI proteins also function in the nucleus, where they scan for nascent target transcripts with sequence complementarity, instructing transcriptional silencing and deposition of repressive chromatin marks at transposon loci. Although studies have revealed numerous factors that participate in each branch of the piRNA pathway, the precise molecular roles of these factors often remain unclear. In this review, we summarize our current understanding of the mechanisms involved in piRNA biogenesis and function.

    更新日期:2019-11-18
  • Metabolic Gene Clusters in Eukaryotes
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Hans-Wilhelm Nützmann, Claudio Scazzocchio, Anne Osbourn

    In bacteria, more than half of the genes in the genome are organized in operons. In contrast, in eukaryotes, functionally related genes are usually dispersed across the genome. There are, however, numerous examples of functional clusters of nonhomologous genes for metabolic pathways in fungi and plants. Despite superficial similarities with operons (physical clustering, coordinate regulation), these clusters have not usually originated by horizontal gene transfer from bacteria, and (unlike operons) the genes are typically transcribed separately rather than as a single polycistronic message. This clustering phenomenon raises intriguing questions about the origins of clustered metabolic pathways in eukaryotes and the significance of clustering for pathway function. Here we review metabolic gene clusters from fungi and plants, highlight commonalities and differences, and consider how these clusters form and are regulated. We also identify opportunities for future research in the areas of large-scale genomics, synthetic biology, and experimental evolution.

    更新日期:2019-11-18
  • Genetic Control of Early Cell Lineages in the Mammalian Embryo
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Janet Rossant

    Establishing the different lineages of the early mammalian embryo takes place over several days and several rounds of cell divisions from the fertilized egg. The resulting blastocyst contains the pluripotent cells of the epiblast, from which embryonic stem cells can be derived, as well as the extraembryonic lineages required for a mammalian embryo to survive in the uterine environment. The dynamics of the cellular and genetic interactions controlling the initiation and maintenance of these lineages in the mouse embryo are increasingly well understood through application of the tools of single-cell genomics, gene editing, and in vivo imaging. Exploring the similarities and differences between mouse and human development will be essential for translation of these findings into new insights into human biology, derivation of stem cells, and improvements in fertility treatments.

    更新日期:2019-11-18
  • Shelterin-Mediated Telomere Protection
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Titia de Lange

    For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3′ overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.

    更新日期:2019-11-18
  • Understanding the Genetic Basis of C4 Kranz Anatomy with a View to Engineering C3 Crops
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Olga V. Sedelnikova, Thomas E. Hughes, Jane A. Langdale

    One of the most remarkable examples of convergent evolution is the transition from C3 to C4 photosynthesis, an event that occurred on over 60 independent occasions. The evolution of C4 is particularly noteworthy because of the complexity of the developmental and metabolic changes that took place. In most cases, compartmentalized metabolic reactions were facilitated by the development of a distinct leaf anatomy known as Kranz. C4 Kranz anatomy differs from ancestral C3 anatomy with respect to vein spacing patterns across the leaf, cell-type specification around veins, and cell-specific organelle function. Here we review our current understanding of how Kranz anatomy evolved and how it develops, with a focus on studies that are dissecting the underlying genetic mechanisms. This research field has gained prominence in recent years because understanding the genetic regulation of Kranz may enable the C3-to-C4 transition to be engineered, an endeavor that would significantly enhance crop productivity.

    更新日期:2019-11-18
  • Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Jerome Mertens, Dylan Reid, Shong Lau, Yongsung Kim, Fred H. Gage

    Age-associated neurological diseases represent a profound challenge in biomedical research as we are still struggling to understand the interface between the aging process and the manifestation of disease. Various pathologies in the elderly do not directly result from genetic mutations, toxins, or infectious agents but are primarily driven by the many manifestations of biological aging. Therefore, the generation of appropriate model systems to study human aging in the nervous system demands new concepts that lie beyond transgenic and drug-induced models. Although access to viable human brain specimens is limited and induced pluripotent stem cell models face limitations due to reprogramming-associated cellular rejuvenation, the direct conversion of somatic cells into induced neurons allows for the generation of human neurons that capture many aspects of aging. Here, we review advances in exploring age-associated neurodegenerative diseases using human cell reprogramming models, and we discuss general concepts, promises, and limitations of the field.

    更新日期:2019-11-18
  • Chromosome Dynamics in Response to DNA Damage
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Andrew Seeber, Michael H. Hauer, Susan M. Gasser

    Recent advances in both the technologies used to measure chromatin movement and the biophysical analysis used to model them have yielded a fuller understanding of chromatin dynamics and the polymer structure that underlies it. Changes in nucleosome packing, checkpoint kinase activation, the cell cycle, chromosomal tethers, and external forces acting on nuclei in response to external and internal stimuli can alter the basal mobility of DNA in interphase nuclei of yeast or mammalian cells. Although chromatin movement is assumed to be necessary for many DNA-based processes, including gene activation by distal enhancer–promoter interaction or sequence-based homology searches during double-strand break repair, experimental evidence supporting an essential role in these activities is sparse. Nonetheless, high-resolution tracking of chromatin dynamics has led to instructive models of the higher-order folding and flexibility of the chromatin polymer. Key regulators of chromatin motion in physiological conditions or after damage induction are reviewed here.

    更新日期:2019-11-18
  • Ribosome Hibernation
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2015-12-14
    Thomas Prossliner, Kristoffer Skovbo Winther, Michael Askvad Sørensen, Kenn Gerdes

    Protein synthesis consumes a large fraction of available resources in the cell. When bacteria encounter unfavorable conditions and cease to grow, specialized mechanisms are in place to ensure the overall reduction of costly protein synthesis while maintaining a basal level of translation. A number of ribosome-associated factors are involved in this regulation; some confer an inactive, hibernating state of the ribosome in the form of 70S monomers (RaiA; this and the following are based on Escherichia coli nomenclature) or 100S dimers (RMF and HPF homologs), and others inhibit translation at different stages in the translation cycle (RsfS, YqjD and paralogs, SRA, and EttA). Stationary phase cells therefore exhibit a complex array of different ribosome subpopulations that adjusts the translational capacity of the cell to the encountered conditions and ensures efficient reactivation of translation when conditions improve. Here, we review the current state of research regarding stationary phase-specific translation factors, in particular ribosome hibernation factors and other forms of translational regulation in response to stress conditions.

    更新日期:2019-11-18
  • Chemical Modifications in the Life of an mRNA Transcript
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Sigrid Nachtergaele, Chuan He

    Investigations over the past eight years of chemical modifications on messenger RNA (mRNA) have revealed a new level of posttranscriptional gene regulation in eukaryotes. Rapid progress in our understanding of these modifications, particularly, N6-methyladenosine (m6A), has revealed their roles throughout the life cycle of an mRNA transcript. m6A methylation provides a rapid mechanism for coordinated transcriptome processing and turnover that is important in embryonic development and cell differentiation. In response to cellular signals, m6A can also regulate the translation of specific pools of transcripts. These mechanisms can be hijacked in human diseases, including numerous cancers and viral infection. Beyond m6A, many other mRNA modifications have been mapped in the transcriptome, but much less is known about their biological functions. As methods continue to be developed, we will be able to study these modifications both more broadly and in greater depth, which will likely reveal a wealth of new RNA biology.

    更新日期:2019-11-18
  • Calcium Channelopathies: Structural Insights into Disorders of the Muscle Excitation–Contraction Complex
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Raika Pancaroglu, Filip Van Petegem

    Ion channels are membrane proteins responsible for the passage of ions down their electrochemical gradients and across biological membranes. In this, they generate and shape action potentials and provide secondary messengers for various signaling pathways. They are often part of larger complexes containing auxiliary subunits and regulatory proteins. Channelopathies arise from mutations in the genes encoding ion channels or their associated proteins. Recent advances in cryo-electron microscopy have resulted in an explosion of ion channel structures in multiple states, generating a wealth of new information on channelopathies. Disease-associated mutations fall into different categories, interfering with ion permeation, protein folding, voltage sensing, ligand and protein binding, and allosteric modulation of channel gating. Prime examples of these are Ca2+-selective channels expressed in myocytes, for which multiple structures in distinct conformational states have recently been uncovered. We discuss the latest insights into these calcium channelopathies from a structural viewpoint.

    更新日期:2019-11-18
  • Somatic Mutagenesis in Mammals and Its Implications for Human Disease and Aging
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Lei Zhang, Jan Vijg

    DNA mutations as a consequence of errors during DNA damage repair, replication, or mitosis are the substrate for evolution. In multicellular organisms, mutations can occur in the germline and also in somatic tissues, where they are associated with cancer and other chronic diseases and possibly with aging. Recent advances in high-throughput sequencing have made it relatively easy to study germline de novo mutations, but in somatic cells, the vast majority of mutations are low-abundant and can be detected only in clonal lineages, such as tumors, or single cells. Here we review recent results on somatic mutations in normal human and animal tissues with a focus on their possible functional consequences.

    更新日期:2019-11-18
  • On the Road to Breeding 4.0: Unraveling the Good, the Bad, and the Boring of Crop Quantitative Genomics
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Jason G. Wallace, Eli Rodgers-Melnick, Edward S. Buckler

    Understanding the quantitative genetics of crops has been and will continue to be central to maintaining and improving global food security. We outline four stages that plant breeding either has already achieved or will probably soon achieve. Top-of-the-line breeding programs are currently in Breeding 3.0, where inexpensive, genome-wide data coupled with powerful algorithms allow us to start breeding on predicted instead of measured phenotypes. We focus on three major questions that must be answered to move from current Breeding 3.0 practices to Breeding 4.0: (a) How do we adapt crops to better fit agricultural environments? (b) What is the nature of the diversity upon which breeding can act? (c) How do we deal with deleterious variants? Answering these questions and then translating them to actual gains for farmers will be a significant part of achieving global food security in the twenty-first century.

    更新日期:2019-11-18
  • Phage-Encoded Anti-CRISPR Defenses
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Sabrina Y. Stanley, Karen L. Maxwell

    The battle for survival between bacteria and bacteriophages (phages) is an arms race where bacteria develop defenses to protect themselves from phages and phages evolve counterstrategies to bypass these defenses. CRISPR-Cas adaptive immune systems represent a widespread mechanism by which bacteria protect themselves from phage infection. In response to CRISPR-Cas, phages have evolved protein inhibitors known as anti-CRISPRs. Here, we describe the discovery and mechanisms of action of anti-CRISPR proteins. We discuss the potential impact of anti-CRISPRs on bacterial evolution, speculate on their evolutionary origins, and contemplate the possible next steps in the CRISPR-Cas evolutionary arms race. We also touch on the impact of anti-CRISPRs on the development of CRISPR-Cas-based biotechnological tools.

    更新日期:2019-11-18
  • Unique Archaeal Small RNAs
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    José Vicente Gomes-Filho, Michael Daume, Lennart Randau

    Advances in genome-wide sequence technologies allow for detailed insights into the complexity of RNA landscapes of organisms from all three domains of life. Recent analyses of archaeal transcriptomes identified interaction and regulation networks of noncoding RNAs in this understudied domain. Here, we review current knowledge of small, noncoding RNAs with important functions for the archaeal lifestyle, which often requires adaptation to extreme environments. One focus is RNA metabolism at elevated temperatures in hyperthermophilic archaea, which reveals elevated amounts of RNA-guided RNA modification and virus defense strategies. Genome rearrangement events result in unique fragmentation patterns of noncoding RNA genes that require elaborate maturation pathways to yield functional transcripts. RNA-binding proteins, e.g., L7Ae and LSm, are important for many posttranscriptional control functions of RNA molecules in archaeal cells. We also discuss recent insights into the regulatory potential of their noncoding RNA partners.

    更新日期:2019-11-18
  • Recent Advances in Behavioral (Epi)Genetics in Eusocial Insects
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Comzit Opachaloemphan, Hua Yan, Alexandra Leibholz, Claude Desplan, Danny Reinberg

    Eusocial insects live in societies in which distinct family members serve specific roles in maintaining the colony and advancing the reproductive ability of a few select individuals. Given the genetic similarity of all colony members, the diversity of morphologies and behaviors is surprising. Social communication relies on pheromones and olfaction, as shown by mutants of orco, the universal odorant receptor coreceptor, and through electrophysiological analysis of neuronal responses to pheromones. Additionally, neurohormonal factors and epigenetic regulators play a key role in caste-specific behavior, such as foraging and caste switching. These studies start to allow an understanding of the molecular mechanisms underlying social behavior and provide a technological foundation for future studies of eusocial insects. In this review, we highlight recent findings in eusocial insects that advance our understanding of genetic and epigenetic regulations of social behavior and provide perspectives on future studies using cutting-edge technologies.

    更新日期:2019-11-18
  • The Multiple Levels of Mitonuclear Coregulation
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    R. Stefan Isaac, Erik McShane, L. Stirling Churchman

    Together, the nuclear and mitochondrial genomes encode the oxidative phosphorylation (OXPHOS) complexes that reside in the mitochondrial inner membrane and enable aerobic life. Mitochondria maintain their own genome that is expressed and regulated by factors distinct from their nuclear counterparts. For optimal function, the cell must ensure proper stoichiometric production of OXPHOS subunits by coordinating two physically separated and evolutionarily distinct gene expression systems. Here, we review our current understanding of mitonuclear coregulation primarily at the levels of transcription and translation. Additionally, we discuss other levels of coregulation that may exist but remain largely unexplored, including mRNA modification and stability and posttranslational protein degradation.

    更新日期:2019-11-18
  • X-Chromosome Inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Rafael Galupa, Edith Heard

    In somatic nuclei of female therian mammals, the two X chromosomes display very different chromatin states: One X is typically euchromatic and transcriptionally active, and the other is mostly silent and forms a cytologically detectable heterochromatic structure termed the Barr body. These differences, which arise during female development as a result of X-chromosome inactivation (XCI), have been the focus of research for many decades. Initial approaches to define the structure of the inactive X chromosome (Xi) and its relationship to gene expression mainly involved microscopy-based approaches. More recently, with the advent of genomic techniques such as chromosome conformation capture, molecular details of the structure and expression of the Xi have been revealed. Here, we review our current knowledge of the 3D organization of the mammalian X-chromosome chromatin and discuss its relationship with gene activity in light of the initiation, spreading, and maintenance of XCI, as well as escape from gene silencing.

    更新日期:2019-11-18
  • Immunoglobulin-Like Receptors and Their Impact on Wiring of Brain Synapses
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2018-11-26
    Scott Cameron, A. Kimberley McAllister

    Synapse formation is mediated by a surprisingly large number and wide variety of genes encoding many different protein classes. One of the families increasingly implicated in synapse wiring is the immunoglobulin superfamily (IgSF). IgSF molecules are by definition any protein containing at least one Ig-like domain, making this family one of the most common protein classes encoded by the genome. Here, we review the emerging roles for IgSF molecules in synapse formation specifically in the vertebrate brain, focusing on examples from three classes of IgSF members: (a) cell adhesion molecules, (b) signaling molecules, and (c) immune molecules expressed in the brain. The critical roles for IgSF members in regulating synapse formation may explain their extensive involvement in neuropsychiatric and neurodevelopmental disorders. Solving the IgSF code for synapse formation may reveal multiple new targets for rescuing IgSF-mediated deficits in synapse formation and, eventually, new treatments for psychiatric disorders caused by altered IgSF-induced synapse wiring.

    更新日期:2019-11-18
  • Rules of engagement: molecular insights from host-virus arms races.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2012-11-14
    Matthew D Daugherty,Harmit S Malik

    Mammalian genes and genomes have been shaped by ancient and ongoing challenges from viruses. These genetic imprints can be identified via evolutionary analyses to reveal fundamental details about when (how old), where (which protein domains), and how (what are the functional consequences of adaptive changes) host-virus arms races alter the proteins involved. Just as extreme amino acid conservation can serve to identify key immutable residues in enzymes, positively selected residues point to molecular recognition interfaces between host and viral proteins that have adapted and counter-adapted in a long series of classical Red Queen conflicts. Common rules for the strategies employed by both hosts and viruses have emerged from case studies of innate immunity genes in primates. We are now poised to use these rules to transition from a retrospective view of host-virus arms races to specific predictions about which host genes face pathogen antagonism and how those genetic conflicts transform host and virus evolution.

    更新日期:2019-11-01
  • Recessively inherited forms of osteogenesis imperfecta.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2012-11-14
    Peter H Byers,Shawna M Pyott

    More than 90% of people who have osteogenesis imperfecta (OI) have heterozygous mutations in one of the two type I collagen genes, COL1A1 and COL1A2. The effects of these changes range from death in the perinatal period to barely increased fracture frequency and reflect different types of mutations. Introduction of bisphosphonates during the past 20 years has targeted bone fragility by decreased resorption. The recent recognition of biallelic mutations in genes that affect either collagen assembly and processing or the regulation of osteoblast development has raised hopes for therapies that would be specific for single-gene disorders and identify cellular targets in individuals with the dominant forms of OI. These hopes are yet to be met, but the study of the recessively inherited forms of OI has illuminated the details of the collagen processing pathways.

    更新日期:2019-11-01
  • Transition Metals and Virulence in Bacteria.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2016-09-13
    Lauren D Palmer,Eric P Skaar

    Transition metals are required trace elements for all forms of life. Due to their unique inorganic and redox properties, transition metals serve as cofactors for enzymes and other proteins. In bacterial pathogenesis, the vertebrate host represents a rich source of nutrient metals, and bacteria have evolved diverse metal acquisition strategies. Host metal homeostasis changes dramatically in response to bacterial infections, including production of metal sequestering proteins and the bombardment of bacteria with toxic levels of metals. In response, bacteria have evolved systems to subvert metal sequestration and toxicity. The coevolution of hosts and their bacterial pathogens in the battle for metals has uncovered emerging paradigms in social microbiology, rapid evolution, host specificity, and metal homeostasis across domains. This review focuses on recent advances and open questions in our understanding of the complex role of transition metals at the host-pathogen interface.

    更新日期:2019-11-01
  • Cellular and molecular mechanisms of single and collective cell migrations in Drosophila: themes and variations.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2014-11-26
    Shirin M Pocha,Denise J Montell

    The process of cell migration is essential throughout life, driving embryonic morphogenesis and ensuring homeostasis in adults. Defects in cell migration are a major cause of human disease, with excessive migration causing autoimmune diseases and cancer metastasis, whereas reduced capacity for migration leads to birth defects and immunodeficiencies. Myriad studies in vitro have established a consensus view that cell migrations require cell polarization, Rho GTPase-mediated cytoskeletal rearrangements, and myosin-mediated contractility. However, in vivo studies later revealed a more complex picture, including the discovery that cells migrate not only as single units but also as clusters, strands, and sheets. In particular, the role of E-Cadherin in cell motility appears to be more complex than previously appreciated. Here, we discuss recent advances achieved by combining the plethora of genetic tools available to the Drosophila geneticist with live imaging and biophysical techniques. Finally, we discuss the emerging themes such studies have revealed and ponder the puzzles that remain to be solved.

    更新日期:2019-11-01
  • Clusters of Multiple Mutations: Incidence and Molecular Mechanisms.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2015-12-04
    Kin Chan,Dmitry A Gordenin

    It has been long understood that mutation distribution is not completely random across genomic space and in time. Indeed, recent surprising discoveries identified multiple simultaneous mutations occurring in tiny regions within chromosomes while the rest of the genome remains relatively mutation-free. Mechanistic elucidation of these phenomena, called mutation showers, mutation clusters, or kataegis, in parallel with findings of abundant clustered mutagenesis in cancer genomes, is ongoing. So far, the combination of factors most important for clustered mutagenesis is the induction of DNA lesions within unusually long and persistent single-strand DNA intermediates. In addition to being a fascinating phenomenon, clustered mutagenesis also became an indispensable tool for identifying a previously unrecognized major source of mutation in cancer, APOBEC cytidine deaminases. Future research on clustered mutagenesis may shed light onto important mechanistic details of genome maintenance, with potentially profound implications for human health.

    更新日期:2019-11-01
  • Eukaryotic Mismatch Repair in Relation to DNA Replication.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2015-10-06
    Thomas A Kunkel,Dorothy A Erie

    Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation, occasional mismatches that do form are proofread during replication, and rare mismatches that escape proofreading are corrected by mismatch repair (MMR). This review focuses on MMR in light of increasing knowledge about nuclear DNA replication enzymology and the rate and specificity with which mismatches are generated during leading- and lagging-strand replication. We consider differences in MMR efficiency in relation to mismatch recognition, signaling to direct MMR to the nascent strand, mismatch removal, and the timing of MMR. These studies are refining our understanding of relationships between generating and repairing replication errors to achieve accurate replication of both DNA strands of the nuclear genome.

    更新日期:2019-11-01
  • Conservation of Planar Polarity Pathway Function Across the Animal Kingdom.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2015-09-12
    Rosalind Hale,David Strutt

    Planar polarity is a well-studied phenomenon resulting in the directional coordination of cells in the plane of a tissue. In invertebrates and vertebrates, planar polarity is established and maintained by the largely independent core and Fat/Dachsous/Four-jointed (Ft-Ds-Fj) pathways. Loss of function of these pathways can result in a wide range of developmental or cellular defects, including failure of gastrulation and problems with placement and function of cilia. This review discusses the conservation of these pathways across the animal kingdom. The lack of vital core pathway components in basal metazoans suggests that the core planar polarity pathway evolved shortly after, but not necessarily alongside, the emergence of multicellularity.

    更新日期:2019-11-01
  • RNase III: Genetics and function; structure and mechanism.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2013-11-28
    Donald L Court,Jianhua Gan,Yu-He Liang,Gary X Shaw,Joseph E Tropea,Nina Costantino,David S Waugh,Xinhua Ji

    RNase III is a global regulator of gene expression in Escherichia coli that is instrumental in the maturation of ribosomal and other structural RNAs. We examine here how RNase III itself is regulated in response to growth and other environmental changes encountered by the cell and how, by binding or processing double-stranded RNA (dsRNA) intermediates, RNase III controls the expression of genes. Recent insight into the mechanism of dsRNA binding and processing, gained from structural studies of RNase III, is reviewed. Structural studies also reveal new cleavage sites in the enzyme that can generate longer 3' overhangs.

    更新日期:2019-11-01
  • Mutations arising during repair of chromosome breaks.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2012-11-14
    Anna Malkova,James E Haber

    Mutations stimulate evolutionary change and lead to birth defects and cancer in humans as well as to antibiotic resistance in bacteria. According to the classic view, most mutations arise in dividing cells and result from uncorrected errors of S-phase DNA replication, which is highly accurate because of the involvement of selective DNA polymerases and efficient error-correcting mechanisms. In contrast, studies in bacteria and yeast reveal that DNA synthesis associated with repair of double-strand chromosomal breaks (DSBs) by homologous recombination is highly inaccurate, thus making DSBs and their repair an important source of mutations. Different error-prone mechanisms appear to operate in different repair scenarios. In the filling in of single-stranded DNA regions, error-prone translesion DNA polymerases appear to produce most errors. In contrast, in gene conversion gap repair and in break-induced replication, errors are independent of translesion polymerases, and many mutations have the signatures of template switching during DNA repair synthesis. DNA repair also appears to create complex copy-number variants. Overall, homologous recombination, which is traditionally considered a safe pathway of DSB repair, is an important source of mutagenesis that may contribute to human disease and evolution.

    更新日期:2019-11-01
  • Human copy number variation and complex genetic disease.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2011-08-23
    Santhosh Girirajan,Catarina D Campbell,Evan E Eichler

    Copy number variants (CNVs) play an important role in human disease and population diversity. Advancements in technology have allowed for the analysis of CNVs in thousands of individuals with disease in addition to thousands of controls. These studies have identified rare CNVs associated with neuropsychiatric diseases such as autism, schizophrenia, and intellectual disability. In addition, copy number polymorphisms (CNPs) are present at higher frequencies in the population, show high diversity in copy number, sequence, and structure, and have been associated with multiple phenotypes, primarily related to immune or environmental response. However, the landscape of copy number variation still remains largely unexplored, especially for smaller CNVs and those embedded within complex regions of the human genome. An integrated approach including characterization of single nucleotide variants and CNVs in a large number of individuals with disease and normal genomes holds the promise of thoroughly elucidating the genetic basis of human disease and diversity.

    更新日期:2019-11-01
  • Man's best friend becomes biology's best in show: genome analyses in the domestic dog.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2010-11-05
    Heidi G Parker,Abigail L Shearin,Elaine A Ostrander

    In the last five years, canine genetics has gone from map construction to complex disease deconstruction. The availability of a draft canine genome sequence, dense marker chips, and an understanding of the genome architecture has changed the types of studies canine geneticists can undertake. There is now a clear recognition that the dog system offers the opportunity to understand the genetics of both simple and complex traits, including those associated with morphology, disease susceptibility, and behavior. In this review, we summarize recent findings regarding canine domestication and review new information on the organization of the canine genome. We discuss studies aimed at finding genes controlling morphological phenotypes and provide examples of the way such paradigms may be applied to studies of behavior. We also discuss the many ways in which the dog has illuminated our understanding of human disease and conclude with a discussion on where the field is likely headed in the next five years.

    更新日期:2019-11-01
  • Bacterial antisense RNAs: how many are there, and what are they doing?
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2010-08-17
    Maureen Kiley Thomason,Gisela Storz

    Antisense RNAs encoded on the DNA strand opposite another gene have the potential to form extensive base-pairing interactions with the corresponding sense RNA. Unlike other smaller regulatory RNAs in bacteria, antisense RNAs range in size from tens to thousands of nucleotides. The numbers of antisense RNAs reported for different bacteria vary extensively, but hundreds have been suggested in some species. If all of these reported antisense RNAs are expressed at levels sufficient to regulate the genes encoded opposite them, antisense RNAs could significantly impact gene expression in bacteria. Here, we review the evidence for these RNA regulators and describe what is known about the functions and mechanisms of action for some of these RNAs. Important considerations for future research as well as potential applications are also discussed.

    更新日期:2019-11-01
  • The kinetochore and the centromere: a working long distance relationship.
    Annu. Rev. Genet. (IF 9.184) Pub Date : 2009-11-06
    Marcin R Przewloka,David M Glover

    Accurate chromosome segregation is a prerequisite for the maintenance of the genomic stability. Consequently, elaborate molecular machineries and mechanisms emerged during the course of evolution in order to ensure proper division of the genetic material. The kinetochore, an essential multiprotein complex assembled on mitotic or meiotic centromeres, is an example of such machinery. Recently considerable progress has been made in understanding their composition, the recruitment hierarchy of their components, and the principles of their regulation. However, these advances are accompanied by a growing number of unanswered questions about the function of the individual subunits and of how the structure of the different subcomplexes relates to function. Here we review our rapidly growing knowledge on interacting networks of structural and regulatory proteins of the metazoan mitotic kinetochore: its centromeric foundations, its structural core, its components that interact with spindle microtubules and the spindle assembly checkpoint.

    更新日期:2019-11-01
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