Switch and Trace: Recombinase Genetics in Zebrafish Trends Genet. (IF 10.844) Pub Date : 2018-02-08 Tom J. Carney, Christian Mosimann
Transgenic approaches are instrumental for labeling and manipulating cells and cellular machineries in vivo. Transgenes have traditionally been static entities that remained unaltered following genome integration, limiting their versatility. The development of DNA recombinase-based methods to modify, excise, or rearrange transgene cassettes has introduced versatile control of transgene activity and function. In particular, recombinase-controlled transgenes enable regulation of exogenous gene expression, conditional mutagenesis, and genetic lineage tracing. In zebrafish, transgenesis-based recombinase genetics using Cre/lox, Flp/FRT, and ΦC31 are increasingly applied to study development and homeostasis, and to generate disease models. Intersected with the versatile imaging capacity of the zebrafish model and recent breakthroughs in genome editing, we review and discuss past, current, and potential future approaches and resources for recombinase-based techniques in zebrafish.
Deregulation of CRTCs in Aging and Age-Related Disease Risk: (Trends in Genetics, 33, 303–321, 2017) Trends Genet. (IF 10.844) Pub Date : 2018-03-07 Caroline C. Escoubas, Carlos G. Silva-García, William B. Mair
Genetic Villains: Killer Meiotic Drivers Trends Genet. (IF 10.844) Pub Date : 2018-02-27 María Angélica Bravo Núñez, Nicole L. Nuckolls, Sarah E. Zanders
Unbiased allele transmission into progeny is a fundamental genetic concept canonized as Mendel’s Law of Segregation. Not all alleles, however, abide by the law. Killer meiotic drivers are ultra-selfish DNA sequences that are transmitted into more than half (sometimes all) of the meiotic products generated by a heterozygote. As their name implies, these loci gain a transmission advantage in heterozygotes by destroying otherwise viable meiotic products that do not inherit the driver. We review and classify killer meiotic drive genes across a wide spectrum of eukaryotes. We discuss how analyses of these ultra-selfish genes can lead to greater insight into the mechanisms of gametogenesis and the causes of infertility.
Sphingolipid Turnover Turns Over the Fate of Aneuploid Cells Trends Genet. (IF 10.844) Pub Date : 2018-02-21 Zuzana Storchová
Aneuploidy, or unbalanced chromosome number, is a hallmark of cancer. Recently established model systems revealed that aneuploidy affects many aspects of cellular physiology, among them sphingolipid metabolism. The new finding that the proliferation of aneuploid cells depends on sphingolipid homeostasis offers an appealing opportunity for cancer treatment.
Through Sex, Nature Is Telling Us Something Important Trends Genet. (IF 10.844) Pub Date : 2018-02-04 Alexey S. Kondrashov
Theoretically, a variety of mechanisms can make amphimixis advantageous due to reshuffling of offspring genotypes. Recently, it has been shown experimentally that some of these mechanisms can indeed work in artificial populations. However, we still do not know which of them, if any, are relevant in nature, and the available indirect estimates seem to suggest that neither negative nor positive selection in natural populations is strong enough to provide evolutionary protection for obligate amphimixis. Thus, progress in understanding the evolution of amphimixis will depend on direct measurements of the strength of natural selection.
Raw Genomic Data: Storage, Access, and Sharing Trends Genet. (IF 10.844) Pub Date : 2017-11-10 Mahsa Shabani, Danya Vears, Pascal Borry
Patients are increasingly being encouraged and supported to access and control their own medical and genomic data. We argue that well-established and transparent raw genomic data retention and returning policies are imperative to enable patients to practice their rights to access and control raw data.
Development and Evolution through the Lens of Global Gene Regulation Trends Genet. (IF 10.844) Pub Date : 2017-10-20 Itai Yanai
Evolution and development are two inherently intertwined processes. As the embryo develops it does so in ways that both reflect past constraints and bias the future evolution of the species. While research exploiting this insight typically studies individual genes, transcriptomic analyses have sparked a new wave of discoveries. In this opinion piece, I review the evidence arising from transcriptomics on the topics of the evolution of germ layers, the phylotypic stage, and developmental constraints. The spatiotemporal pattern of gene expression across germ layers provides evidence that the endoderm was the first germ layer to evolve. Comparing transcriptome dynamics throughout developmental time across distant species reveals a mid-developmental transition under strong developmental constraints. These studies highlight the efficiency of exploratory data analysis using computational tools and comparative approaches for discovery.
Tag team: Roles of miRNAs and Proteolytic Regulators in Ensuring Robust Gene Expression Dynamics Trends Genet. (IF 10.844) Pub Date : 2017-10-13 Benjamin P. Weaver, Min Han
Lack of prominent developmental defects arising from loss of many individual miRNAs is consistent with the observations of collaborative networks between miRNAs and roles for miRNAs in regulating stress responses. However, these characteristics may only partially explain the seemingly nonessential nature of many miRNAs. Non-miRNA gene expression regulatory mechanisms also collaborate with miRNA-induced silencing complex (miRISC) to support robust gene expression dynamics. Genetic enhancer screens have revealed roles of miRNAs and other gene repressive mechanisms in development or other cellular processes that were masked by genetic redundancy. Besides discussing the breadth of the non-miRNA genes, we use LIN-28 as an example to illustrate how distinct regulatory systems, including miRNAs and multiple protein stability mechanisms, work at different levels to target expression of a given gene and provide tissue-specific and stage-specific regulation of gene expression.
Functional Genomics of Host–Microbiome Interactions in Humans Trends Genet. (IF 10.844) Pub Date : 2017-10-26 Francesca Luca, Sonia S. Kupfer, Dan Knights, Alexander Khoruts, Ran Blekhman
The human microbiome has been linked to various host phenotypes and has been implicated in many complex human diseases. Recent genome-wide association studies (GWASs) have used microbiome variation as a complex trait and have uncovered human genetic variants that are associated with the microbiome. Here we summarize results from these studies and illustrate potential regulatory mechanisms by which host genetic variation can interact with microbiome composition. We argue that, similar to human GWASs, it is important to use functional genomics techniques to gain a mechanistic understanding of causal host–microbiome interactions and their role in human disease. We highlight experimental, functional, and computational genomics methodologies for the study of the genomic basis of host–microbiome interactions and describe how these approaches can be utilized to explain how human genetic variation can modulate the effects of the microbiome on the host.
Caenorhabditis elegans Dosage Compensation: Insights into Condensin-Mediated Gene Regulation Trends Genet. (IF 10.844) Pub Date : 2017-10-13 Sarah Elizabeth Albritton, Sevinç Ercan
Recent work demonstrating the role of chromosome organization in transcriptional regulation has sparked substantial interest in the molecular mechanisms that control chromosome structure. Condensin, an evolutionarily conserved multisubunit protein complex, is essential for chromosome condensation during cell division and functions in regulating gene expression during interphase. In Caenorhabditis elegans, a specialized condensin forms the core of the dosage compensation complex (DCC), which specifically binds to and represses transcription from the hermaphrodite X chromosomes. DCC serves as a clear paradigm for addressing how condensins target large chromosomal domains and how they function to regulate chromosome structure and transcription. Here, we discuss recent research on C. elegans DCC in the context of canonical condensin mechanisms as have been studied in various organisms.
Intergenerational Transmission of Gene Regulatory Information in Caenorhabditis elegans Trends Genet. (IF 10.844) Pub Date : 2017-11-02 Olga Minkina, Craig P. Hunter
Epigenetic mechanisms can stably maintain gene expression states even after the initiating conditions have changed. Often epigenetic information is transmitted only to daughter cells, but evidence is emerging, in both vertebrate and invertebrate systems, for transgenerational epigenetic inheritance (TEI), the transmission of epigenetic gene regulatory information across generations. Each new description of TEI helps uncover the properties, molecular mechanisms and biological roles for TEI. The nematode Caenorhabditis elegans has been particularly instrumental in the effort to understand TEI, as multiple environmental and genetic triggers can initiate an epigenetic signal that can alter the expression of both transgenes and endogenous loci. Here, we review recent studies of TEI in C. elegans.
Keeping Neurons Young and Foxy: FoxOs Promote Neuronal Plasticity Trends Genet. (IF 10.844) Pub Date : 2017-11-01 Colleen N. McLaughlin, Heather T. Broihier
Any adult who has tried to take up the piano or learn a new language is faced with the sobering realization that acquiring such skills is more challenging as an adult than as a child. Neuronal plasticity, or the malleability of brain circuits, declines with age. Young neurons tend to be more adaptable and can alter the size and strength of their connections more readily than can old neurons. Myriad circuit- and synapse-level mechanisms that shape plasticity have been identified. Yet, molecular mechanisms setting the overall competence of young neurons for distinct forms of plasticity remain largely obscure. Recent studies indicate evolutionarily conserved roles for FoxO proteins in establishing the capacity for cell-fate, morphological, and synaptic plasticity in neurons.
SAMHD1 Sheds Moonlight on DNA Double-Strand Break Repair Trends Genet. (IF 10.844) Pub Date : 2017-09-29 Maria Jose Cabello-Lobato, Siyue Wang, Christine Katrin Schmidt
SAMHD1 (sterile α motif and histidine (H) aspartate (D) domain-containing protein 1) is known for its antiviral activity of hydrolysing deoxynucleotides required for virus replication. Daddacha et al. identify a hydrolase-independent, moonlighting function of SAMHD1 that facilitates homologous recombination of DNA double-strand breaks (DSBs) by promoting recruitment of C-terminal binding protein interacting protein (CTIP), a DNA-end resection factor, to damaged DNA. These findings could benefit anticancer treatment.
Faithful Artificial Chromosome Propagation Using Spermatogonial Stem Cells Trends Genet. (IF 10.844) Pub Date : 2017-10-26 M. Yamada, M. Seandel
Artificial chromosomes are useful in making functional vectors for very large genes, studying chromosome physiology, and modeling chromosomal disorders. Shinohara et al. have succeeded for the first time in creating transchromosomic mice by manipulating spermatogonial stem cells (SSCs), which exhibited superior chromosomal stability compared with embryonic stem cells (ESCs).
Choosing the Active X: The Human Version of X Inactivation Trends Genet. (IF 10.844) Pub Date : 2017-10-05 Barbara R. Migeon
Humans and rodents differ in how they carry out X inactivation (XI), the mammalian method to compensate for the different number of X chromosomes in males and females. Evolutionary changes in staging embryogenesis and in mutations within the XI center alter the process among mammals. The mouse model of XI is predicated on X counting and subsequently choosing the X to ‘inactivate’. However, new evidence suggests that humans initiate XI by protecting one X in both sexes from inactivation by XIST, the noncoding RNA that silences the inactive X. This opinion article explores the question of how the active X is protected from silencing by its own Xist locus, and the possibility of different solutions for mouse and human.
Arresting Evolution Trends Genet. (IF 10.844) Pub Date : 2017-10-10 James J. Bull, Jeffrey E. Barrick
Evolution in the form of selective breeding has long been harnessed as a useful tool by humans. However, rapid evolution can also be a danger to our health and a stumbling block for biotechnology. Unwanted evolution can underlie the emergence of drug and pesticide resistance, cancer, and weeds. It makes live vaccines and engineered cells inherently unreliable and unpredictable, and therefore potentially unsafe. Yet, there are strategies that have been and can possibly be used to stop or slow many types of evolution. We review and classify existing population genetics-inspired methods for arresting evolution. Then, we discuss how genome editing techniques enable a radically new set of approaches to limit evolution.
Alternative Lengthening of Telomeres: DNA Repair Pathways Converge Trends Genet. (IF 10.844) Pub Date : 2017-09-29 Alexander P. Sobinoff, Hilda A. Pickett
Telomeres shorten during each cellular division, with cumulative attrition resulting in telomeric damage and replicative senescence. Bypass of replicative senescence precipitates catastrophic telomere shortening or crisis, and is characterized by widespread genomic instability. Activation of a telomere maintenance mechanism (TMM) is necessary to stabilise the genome and establish cellular immortality through the reconstitution of telomere capping function. The alternative lengthening of telomeres (ALT) pathway is a TMM frequently activated in tumors of mesenchymal or neuroepithelial origin. ALT is a homology-directed recombination-dependent replication pathway that utilizes telomeric templates for synthesis; however, its precise protein requirements have remained elusive. Recently, several developments have shed light on the DNA repair pathways that become engaged at ALT telomeres, implicating ALT telomeres as DNA repair hot spots. Here, we review recent discoveries regarding the ALT mechanism, and discuss how DNA repair pathways converge to maintain the length and functional integrity of telomeres in ALT cancers.
Playing Well with Others: Extrinsic Cues Regulate Neural Progenitor Temporal Identity to Generate Neuronal Diversity Trends Genet. (IF 10.844) Pub Date : 2017-09-09 Mubarak Hussain Syed, Brandon Mark, Chris Q. Doe
During neurogenesis, vertebrate and Drosophila progenitors change over time as they generate a diverse population of neurons and glia. Vertebrate neural progenitors have long been known to use both progenitor-intrinsic and progenitor-extrinsic cues to regulate temporal patterning. In contrast, virtually all temporal patterning mechanisms discovered in Drosophila neural progenitors (neuroblasts) involve progenitor-intrinsic temporal transcription factor cascades. Recent results, however, have revealed several extrinsic pathways that regulate Drosophila neuroblast temporal patterning: nutritional cues regulate the timing of neuroblast proliferation/quiescence and a steroid hormone cue that is required for temporal transcription factor expression. Here, we discuss newly discovered extrinsic cues regulating neural progenitor temporal identity in Drosophila, highlight conserved mechanisms, and raise open questions for the future.
Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity Trends Genet. (IF 10.844) Pub Date : 2017-09-14 Nicolas Skrypek, Steven Goossens, Eva De Smedt, Niels Vandamme, Geert Berx
Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells lose their junctions and polarity to gain a motile mesenchymal phenotype. EMT is essential during embryogenesis and adult physiological processes like wound healing, but is aberrantly activated in pathological conditions like fibrosis and cancer. A series of transcription factors (EMT-inducing transcription factor; EMT-TF) regulate the induction of EMT by repressing the transcription of epithelial genes while activating mesenchymal genes through mechanisms still debated. The nuclear interaction of EMT-TFs with larger protein complexes involved in epigenetic genome modulation has attracted recent attention to explain functions of EMT-TFs during reprogramming and cellular differentiation. In this review, we discuss recent advances in understanding the interplay between epigenetic regulators and EMT transcription factors and how these findings could be used to establish new therapeutic approaches to tackle EMT-related diseases.
Stay Connected: A Germ Cell Strategy Trends Genet. (IF 10.844) Pub Date : 2017-09-22 Kevin Lu, Lindy Jensen, Lei Lei, Yukiko M. Yamashita
Germ cells develop as a cyst of interconnected sibling cells in a broad range of organisms in both sexes. A well-established function of intercellular connectivity is to transport cytoplasmic materials from ‘nurse’ cells to oocytes, a critical process for developing functional oocytes in ovaries of many species. However, there are situations where connectivity exists without a nursing mechanism, and the biological meaning of such connectivity remains obscure. In this review, we summarize current knowledge on the formation of intercellular connectivity, and discuss its meaning by visiting multiple examples of germ cell connectivity observed in evolutionarily distant species.
A Toolkit of Engineered Recombinational Balancers in C. elegans Trends Genet. (IF 10.844) Pub Date : 2018-01-31 Hillel T. Schwartz, Paul W. Sternberg
Dejima and colleagues report using CRISPR/Cas9 to generate a new collection of greatly improved balancer chromosomes in the standard laboratory nematode Caenorhabditis elegans, using methods previously reported by the same laboratory, expanding the set of C. elegans balancers to cover nearly 90% of coding genes.
RNA Biology in Retinal Development and Disease Trends Genet. (IF 10.844) Pub Date : 2018-01-31 Lina Zelinger, Anand Swaroop
For decades, RNA has served in a supporting role between the genetic carrier (DNA) and the functional molecules (proteins). It is finally time for RNA to take center stage in all aspects of biology. The retina provides a unique opportunity to dissect the molecular underpinnings of neuronal diversity and disease. Transcriptome profiles of the retina and its resident cell types have unraveled unique features of the RNA landscape. The discovery of distinct RNA molecules and the recognition that RNA processing is a major cause of retinal neurodegeneration have prompted the design of biomarkers and novel therapeutic paradigms. We review here RNA biology as it pertains to the retina, emphasizing new avenues for investigations in development and disease.
Stable Intronic Sequence RNAs Engage in Feedback Loops Trends Genet. (IF 10.844) Pub Date : 2018-01-31 Jun Wei Pek
Stable intronic sequence RNAs (sisRNAs) are conserved in various organisms. Recent observations in Drosophila suggest that sisRNAs often engage in regulatory feedback loops to control the expression of their parental genes. The use of sisRNAs as mediators for local feedback control may be a general phenomenon.
The Definition of Open Reading Frame Revisited Trends Genet. (IF 10.844) Pub Date : 2018-01-30 Patricia Sieber, Matthias Platzer, Stefan Schuster
The term open reading frame (ORF) is of central importance to gene finding. Surprisingly, at least three definitions are in use. We discuss several molecular biological and bioinformatics aspects, and we recommend using the definition in which an ORF is bounded by stop codons.
Insights into Modern Human Prehistory Using Ancient Genomes Trends Genet. (IF 10.844) Pub Date : 2018-01-25 Melinda A. Yang, Qiaomei Fu
The genetic relationship of past modern humans to today’s populations and each other was largely unknown until recently, when advances in ancient DNA sequencing allowed for unprecedented analysis of the genomes of these early people. These ancient genomes reveal new insights into human prehistory not always observed studying present-day populations, including greater details on the genetic diversity, population structure, and gene flow that characterized past human populations, particularly in early Eurasia, as well as increased insight on the relationship between archaic and modern humans. Here, we review genetic studies on ∼45 000- to 7500-year-old individuals associated with mainly preagricultural cultures found in Eurasia, the Americas, and Africa.
Time for Bed: Genetic Mechanisms Mediating the Circadian Regulation of Sleep Trends Genet. (IF 10.844) Pub Date : 2018-01-24 Ian D. Blum, Benjamin Bell, Mark N. Wu
Sleep is an evolutionarily conserved behavior that is increasingly recognized as important for human health. While its precise function remains controversial, sleep has been suggested to play a key role in a variety of biological phenomena ranging from synaptic plasticity to metabolic clearance. Although it is clear that sleep is regulated by the circadian clock, how this occurs remains enigmatic. Here we examine the genetic mechanisms by which the circadian clock regulates sleep, drawing on recent work in fruit flies, zebrafish, mice, and humans. These studies reveal that central and local clocks utilize diverse mechanisms to regulate different aspects of sleep, and a better understanding of this multilayered regulation may lead to a better understanding of the functions of sleep.
PRDM9 and Its Role in Genetic Recombination Trends Genet. (IF 10.844) Pub Date : 2018-01-21 Kenneth Paigen, Petko M. Petkov
PRDM9 is a zinc finger protein that binds DNA at specific locations in the genome where it trimethylates histone H3 at lysines 4 and 36 at surrounding nucleosomes. During meiosis in many species, including humans and mice where PRDM9 has been most intensely studied, these actions determine the location of recombination hotspots, where genetic recombination occurs. In addition, PRDM9 facilitates the association of hotspots with the chromosome axis, the site of the programmed DNA double-strand breaks (DSBs) that give rise to genetic exchange between chromosomes. In the absence of PRDM9 DSBs are not properly repaired. Collectively, these actions determine patterns of genetic linkage and the possibilities for chromosome reorganization over successive generations.
Caught with One's Zinc Fingers in the Genome Integrity Cookie Jar Trends Genet. (IF 10.844) Pub Date : 2018-01-19 Caroline K. Vilas, Lara E. Emery, Eros Lazzerini Denchi, Kyle M. Miller
Zinc finger (ZnF) domains are present in at least 5% of human proteins. First characterized as binding to DNA, ZnFs display extraordinary binding plasticity and can bind to RNA, lipids, proteins, and protein post-translational modifications (PTMs). The diverse binding properties of ZnFs have made their functional characterization challenging. While once confined to large and poorly characterized protein families, proteomic, cellular, and molecular studies have begun to shed light on their involvement as protectors of the genome. We focus here on the emergent roles of ZnF domain-containing proteins in promoting genome integrity, including their involvement in telomere maintenance and DNA repair. These findings have highlighted the need for further characterization of ZnF proteins, which can reveal the functions of this large gene class in normal cell function and human diseases, including those involving genome instability such as aging and cancer.
Big Strides in Cellular MicroRNA Expression Trends Genet. (IF 10.844) Pub Date : 2018-01-18 Marc K. Halushka, Bastian Fromm, Kevin J. Peterson, Matthew N. McCall
A lack of knowledge of the cellular origin of miRNAs has greatly confounded functional and biomarkers studies. Recently, three studies characterized miRNA expression patterns across >78 human cell types. These combined data expand our knowledge of miRNA expression localization and confirm that many miRNAs show cell type-specific expression patterns.
mRNA Translation Gone Awry: Translation Fidelity and Neurological Disease Trends Genet. (IF 10.844) Pub Date : 2018-01-16 Mridu Kapur, Susan L. Ackerman
Errors during mRNA translation can lead to a reduction in the levels of functional proteins and an increase in deleterious molecules. Advances in next-generation sequencing have led to the discovery of rare genetic disorders, many caused by mutations in genes encoding the mRNA translation machinery, as well as to a better understanding of translational dynamics through ribosome profiling. We discuss here multiple neurological disorders that are linked to errors in tRNA aminoacylation and ribosome decoding. We draw on studies from genetic models, including yeast and mice, to enhance our understanding of the translational defects observed in these diseases. Finally, we emphasize the importance of tRNA, their associated enzymes, and the inextricable link between accuracy and efficiency in the maintenance of translational fidelity.
Computational Strategies for Exploring Circular RNAs Trends Genet. (IF 10.844) Pub Date : 2018-01-12 Yuan Gao, Fangqing Zhao
Recent studies have demonstrated that circular RNAs (circRNAs) are ubiquitous and have diverse functions and mechanisms of biogenesis. In these studies, computational profiling of circRNAs has been prevalently used as an indispensable method to provide high-throughput approaches to detect and analyze circRNAs. However, without an overall understanding of the underlying strategies, these computational methods may not be appropriately selected or used for a specific research purpose, and some misconceptions may result in biases in the analyses. In this review we attempt to illustrate the key steps and summarize tradeoff of different strategies, covering all popular algorithms for circRNA detection and various downstream analyses. We also clarify some common misconceptions and put emphasis on the fields of application for these computational methods.
Defining B Cell Chromatin: Lessons from EBF1 Trends Genet. (IF 10.844) Pub Date : 2018-01-11 Sören Boller, Rui Li, Rudolf Grosschedl
Hematopoiesis is regulated by signals from the microenvironment, transcription factor networks, and changes of the epigenetic landscape. Transcription factors interact with and shape chromatin to allow for lineage- and cell type-specific changes in gene expression. During B lymphopoiesis, epigenetic regulation is observed in multilineage progenitors in which a specific chromatin context is established, at the onset of the B cell differentiation when early B cell factor 1 (EBF1) induces lineage-specific changes in chromatin, during V(D)J recombination and after antigen-driven activation of B cells and terminal differentiation. In this review, we discuss the epigenetic changes underlying B cell differentiation, focusing on the role of transcription factor EBF1 in B cell lineage priming.
Detecting and Avoiding Problems When Using the Cre–lox System Trends Genet. (IF 10.844) Pub Date : 2018-01-11 Allisa J. Song, Richard D. Palmiter
The Cre–lox recombination approach is commonly used to generate cell-specific gene inactivation (or activation). We have noticed that the breeding and genotyping sections of papers utilizing Cre–lox techniques are frequently incomplete. While seemingly straightforward, there are important considerations that need to be implemented in the breeding and genotyping methods to prevent the introduction of experimental confounds. Germline recombination and transient expression of Cre recombinase during development are some examples of the complications that can occur, and conventional genotyping methods may fail to identify these events. In this opinion article, we highlight the importance of testing for unexpected recombination events, suggest strategies to isolate and minimize adverse recombination events, and encourage editors and reviewers to expect more definitive statements regarding the validation of genotyping.
Supervised Machine Learning for Population Genetics: A New Paradigm Trends Genet. (IF 10.844) Pub Date : 2018-01-10 Daniel R. Schrider, Andrew D. Kern
As population genomic datasets grow in size, researchers are faced with the daunting task of making sense of a flood of information. To keep pace with this explosion of data, computational methodologies for population genetic inference are rapidly being developed to best utilize genomic sequence data. In this review we discuss a new paradigm that has emerged in computational population genomics: that of supervised machine learning (ML). We review the fundamentals of ML, discuss recent applications of supervised ML to population genetics that outperform competing methods, and describe promising future directions in this area. Ultimately, we argue that supervised ML is an important and underutilized tool that has considerable potential for the world of evolutionary genomics.
Regulatory Potential of the RNA Processing Machinery: Implications for Human Disease Trends Genet. (IF 10.844) Pub Date : 2018-01-09 Kirstyn T. Carey, Vihandha O. Wickramasinghe
Splicing and nuclear export of mRNA are critical steps in the gene expression pathway. While RNA processing factors can perform general, essential functions for intron removal and bulk export of mRNA, emerging evidence highlights that the core RNA splicing and export machineries also display regulatory potential. Here, we discuss recent insights into how this regulatory potential can selectively alter gene expression and regulate important biological processes. We also highlight the participation of RNA processing pathways in the cellular response to DNA damage at multiple levels. These findings have important implications for the contribution of selective mRNA processing and export to the development of human cancers and neurodegenerative disorders.
Discoveries of Extrachromosomal Circles of DNA in Normal and Tumor Cells Trends Genet. (IF 10.844) Pub Date : 2018-01-09 Teressa Paulsen, Pankaj Kumar, M. Murat Koseoglu, Anindya Dutta
While the vast majority of cellular DNA in eukaryotes is contained in long linear strands in chromosomes, we have long recognized some exceptions like mitochondrial DNA, plasmids in yeasts, and double minutes (DMs) in cancer cells where the DNA is present in extrachromosomal circles. In addition, specialized extrachromosomal circles of DNA (eccDNA) have been noted to arise from repetitive genomic sequences like telomeric DNA or rDNA. Recently eccDNA arising from unique (nonrepetitive) DNA have been discovered in normal and malignant cells, raising interesting questions about their biogenesis, function and clinical utility. Here, we review recent results and future directions of inquiry on these new forms of eccDNA.
Zipping and Unzipping: Protein Modifications Regulating Synaptonemal Complex Dynamics Trends Genet. (IF 10.844) Pub Date : 2017-12-28 Jinmin Gao, Monica P. Colaiácovo
The proteinaceous zipper-like structure known as the synaptonemal complex (SC), which forms between pairs of homologous chromosomes during meiosis from yeast to humans, plays important roles in promoting interhomolog crossover formation, regulating cessation of DNA double-strand break (DSB) formation following crossover designation, and ensuring accurate meiotic chromosome segregation. Recent studies are starting to reveal critical roles for different protein modifications in regulating SC dynamics. Protein SUMOylation, N-terminal acetylation, and phosphorylation have been shown to be essential for the regulated assembly and disassembly of the SC. Moreover, phosphorylation of specific SC components has been found to link changes in SC dynamics with meiotic recombination. This review highlights the latest findings on how protein modifications regulate SC dynamics and functions.
Are Lethal Alleles Too Abundant in Humans? Trends Genet. (IF 10.844) Pub Date : 2017-12-28 Mallory A. Ballinger, Mohamed A.F. Noor
Across species, many individuals carry one or more recessive lethal alleles, posing an evolutionary conundrum for their persistence. Using a population genomic approach, Amorim et al. studied the abundance of lethal disease-causing mutations in humans and found that, while appearing more common than expected, most may nonetheless persist at frequencies predicted by mutation–selection balance.
Releasing Addiction Memories Trapped in Perineuronal Nets Trends Genet. (IF 10.844) Pub Date : 2017-12-27 Amy W. Lasek, Hu Chen, Wei-Yang Chen
Drug addiction can be conceptualized at a basic level as maladaptive learning and memory. Addictive substances elicit changes in brain circuitry involved in reward, cognition, and emotional state, leading to the formation and persistence of strong drug-associated memories that lead to craving and relapse. Recently, perineuronal nets (PNNs), extracellular matrix (ECM) structures surrounding neurons, have emerged as regulators of learning, memory, and addiction behaviors. PNNs do not merely provide structural support to neurons but are dynamically remodeled in an experience-dependent manner by metalloproteinases. They function in various brain regions through constituent proteins such as brevican that are implicated in neural plasticity. Understanding the function of PNN components in memory processes may lead to new therapeutic approaches to treating addiction.
Everybody In! No Bouncers at Tumor Gates Trends Genet. (IF 10.844) Pub Date : 2017-12-23 Ilio Vitale, Lorenzo Galluzzi
Two recent genomic studies suggest that a large fraction of human tumors evolves in the presence of limited negative selection against somatic mutations. In this context, specific genetic defects enable the establishment of a hypermutant state that may constitute a target for immunotherapeutic interventions.
Reassessing the Role of Hox Genes during Vertebrate Development and Evolution Trends Genet. (IF 10.844) Pub Date : 2017-12-18 Moisés Mallo
Since their discovery Hox genes have been at the core of the established models explaining the development and evolution of the vertebrate body plan as well as its paired appendages. Recent work brought new light to their role in the patterning processes along the main body axis. These studies show that Hox genes do not control the basic layout of the vertebrate body plan but carry out region-specific patterning instructions loaded on the derivatives of axial progenitors by Hox-independent processes. Furthermore, the finding that Hox clusters are embedded in functional chromatin domains, which critically impacts their expression, has significantly altered our understanding of the mechanisms of Hox gene regulation. This new conceptual framework has broadened our understanding of both limb development and the evolution of vertebrate paired appendages.
Multifaceted Fanconi Anemia Signaling Trends Genet. (IF 10.844) Pub Date : 2017-12-16 Raymond Che, Jun Zhang, Manoj Nepal, Bing Han, Peiwen Fei
In 1927 Guido Fanconi described a hereditary condition presenting panmyelopathy accompanied by short stature and hyperpigmentation, now better known as Fanconi anemia (FA). With this discovery the genetic and molecular basis underlying FA has emerged as a field of great interest. FA signaling is crucial in the DNA damage response (DDR) to mediate the repair of damaged DNA. This has attracted a diverse range of investigators, especially those interested in aging and cancer. However, recent evidence suggests FA signaling also regulates functions outside the DDR, with implications for many other frontiers of research. We discuss here the characteristics of FA functions and expand upon current perspectives regarding the genetics of FA, indicating that FA plays a role in a myriad of molecular and cellular processes.
Nuclear Long Noncoding RNAs: Key Regulators of Gene Expression Trends Genet. (IF 10.844) Pub Date : 2017-12-14 Qinyu Sun, Qinyu Hao, Kannanganattu V. Prasanth
A significant portion of the human genome encodes genes that transcribe long nonprotein-coding RNAs (lncRNAs). A large number of lncRNAs localize in the nucleus, either enriched on the chromatin or localized to specific subnuclear compartments. Nuclear lncRNAs participate in several biological processes, including chromatin organization, and transcriptional and post-transcriptional gene expression, and also act as structural scaffolds of nuclear domains. Here, we highlight recent studies demonstrating the role of lncRNAs in regulating gene expression and nuclear organization in mammalian cells. In addition, we update current knowledge about the involvement of the most-abundant and conserved lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), in gene expression control.
Beyond Hemoglobin: Screening for Malaria Host Factors Trends Genet. (IF 10.844) Pub Date : 2017-12-14 Elizabeth S. Egan
Severe malaria is caused by the Apicomplexan parasite Plasmodium falciparum, and results in significant global morbidity and mortality, particularly among young children and pregnant women. P. falciparum exclusively infects human erythrocytes during clinical illness, and several natural erythrocyte polymorphisms are protective against severe malaria. Since erythrocytes are enucleated and lack DNA, genetic approaches to understand erythrocyte determinants of malaria infection have historically been limited. This review highlights recent advances in the use of hematopoietic stem cells to facilitate genetic screening for malaria host factors. While challenges still exist, this approach holds promise for gaining new insights into host–pathogen interactions in malaria.
Epigenetic Regulation of Biological Rhythms: An Evolutionary Ancient Molecular Timer Trends Genet. (IF 10.844) Pub Date : 2017-12-05 Tyler J. Stevenson
Biological rhythms are pervasive in nature, yet our understanding of the molecular mechanisms that govern timing is far from complete. The rapidly emerging research focus on epigenetic plasticity has revealed a system that is highly dynamic and reversible. In this Opinion, I propose an epigenetic clock model that outlines how molecular modifications, such as DNA methylation, are integral components for timing endogenous biological rhythms. The hypothesis proposed is that an epigenetic clock serves to maintain the period of molecular rhythms via control over the phase of gene transcription and this timing mechanism resides in all cells, from unicellular to complex organisms. The model also provides a novel framework for the timing of epigenetic modifications during the lifespan and transgenerational inheritance of an organism.
The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years Trends Genet. (IF 10.844) Pub Date : 2017-10-05 Sergio E. Baranzini, Jorge R. Oksenberg
Multiple sclerosis (MS) is a common autoimmune disease that targets myelin in the central nervous system (CNS). Multiple genome-wide association studies (GWAS) over the past 10 years have uncovered more than 200 loci that independently contribute to disease pathogenesis. As with many other complex diseases, risk of developing MS is driven by multiple common variants whose biological effects are not immediately clear. Here, we present a historical perspective on the progress made in MS genetics and discuss current work geared towards creating a more complete model that accurately represents the genetic landscape of MS susceptibility. Such a model necessarily includes a better understanding of the individual contributions of each common variant to the cellular phenotypes, and interactions with other genes and with the environment. Future genetic studies in MS will likely focus on the role of rare variants and endophenotypes.
Fantastic Beasts and How To Sequence Them: Ecological Genomics for Obscure Model Organisms Trends Genet. (IF 10.844) Pub Date : 2017-11-29 Mikhail V. Matz
The application of genomic approaches to ‘obscure model organisms’ (OMOs), meaning species with no prior genomic resources, enables increasingly sophisticated studies of the genomic basis of evolution, acclimatization, and adaptation in real ecological contexts. I consider here ecological questions that can be addressed using OMOs, and indicate optimal sequencing and data-handling solutions for each case. With this I hope to promote the diversity of OMO-based projects that would capitalize on the peculiarities of the natural history of OMOs and could feasibly be completed within the scope of a single PhD thesis.
When DNA Topology Turns Deadly – RNA Polymerases Dig in Their R-Loops to Stand Their Ground: New Positive and Negative (Super)Twists in the Replication–Transcription Conflict Trends Genet. (IF 10.844) Pub Date : 2017-11-25 Andrei Kuzminov
Head-on replication–transcription conflict is especially bitter in bacterial chromosomes, explaining why actively transcribed genes are always co-oriented with replication. The mechanism of this conflict remains unclear, besides the anticipated accumulation of positive supercoils between head-on-conflicting polymerases. Unexpectedly, experiments in bacterial and human cells reveal that head-on replication–transcription conflict induces R-loops, indicating hypernegative supercoiling [(−)sc] in the region – precisely the opposite of that assumed. Further, as a result of these R-loops, both replication and transcription in the affected region permanently stall, so the failure of R-loop removal in RNase H-deficient bacteria becomes lethal. How hyper(−)sc emerges in the middle of a positively supercoiled chromosomal domain is a mystery that requires rethinking of topoisomerase action around polymerases.
Mitochondrial Genome Engineering: The Revolution May Not Be CRISPR-Ized Trends Genet. (IF 10.844) Pub Date : 2017-11-24 Payam A. Gammage, Carlos T. Moraes, Michal Minczuk
In recent years mitochondrial DNA (mtDNA) has transitioned to greater prominence across diverse areas of biology and medicine. The recognition of mitochondria as a major biochemical hub, contributions of mitochondrial dysfunction to various diseases, and several high-profile attempts to prevent hereditary mtDNA disease through mitochondrial replacement therapy have roused interest in the organellar genome. Subsequently, attempts to manipulate mtDNA have been galvanized, although with few robust advances and much controversy. Re-engineered protein-only nucleases such as mtZFN and mitoTALEN function effectively in mammalian mitochondria, although efficient delivery of nucleic acids into the organelle remains elusive. Such an achievement, in concert with a mitochondria-adapted CRISPR/Cas9 platform, could prompt a revolution in mitochondrial genome engineering and biological understanding. However, the existence of an endogenous mechanism for nucleic acid import into mammalian mitochondria, a prerequisite for mitochondrial CRISPR/Cas9 gene editing, remains controversial.
piRNA Biogenesis in Drosophila melanogaster Trends Genet. (IF 10.844) Pub Date : 2017-09-27 Xiawei Huang, Katalin Fejes Tóth, Alexei A. Aravin
The PIWI-interacting RNA (piRNA) pathway is a conserved defense system that protects the genome integrity of the animal germline from deleterious transposable elements. Targets of silencing are recognized by small noncoding piRNAs that are processed from long precursor molecules. Although piRNAs and other classes of small noncoding RNAs, such as miRNAs and small interfering (si)RNAs, interact with members of the same family of Argonaute (Ago) proteins and their function in target repression is similar, the biogenesis of piRNAs differs from those of the other two small RNAs. Recently, many aspects of piRNA biogenesis have been revealed in Drosophila melanogaster. In this review, we elaborate on piRNA biogenesis in Drosophila somatic and germline cells. We focus on the mechanisms by which piRNA precursor transcription is regulated and highlight recent work that has advanced our understanding of piRNA precursor processing to mature piRNAs. We finish by discussing current models to the still unresolved question of how piRNA precursors are selected and channeled into the processing machinery.
Gene Therapy with the Sleeping Beauty Transposon System Trends Genet. (IF 10.844) Pub Date : 2017-09-27 Partow Kebriaei, Zsuzsanna Izsvák, Suneel A. Narayanavari, Harjeet Singh, Zoltán Ivics
The widespread clinical implementation of gene therapy requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective, and economical manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient nonviral gene delivery approaches that are prevalent in ongoing clinical trials. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here, we review the most important aspects of using SB for gene therapy, including vectorization as well as genomic integration features. We also illustrate the path to successful clinical implementation by highlighting the application of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy.
Revisiting the Relationship between Transposable Elements and the Eukaryotic Stress Response Trends Genet. (IF 10.844) Pub Date : 2017-09-22 Vivien Horváth, Miriam Merenciano, Josefa González
A relationship between transposable elements (TEs) and the eukaryotic stress response was suggested in the first publications describing TEs. Since then, it has often been assumed that TEs are activated by stress, and that this activation is often beneficial for the organism. In recent years, the availability of new high-throughput experimental techniques has allowed further interrogation of the relationship between TEs and stress. By reviewing the recent literature, we conclude that although there is evidence for a beneficial effect of TE activation under stress conditions, the relationship between TEs and the eukaryotic stress response is quite complex.
The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution Trends Genet. (IF 10.844) Pub Date : 2017-09-19 Peng Yang, Yixuan Wang, Todd S. Macfarlan
Kruppel-associated box zinc-finger proteins (KRAB-ZFPs) make up the largest family of transcription factors in humans. These proteins emerged in the last common ancestor of coelacanth and tetrapods, and have expanded and diversified in the mammalian lineage. Although their mechanism of transcriptional repression has been well studied for over a decade, the DNA-binding activities and the biological functions of these proteins have been largely unexplored. Recent large-scale ChIP-seq studies and loss-of-function experiments have revealed that KRAB-ZFPs play a major role in the recognition and transcriptional silencing of transposable elements (TEs), consistent with an ‘arms race model’ of KRAB-ZFP evolution against invading TEs. However, this model is insufficient to explain the evolution of many KRAB-ZFPs that appear to domesticate TEs for novel host functions. We highlight some of the mammalian regulatory innovations driven by specific KRAB-ZFPs, including genomic imprinting, meiotic recombination hotspot choice, and placental growth.
Transposons As Tools for Functional Genomics in Vertebrate Models Trends Genet. (IF 10.844) Pub Date : 2017-09-06 Koichi Kawakami, David A. Largaespada, Zoltán Ivics
Genetic tools and mutagenesis strategies based on transposable elements are currently under development with a vision to link primary DNA sequence information to gene functions in vertebrate models. By virtue of their inherent capacity to insert into DNA, transposons can be developed into powerful tools for chromosomal manipulations. Transposon-based forward mutagenesis screens have numerous advantages including high throughput, easy identification of mutated alleles, and providing insight into genetic networks and pathways based on phenotypes. For example, the Sleeping Beauty transposon has become highly instrumental to induce tumors in experimental animals in a tissue-specific manner with the aim of uncovering the genetic basis of diverse cancers. Here, we describe a battery of mutagenic cassettes that can be applied in conjunction with transposon vectors to mutagenize genes, and highlight versatile experimental strategies for the generation of engineered chromosomes for loss-of-function as well as gain-of-function mutagenesis for functional gene annotation in vertebrate models, including zebrafish, mice, and rats.
Beyond Read-Counts: Ribo-seq Data Analysis to Understand the Functions of the Transcriptome Trends Genet. (IF 10.844) Pub Date : 2017-09-05 Lorenzo Calviello, Uwe Ohler
By mapping the positions of millions of translating ribosomes in the cell, ribosome profiling (Ribo-seq) has established its role as a powerful tool to study gene expression. Several laboratories have introduced modifications to the experimental protocol and expanded the repertoire of biochemical methods to study translation transcriptome-wide. However, the diversity of protocols highlights a need for standardization. At the same time, different computational analysis strategies have used Ribo-seq data to identify the set of translated sequences with high confidence. In this review we present an overview of such methodologies, outlining their assumptions, data requirements, and availability. At the interface between RNA and proteins, Ribo-seq can complement data from multiple omics approaches, zooming in on the central role of translation in the molecular cell.
Time to Go Bigger: Emerging Patterns in Macrogenetics Trends Genet. (IF 10.844) Pub Date : 2017-07-15 Simon Blanchet, Jérôme G. Prunier, Hanne De Kort
The increasing availability of large-scale and high-resolution data sets in population genetics is moving the field toward a novel research agenda. Here, we show how this shift toward macrogenetics should generate new perspectives and theories allowing the description, understanding, and prediction of patterns of genetic diversity at broad spatial, temporal, and taxonomic scales.
CRISPRing the Regulatory Genome, the Challenge Ahead Trends Genet. (IF 10.844) Pub Date : 2017-07-29 Stephanie E. Sansbury, Katelyn M. Sweeney, Ophir Shalem
CRISPR saturation mutagenesis has the potential to dissect the functional landscape of noncoding regions, but is highly susceptible to false discovery and misinterpretation. As recently published, Canver et al. have now taken the first steps towards addressing these issues by increasing screening resolution and analyzing the effects of off targets on hit calling.
Evolutionary Dynamics of Unreduced Gametes Trends Genet. (IF 10.844) Pub Date : 2017-07-18 Julia M. Kreiner, Paul Kron, Brian C. Husband
Unreduced gametes, which have the somatic (2n) chromosome number, are an important precursor to polyploid formation and apomixis. The product of irregularities in meiosis, 2n gametes are expected to be rare and deleterious in most natural populations, contrary to their wide taxonomic distribution and the prevalence of polyploidy. To better understand this discrepancy, we review contemporary evidence related to four aspects of 2n gamete dynamics in natural populations: (i) estimates of their frequency; (ii) their environmental and genetic determinants; (iii) adaptive and nonadaptive processes regulating their evolution; and (iv) factors regulating their union and production of polyploids in diploid populations. Aided by high-throughput methods of detection, these foci will advance our understanding of variation in 2n gametes within and among species, and their role in polyploid evolution.
Roles of RNase P and Its Subunits Trends Genet. (IF 10.844) Pub Date : 2017-07-08 Nayef Jarrous
Recent studies show that nuclear RNase P is linked to chromatin structure and function. Thus, variants of this ribonucleoprotein (RNP) complex bind to chromatin of small noncoding RNA genes; integrate into initiation complexes of RNA polymerase (Pol) III; repress histone H3.3 nucleosome deposition; control tRNA and PIWI-interacting RNA (piRNA) gene clusters for genome defense; and respond to Werner syndrome helicase (WRN)-related replication stress and DNA double-strand breaks (DSBs). Likewise, the related RNase MRP and RMRP-TERT (telomerase reverse transcriptase) are implicated in RNA-dependent RNA polymerization for chromatin silencing, whereas the telomerase carries out RNA-dependent DNA polymerization for telomere lengthening. Remarkably, the four RNPs share several protein subunits, including two Alba-like chromatin proteins that possess DEAD-like and ATPase motifs found in chromatin modifiers and remodelers. Based on available data, RNase P and related RNPs act in transition processes of DNA to RNA and vice versa and connect these processes to genome preservation, including replication, DNA repair, and chromatin remodeling.
High-Throughput Imaging for the Discovery of Cellular Mechanisms of Disease Trends Genet. (IF 10.844) Pub Date : 2017-07-18 Gianluca Pegoraro, Tom Misteli
High-throughput imaging (HTI) is a powerful tool in the discovery of cellular disease mechanisms. While traditional approaches to identify disease pathways often rely on knowledge of the causative genetic defect, HTI-based screens offer an unbiased discovery approach based on any morphological or functional defects of disease cells or tissues. In this review, we provide an overview of the use of HTI for the study of human disease mechanisms. We discuss key technical aspects of HTI and highlight representative examples of its practical applications for the discovery of molecular mechanisms of disease, focusing on infectious diseases and host–pathogen interactions, cancer, and rare genetic diseases. We also present some of the current challenges and possible solutions offered by novel cell culture systems and genome engineering approaches.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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