当前期刊: Trends in Genetics Go to current issue    加入关注   
显示样式:        排序: 导出
  • Therapeutic Germline Editing: Sense and Sensibility
    Trends Genet. (IF 10.627) Pub Date : 2020-01-22
    Eli Y. Adashi; I. Glenn Cohen

    Safe and effective heritable editing of the human genome is years away from the clinic because of formidable technical, statutory, regulatory, and societal challenges. In particular, we note the fledgling state of the science, the imperatives of editing efficiency, specificity, and uniformity, and the extant legal roadblock.

  • Clonal Reproduction through Seeds in Sight for Crops
    Trends Genet. (IF 10.627) Pub Date : 2020-01-20
    Peggy Ozias-Akins; Joann A. Conner

    Apomixis or asexual reproduction through seeds, enables the preservation of hybrid vigor. Hybrids are heterozygous and segregate for genotype and phenotype upon sexual reproduction. While apomixis, that is, clonal reproduction, is intuitively antithetical to diversity, it is rarely obligate and actually provides a mechanism to recover and maintain superior hybrid gene combinations for which sexual reproduction would reveal deleterious alleles in less fit genotypes. Apomixis, widespread across flowering plant orders, does not occur in major crop species, yet its introduction could add a valuable tool to the breeder’s toolbox. In the past decade, discovery of genetic mechanisms regulating meiosis, embryo and endosperm development have facilitated proof-of-concept for the synthesis of apomixis, bringing apomictic crops closer to reality.

  • Molecular Mechanisms Driving mRNA Degradation by m6A Modification
    Trends Genet. (IF 10.627) Pub Date : 2020-01-18
    Yujin Lee; Junho Choe; Ok Hyun Park; Yoon Ki Kim

    N6-Methyladenosine (m6A), the most prevalent internal modification associated with eukaryotic mRNAs, influences many steps of mRNA metabolism, including splicing, export, and translation, as well as stability. Recent studies have revealed that m6A-containing mRNAs undergo one of two distinct pathways of rapid degradation: deadenylation via the YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2; an m6A reader protein)–CCR4/NOT (deadenylase) complex or endoribonucleolytic cleavage by the YTHDF2–HRSP12–ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some m6A-containing circular RNAs (circRNAs) are also subject to endoribonucleolytic cleavage by YTHDF2–HRSP12–RNase P/MRP. Here, we highlight recent progress on the molecular mechanisms underlying rapid mRNA degradation via m6A and describe our current understanding of the dynamic regulation of m6A-mediated mRNA decay through the crosstalk between m6A (or YTHDF2) and other cellular factors.

  • From Summary Statistics to Gene Trees: Methods for Inferring Positive Selection
    Trends Genet. (IF 10.627) Pub Date : 2020-01-15
    Hussein A. Hejase; Noah Dukler; Adam Siepel

    Methods to detect signals of natural selection from genomic data have traditionally emphasized the use of simple summary statistics. Here, we review a new generation of methods that consider combinations of conventional summary statistics and/or richer features derived from inferred gene trees and ancestral recombination graphs (ARGs). We also review recent advances in methods for population genetic simulation and ARG reconstruction. Finally, we describe opportunities for future work on a variety of related topics, including the genetics of speciation, estimation of selection coefficients, and inference of selection on polygenic traits. Together, these emerging methods offer promising new directions in the study of natural selection.

  • Flipping Shells! Unwinding LR Asymmetry in Mirror-Image Molluscs
    Trends Genet. (IF 10.627) Pub Date : 2020-01-14
    Angus Davison

    In seeking to understand the establishment of left–right (LR) asymmetry, a limiting factor is that most animals are ordinarily invariant in their asymmetry, except when manipulated or mutated. It is therefore surprising that the wider scientific field does not appear to fully appreciate the remarkable fact that normal development in molluscs, especially snails, can flip between two chiral types without pathology. Here, I describe recent progress in understanding the evolution, development, and genetics of chiral variation in snails, and place it in context with other animals. I argue that the natural variation of snails is a crucial resource towards understanding the invariance in other animal groups and, ultimately, will be key in revealing the common factors that define cellular and organismal LR asymmetry.

  • Small RNAs in the Transgenerational Inheritance of Epigenetic Information
    Trends Genet. (IF 10.627) Pub Date : 2020-01-14
    Lea Duempelmann; Merle Skribbe; Marc Bühler

    In recent years it has become evident that RNA interference-related mechanisms can mediate the deposition and transgenerational inheritance of specific chromatin modifications in a truly epigenetic fashion. Rapid progress has been made in identifying the RNAi effector proteins and how they work together to confer long-lasting epigenetic responses, and initial studies hint at potential physiological relevance of such regulation. In this review, we highlight mechanistic studies in model organisms that advance our understanding of how small RNAs trigger long-lasting epigenetic changes in gene expression and we discuss observations that lend support for the idea that small RNAs might participate in mechanisms that trigger epigenetic gene expression changes in response to environmental cues and the effects these could have on population adaptation.

  • Omics in Neurodegenerative Disease: Hope or Hype?
    Trends Genet. (IF 10.627) Pub Date : 2020-01-10
    Maria E. Diaz-Ortiz; Alice S. Chen-Plotkin

    The past 15 years have seen a boom in the use and integration of ‘omic’ approaches (limited here to genomic, transcriptomic, and epigenomic techniques) to study neurodegenerative disease in an unprecedented way. We first highlight advances in and the limitations of using such approaches in the neurodegenerative disease literature, with a focus on Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). We next discuss how these studies can advance human health in the form of generating leads for downstream mechanistic investigation or yielding polygenic risk scores (PRSs) for prognostication. However, we argue that these approaches constitute a new form of molecular description, analogous to clinical or pathological description, that alone does not hold the key to solving these complex diseases.

  • Silencers, Enhancers, and the Multifunctional Regulatory Genome
    Trends Genet. (IF 10.627) Pub Date : 2020-01-07
    Marc S. Halfon

    Negative regulation of gene expression by transcriptional silencers has been difficult to study due to limited defined examples. A new study by Gisselbrecht et al. has dramatically increased the number of identified silencers and reveals that they are bifunctional regulatory sequences that also act as gene expression-promoting enhancers.

  • Pangenomics Comes of Age: From Bacteria to Plant and Animal Applications
    Trends Genet. (IF 10.627) Pub Date : 2019-12-24
    Agnieszka A. Golicz; Philipp E. Bayer; Prem L. Bhalla; Jacqueline Batley; David Edwards

    The pangenome refers to a collection of genomic sequence found in the entire species or population rather than in a single individual; the sequence can be core, present in all individuals, or accessory (variable or dispensable), found in a subset of individuals only. While pangenomic studies were first undertaken in bacterial species, developments in genome sequencing and assembly approaches have allowed construction of pangenomes for eukaryotic organisms, fungi, plants, and animals, including two large-scale human pangenome projects. Analysis of the these pangenomes revealed key differences, most likely stemming from divergent evolutionary histories, but also surprising similarities.

  • Unknown to Known: Advancing Knowledge of Coral Gene Function
    Trends Genet. (IF 10.627) Pub Date : 2019-12-24
    Phillip A. Cleves; Alexander Shumaker; JunMo Lee; Hollie M. Putnam; Debashish Bhattacharya

    Given the catastrophic changes befalling coral reefs, understanding coral gene function is essential to advance reef conservation. This has proved challenging due to the paucity of genomic data and genetic tools available for corals. Recently, CRISPR/Cas9 gene editing was applied to these species; however, a major bottleneck is the identification and prioritization of candidate genes for manipulation. This issue is exacerbated by the many unknown (‘dark’) coral genes that may play key roles in the stress response. We review the use of gene coexpression networks that incorporate both known and unknown genes to identify targets for reverse genetic analysis. This approach also provides a framework for the annotation of dark genes in established interaction networks to improve our fundamental knowledge of coral gene function.

  • Ubiquitously Expressed Proteins and Restricted Phenotypes: Exploring Cell-Specific Sensitivities to Impaired tRNA Charging
    Trends Genet. (IF 10.627) Pub Date : 2019-12-12
    Molly E. Kuo; Anthony Antonellis

    Aminoacyl-tRNA synthetases (ARS) are ubiquitously expressed, essential enzymes that charge tRNA with cognate amino acids. Variants in genes encoding ARS enzymes lead to myriad human inherited diseases. First, missense alleles cause dominant peripheral neuropathy. Second, missense, nonsense, and frameshift alleles cause recessive multisystem disorders that differentially affect tissues depending on which ARS is mutated. A preponderance of evidence has shown that both phenotypic classes are associated with loss-of-function alleles, suggesting that tRNA charging plays a central role in disease pathogenesis. However, it is currently unclear how perturbation in the function of these ubiquitously expressed enzymes leads to tissue-specific or tissue-predominant phenotypes. Here, we review our current understanding of ARS-associated disease phenotypes and discuss potential explanations for the observed tissue specificity.

  • New Roles for Canonical Transcription Factors in Repeat Expansion Diseases
    Trends Genet. (IF 10.627) Pub Date : 2019-12-11
    Lindsey D. Goodman, Nancy M. Bonini

    The presence of microsatellite repeat expansions within genes is associated with >30 neurological diseases. Of interest, (GGGGCC)>30-repeats within C9orf72 are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These expansions can be 100s to 1000s of units long. Thus, it is perplexing how RNA-polymerase II (RNAPII) can successfully transcribe them. Recent investigations focusing on GGGGCC-transcription have identified specific, canonical complexes that may promote RNAPII-transcription at these GC-rich microsatellites: the DSIF complex and PAF1C. These complexes may be important for resolving the unique secondary structures formed by GGGGCC-DNA during transcription. Importantly, this process can produce potentially toxic repeat-containing RNA that can encode potentially toxic peptides, impacting neuron function and health. Understanding how transcription of these repeats occurs has implications for therapeutics in multiple diseases.

  • Emerging Role of C/EBPβ and Epigenetic DNA Methylation in Ageing
    Trends Genet. (IF 10.627) Pub Date : 2019-12-07
    Christof Niehrs, Cornelis F. Calkhoven

    Changes in epigenetic DNA methylation are the most promising predictor of biological age and lifespan in humans, but whether methylation changes affect ageing is unresolved. Here, we discuss converging data, which indicate that one mode by which aberrant DNA methylation can affect ageing is via CCAAT/enhancer binding protein beta (C/EBPβ). This basic leucine-zipper (bZIP) transcription factor is controlled by the lifespan regulator mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and plays an important role in energy homeostasis and adipose tissue differentiation. Emerging evidence indicates that access of C/EBPβ proteins to cognate binding sites is regulated by DNA demethylation via ten-eleven translocation (TET) methylcytosine dioxygenases and their adaptor proteins growth arrest and DNA damage-inducible protein 45 alpha (GADD45α) and inhibitor of growth 1 (ING1). We discuss the emerging causal nexus between C/EBPβ, energy metabolism, and DNA demethylation in organismal ageing.

  • The Bivalent Genome: Characterization, Structure, and Regulation
    Trends Genet. (IF 10.627) Pub Date : 2019-12-06
    Enrique Blanco, Mar González-Ramírez, Anna Alcaine-Colet, Sergi Aranda, Luciano Di Croce

    An intricate molecular machinery is at the core of gene expression regulation in every cell. During the initial stages of organismal development, the coordinated activation of diverse transcriptional programs is crucial and must be carefully executed to shape every organ and tissue. Bivalent promoters and poised enhancers are regulatory regions decorated with histone marks that are associated with both positive and negative transcriptional outcomes. These apparently contradictory signals are important for setting bivalent genes in a poised state, which is subsequently resolved during differentiation into either active or repressive states. We discuss the origins of bivalent promoters and the mechanisms implicated in their acquisition and maintenance. We further review how the presence of bivalent marks influences genome architecture. Finally, we highlight the potential link between bivalency and cancer which could drive biomedical research in disease etiology and treatment.

  • The Biogenesis and Precise Control of RNA m6A Methylation
    Trends Genet. (IF 10.627) Pub Date : 2019-12-04
    Huilin Huang, Hengyou Weng, Jianjun Chen

    N6-Methyladenosine (m6A) is the most prevalent internal RNA modification in mRNA, and has been found to be highly conserved and hard-coded in mammals and other eukaryotic species. The importance of m6A for gene expression regulation and cell fate decisions has been well acknowledged in the past few years. However, it was only until recently that the mechanisms underlying the biogenesis and specificity of m6A modification in cells were uncovered. We review up-to-date knowledge on the biogenesis of the RNA m6A modification, including the cis-regulatory elements and trans-acting factors that determine general de novo m6A deposition and modulate cell type-specific m6A patterns, and we discuss the biological significance of such regulation.

  • Population Genetics in the Human Microbiome
    Trends Genet. (IF 10.627) Pub Date : 2019-11-25
    Nandita R. Garud, Katherine S. Pollard

    While the human microbiome’s structure and function have been extensively studied, its within-species genetic diversity is less well understood. However, genetic mutations in the microbiome can confer biomedically relevant traits, such as the ability to extract nutrients from food, metabolize drugs, evade antibiotics, and communicate with the host immune system. The population genetic processes by which these traits evolve are complex, in part due to interacting ecological and evolutionary forces in the microbiome. Advances in metagenomic sequencing, coupled with bioinformatics tools and population genetic models, facilitate quantification of microbiome genetic variation and inferences about how this diversity arises, evolves, and correlates with traits of both microbes and hosts. In this review, we explore the population genetic forces (mutation, recombination, drift, and selection) that shape microbiome genetic diversity within and between hosts, as well as efforts towards predictive models that leverage microbiome genetics.

  • Asymmetric Histone Inheritance in Asymmetrically Dividing Stem Cells
    Trends Genet. (IF 10.627) Pub Date : 2019-11-18
    Matthew Wooten, Rajesh Ranjan, Xin Chen

    Epigenetic mechanisms play essential roles in determining distinct cell fates during the development of multicellular organisms. Histone proteins represent crucial epigenetic components that help specify cell identities. Previous work has demonstrated that during the asymmetric cell division of Drosophila male germline stem cells (GSCs), histones H3 and H4 are asymmetrically inherited, such that pre-existing (old) histones are segregated towards the self-renewing GSC whereas newly synthesized (new) histones are enriched towards the differentiating daughter cell. In order to further understand the molecular mechanisms underlying this striking phenomenon, two key questions must be answered: when and how old and new histones are differentially incorporated by sister chromatids, and how epigenetically distinct sister chromatids are specifically recognized and segregated. Here, we discuss recent advances in our understanding of the molecular mechanisms and cellular bases underlying these fundamental and important biological processes responsible for generating two distinct cells through one cell division.

  • Evolution of Epistatic Networks and the Genetic Basis of Innate Behaviors
    Trends Genet. (IF 10.627) Pub Date : 2019-11-07
    Robert R.H. Anholt

    Instinctive behaviors are genetically programmed behaviors that occur independent of experience. How genetic programs that give rise to the manifestation of such behaviors evolve remains an unresolved question. I propose that evolution of species-specific innate behaviors is accomplished through progressive modifications of pre-existing genetic networks composed of allelic variants. I hypothesize that changes in frequencies of one or more constituent allelic variants within the network leads to changes in gene network connectivity and the emergence of a reorganized network that can support the emergence of a novel behavioral phenotype and becomes stabilized when key allelic variants are driven to fixation.

  • Evolvability Costs of Niche Expansion
    Trends Genet. (IF 10.627) Pub Date : 2019-11-05
    Lisa M. Bono, Jeremy A. Draghi, Paul E. Turner

    What prevents generalists from displacing specialists, despite obvious competitive advantages of utilizing a broad niche? The classic genetic explanation is antagonistic pleiotropy: genes underlying the generalism produce ‘jacks-of-all-trades’ that are masters of none. However, experiments challenge this assumption that mutations enabling niche expansion must reduce fitness in other environments. Theory suggests an alternative cost of generalism: decreased evolvability, or the reduced capacity to adapt. Generalists using multiple environments experience relaxed selection in any one environment, producing greater relative lag load. Additionally, mutations fixed by generalist lineages early during their evolution that avoid or compensate for antagonistic pleiotropy may limit access to certain future evolutionary trajectories. Hypothesized evolvability costs of generalism warrant further exploration, and we suggest outstanding questions meriting attention.

  • Long Noncoding RNAs and Repetitive Elements: Junk or Intimate Evolutionary Partners?
    Trends Genet. (IF 10.627) Pub Date : 2019-10-29
    Hyunmin Lee, Zhaolei Zhang, Henry M. Krause

    Our recent ability to sequence entire genomes, along with all of their transcribed RNAs, has led to the surprising finding that only ∼1% of the human genome is used to encode proteins. This finding has led to vigorous debate over the functional importance of the transcribed but untranslated portions of the genome. Currently, scientists tend to assume coding genes are functional until proven not to be, while the opposite is true for noncoding genes. This review takes a new look at the evidence for and against widespread noncoding gene functionality. We focus in particular on long noncoding RNA (noncoding RNAs longer than 200 nucleotides) genes and their ‘junk’ associates, transposable elements, and satellite repeats. Taken together, the suggestion put forward is that more of this junk DNA may be functional than nonfunctional and that noncoding RNAs and transposable elements act symbiotically to drive evolution.

  • The Selfishness of Law-Abiding Genes
    Trends Genet. (IF 10.627) Pub Date : 2019-10-29
    Adrian Bird

    Selfish genes were once controversial, but it is now accepted that the genome contains parasitic elements in addition to a complement of conventional genes. This opinion article argues that ‘law-abiding’ genes also indulge in game playing to ensure their propagation, so that initially nonessential processes secure a genetic heritage. A gene-centered view of this kind can help to explain otherwise puzzling aspects of biology, including the complexity and stability of living systems.

  • Introns: Good Day Junk Is Bad Day Treasure
    Trends Genet. (IF 10.627) Pub Date : 2019-10-25
    Julie Parenteau, Sherif Abou Elela

    Introns are ubiquitous in eukaryotic transcripts. They are often viewed as junk RNA but the huge energetic burden of transcribing, removing, and degrading them suggests a significant evolutionary advantage. Ostensibly, an intron functions within the host pre-mRNA to regulate its splicing, transport, and degradation. However, recent studies have revealed an entirely new class of trans-acting functions where the presence of intronic RNA in the cell impacts the expression of other genes in trans. Here, we review possible new mechanisms of intron functions, with a focus on the role of yeast introns in regulating the cell growth response to starvation.

  • A Genetic Instruction Code Based on DNA Conformation
    Trends Genet. (IF 10.627) Pub Date : 2019-10-25
    Alan Herbert

    Flipons are sequences capable of forming either right- or left-handed DNA under physiological conditions, forming a class of dissipative structures that trade metabolic energy for information by cycling DNA between different chromatin states. Flipons enhance the diversity of transcriptomes, increasing entropy while enabling the evolution of features both new and unexpected.

  • A New Role for SMCHD1 in Life’s Master Switch and Beyond
    Trends Genet. (IF 10.627) Pub Date : 2019-10-25
    Peter Z. Schall, Meghan L. Ruebel, Keith E. Latham

    Structural maintenance of chromosomes flexible hinge-domain containing protein 1 (SMCHD1) has emerged as a key regulator of embryonic genome function. Its functions have now extended well beyond the initial findings of effects on X chromosome inactivation associated with lethality in female embryos homozygous for a null allele. Autosomal dominant effects impact stem cell properties as well as postnatal health. Recent studies have revealed that SMCHD1 plays an important role as a maternal effect gene that regulates the master switch of life, namely embryonic genome activation, as well as subsequent preimplantation development and term viability. These discoveries mark SMCHD1 as a major regulator linking developmental processes to adult disorders including a form of muscular dystrophy.

  • Somatic Variants: New Kids on the Block in Human Immunogenetics
    Trends Genet. (IF 10.627) Pub Date : 2019-10-24
    L. Van Horebeek, B. Dubois, A. Goris

    Somatic variants are not inherited but acquired during an individual’s lifetime, and individuals are increasingly considered as complex mosaics of genetically distinct cells. Whereas this concept is long-recognized in cancer, this review focuses on the growing role of somatic variants in immune cells in nonmalignant immune-related disorders, such as primary immunodeficiency and autoimmune diseases. Older case reports described somatic variants early in development, leading to large numbers of affected cells and severe phenotypes. Thanks to technological evolution, it is now feasible to detect somatic variants occurring later in life and affecting fewer cells. Hence, only recently is the scale at which somatic variants contribute to monogenic diseases being uncovered and is their contribution to complex diseases being explored systematically.

  • The Editor’s I on Disease Development
    Trends Genet. (IF 10.627) Pub Date : 2019-10-22
    Mamta Jain, Michael F. Jantsch, Konstantin Licht

    Adenosine-to-inosine (A-to-I) editing of RNA leads to deamination of adenosine to inosine. Inosine is interpreted as guanosine by the cellular machinery, thus altering the coding, folding, splicing, or transport of transcripts. A-to-I editing is tightly regulated. Altered editing has severe consequences for human health and can cause interferonopathies, neurological disorders, and cardiovascular disease, as well as impacting on cancer progression. ADAR1-mediated RNA editing plays an important role in antiviral immunity and is essential for distinguishing between endogenous and viral RNA, thereby preventing autoimmune disorders. Interestingly, A-to-I editing can be used not only to correct genomic mutations at the RNA level but also to modulate tumor antigenicity with large therapeutic potential. We highlight recent developments in the field, focusing on cancer and other human diseases.

  • Many Ways to Build a Polyp
    Trends Genet. (IF 10.627) Pub Date : 2019-10-16
    Detlev Arendt

    The freshwater cnidarian Hydra has been studied for centuries for its unique regenerative capacities. Whole-body single-cell transcriptomics now reveal cellular lineages and gene regulatory networks that build the Hydra polyp. For the first time, transcription factor signatures allow direct comparison of the polyp body plan between Hydra and sea anemone.

  • Gene Regulation Knows Its Boundaries
    Trends Genet. (IF 10.627) Pub Date : 2019-10-14
    Elzo de Wit

    The genome is folded nonrandomly inside the cell nucleus. How this contributes to gene regulation is an important subject of investigation. A new study by Despang et al. shows how the spatial segregation of genes and regulatory regions can influence developmental expression in subtle, but critical ways.

  • Landscape of Noncoding RNA in Prostate Cancer
    Trends Genet. (IF 10.627) Pub Date : 2019-10-14
    Junjie T. Hua, Sujun Chen, Housheng H. He

    The transcriptome of prostate cancer is highly heterogeneous, with noncoding transcripts being essential players. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two unique classes of noncoding RNA drawing increasing attention. Biologically, they have intriguing properties with important regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Recent advancements in technologies have opened up new directions for noncoding RNA research, which include RNA–protein interaction, RNA secondary structure, and spatial transcriptomics. Furthermore, recent work has also evaluated the clinical applications of these noncoding RNAs in noninvasive liquid biopsy and RNA-based therapies. In this review, we summarize recent findings on lncRNAs and circRNAs in prostate cancer, discuss their clinical utilities, and highlight these exciting areas of research.

  • Toward Clinical Implementation of Next-Generation Sequencing-Based Genetic Testing in Rare Diseases: Where Are We?
    Trends Genet. (IF 10.627) Pub Date : 2019-10-14
    Zhichao Liu, Liyuan Zhu, Ruth Roberts, Weida Tong

    Next-generation sequencing (NGS) technologies have changed the landscape of genetic testing in rare diseases. However, the rapid evolution of NGS technologies has outpaced its clinical adoption. Here, we re-evaluate the critical steps in the clinical application of NGS-based genetic testing from an informatics perspective. We suggest a ‘fit-for-purpose’ triage of current NGS technologies. We also point out potential shortcomings in the clinical management of genetic variants and offer ideas for potential improvement. We specifically emphasize the importance of ensuring the accuracy and reproducibility of NGS-based genetic testing in the context of rare disease diagnosis. We highlight the role of artificial intelligence (AI) in enhancing understanding and prioritization of variance in the clinical setting and propose deep learning frameworks for further investigation.

  • De Novo Mutations Reflect Development and Aging of the Human Germline
    Trends Genet. (IF 10.627) Pub Date : 2019-10-11
    J.M. Goldmann, J.A. Veltman, C. Gilissen

    Human germline de novo mutations (DNMs) are both a driver of evolution and an important cause of genetic diseases. In the past few years, whole-genome sequencing (WGS) of parent–offspring trios has facilitated the large-scale detection and study of human DNMs, which has led to exciting discoveries. The overarching theme of all of these studies is that the DNMs of an individual are a complex mixture of mutations that arise through different biological processes acting at different times during human development and life.

  • New Gene Origin and Deep Taxon Phylogenomics: Opportunities and Challenges
    Trends Genet. (IF 10.627) Pub Date : 2019-10-11
    Christian Rödelsperger, Neel Prabh, Ralf J. Sommer

    The immense morphological and phenotypic diversity within eukaryotes coincides with large-scale differences in genic repertoires, including the presence of thousands of new genes in every genome. New genes arise through duplication and divergence of existing coding sequences or de novo from noncoding sequences. These processes together cause individual genomes to contain up to one-third of orphan genes without any detectable homology in other lineages. Recently, deep taxon phylogenomics, the genome comparisons of extremely closely related species, provided novel insight into the evolutionary dynamics of such rapidly evolving genes. This review focuses on deep taxon phylogenomics and its importance in studying the evolution of new genes and discusses challenges and opportunities.

  • De novo DNA Methylation: Who’s Your DADdy?
    Trends Genet. (IF 10.627) Pub Date : 2019-10-06
    Marla E. Tharp, Alex Bortvin

    DNA methylation regulates the organization and function of the genome. Yamanaka et al. now report that de novo methylation of male germ cells of mice involves the transient opening of heterochromatin at megabase-size differentially accessible domains (DADs). This chromatin remodeling likely facilitates de novo methylation of the germ cell genome.

  • Baker’s Yeast Clinical Isolates Provide a Model for How Pathogenic Yeasts Adapt to Stress
    Trends Genet. (IF 10.627) Pub Date : 2019-09-13
    Vandana Raghavan, Charles F. Aquadro, Eric Alani

    Global outbreaks of drug-resistant fungi such as Candida auris are thought to be due at least in part to excessive use of antifungal drugs. Baker’s yeast Saccharomyces cerevisiae has gained importance as an emerging opportunistic fungal pathogen that can cause infections in immunocompromised patients. Analyses of over 1000 S. cerevisiae isolates are providing rich resources to better understand how fungi can grow in human environments. A large percentage of clinical S. cerevisiae isolates are heterozygous across many nucleotide sites, and a significant proportion are of mixed ancestry and/or are aneuploid or polyploid. Such features potentially facilitate adaptation to new environments. These observations provide strong impetus for expanding genomic and molecular studies on clinical and wild isolates to understand the prevalence of genetic diversity and instability-generating mechanisms, and how they are selected for and maintained. Such work can also lead to the identification of new targets for antifungal drugs.

  • Surviving Telomere Attrition with the MiDAS Touch
    Trends Genet. (IF 10.627) Pub Date : 2019-09-13
    Rachel L. Flynn, Christopher M. Heaphy

    Cancer cells maintain telomere lengths through telomerase activity or by alternative lengthening of telomeres (ALT). Using an engineered model system, a recent study by Min et al. reveals that the combination of BLM-mediated DNA resection and telomere clustering, a characteristic of ALT telomeres, catalyzes RAD52-dependent mitotic DNA synthesis (MiDAS) specifically at telomeres to drive ALT activity.

  • Paircounting
    Trends Genet. (IF 10.627) Pub Date : 2019-09-12
    Huy Q. Nguyen, S. Dean Lee, C-ting Wu

    X inactivation presents two longstanding puzzles: the counting and choice of X chromosomes. Here, we consider counting and choice in the context of pairing, both of the X and of the autosomes.

  • Ribosomal DNA and the Nucleolus as Keystones of Nuclear Architecture, Organization, and Function
    Trends Genet. (IF 10.627) Pub Date : 2019-08-22
    Amanda V. Cerqueira, Bernardo Lemos

    The multicopy ribosomal DNA (rDNA) array gives origin to the nucleolus, a large nonmembrane-bound organelle that occupies a substantial volume within the cell nucleus. The rDNA/nucleolus has emerged as a coordinating hub in which seemingly disparate cellular functions converge, and from which a variety of cellular and organismal phenotypes emerge. However, the role of the nucleolus as a determinant and organizer of nuclear architecture and other epigenetic states of the genome is not well understood. We discuss the role of rDNA and the nucleolus in nuclear organization and function – from nucleolus-associated domains (NADs) to the regulation of imprinted loci and X chromosome inactivation, as well as rDNA contact maps that anchor and position the rDNA relative to the rest of the genome. The influence of the nucleolus on nuclear organization undoubtedly modulates diverse biological processes from metabolism to cell proliferation, genome-wide gene expression, maintenance of epigenetic states, and aging.

  • Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway
    Trends Genet. (IF 10.627) Pub Date : 2019-08-19
    Jingyu Chen, Lesley A. Stark

    The nuclear organelle the nucleolus and the transcription factor nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) are both central to the control of cellular homeostasis, dysregulated in common diseases and implicated in the ageing process. Until recently, it was believed that they acted independently to regulate homeostasis in health and disease. However, there is an emerging body of evidence suggesting that nucleoli and NF-κB signalling converge at multiple levels. Here we will review current understanding of this crosstalk. We will discuss activation of the NF-κB pathway by nucleolar stress and induction of apoptosis by nucleolar sequestration of NF-κB/RelA. We will also discuss the role of TIF-IA, COMMD1, and nucleophosmin, which are key players in this crosstalk, and the therapeutic relevance, particularly with respect to the antitumour effects of aspirin.

  • Haploid Induction and Genome Instability
    Trends Genet. (IF 10.627) Pub Date : 2019-08-14
    Luca Comai, Ek Han Tan

    The advent of affordable, large-scale DNA sequencing methods, coupled with advanced computing power, is empowering a detailed analysis of the structure and function of chromosomes. Genomic instability, involving chromosome number and structure changes, has been documented in multiple systems. In plants, haploid induction through genome elimination has recently been connected mechanistically to the formation of complex chromosome reorganizations, known collectively as chromoanagenesis. These abnormalities can be triggered by altering the specialized centromeric histone 3, the epigenetic determinant of centromeres, which leads to loss of centromere function and chromosome missegregation. Other historical and recent instances of genomic instability, at the same time, suggest multiple causes. Their study provides a unique opportunity for a synthesis encompassing genome evolution, its response to stress, as well as the possibility of recruiting the connected mechanisms for genome engineering-based plant breeding.

  • DNA Methylation: Shared and Divergent Features across Eukaryotes
    Trends Genet. (IF 10.627) Pub Date : 2019-08-06
    Robert J. Schmitz, Zachary A. Lewis, Mary G. Goll

    Chemical modification of nucleotide bases in DNA provides one mechanism for conveying information in addition to the genetic code. 5-methylcytosine (5mC) represents the most common chemically modified base in eukaryotic genomes. Sometimes referred to simply as DNA methylation, in eukaryotes 5mC is most prevalent at CpG dinucleotides and is frequently associated with transcriptional repression of transposable elements. However, 5mC levels and distributions are variable across phylogenies, and emerging evidence suggests that the functions of DNA methylation may be more diverse and complex than was previously appreciated. We summarize the current understanding of DNA methylation profiles and functions in different eukaryotic lineages.

  • Mechanisms of rDNA Copy Number Maintenance
    Trends Genet. (IF 10.627) Pub Date : 2019-08-05
    Jonathan O. Nelson, George J. Watase, Natalie Warsinger-Pepe, Yukiko M. Yamashita

    rDNA, the genes encoding the RNA components of ribosomes (rRNA), are highly repetitive in all eukaryotic genomes, containing 100s to 1000s of copies, to meet the demand for ribosome biogenesis. rDNA genes are arranged in large stretches of tandem repeats, forming loci that are highly susceptible to copy loss due to their repetitiveness and active transcription throughout the cell cycle. Despite this inherent instability, rDNA copy number is generally maintained within a particular range in each species, pointing to the presence of mechanisms that maintain rDNA copy number in a homeostatic range. In this review, we summarize the current understanding of these maintenance mechanisms and how they sustain rDNA copy number throughout populations.

  • Ribosomopathies: Old Concepts, New Controversies
    Trends Genet. (IF 10.627) Pub Date : 2019-07-31
    Katherine I. Farley-Barnes, Lisa M. Ogawa, Susan J. Baserga

    Ribosomopathies are a diverse subset of diseases caused by reduced expression of, or mutations in, factors necessary for making ribosomes, the protein translation machinery in the cell. Despite the ubiquitous need for ribosomes in all cell types, ribosomopathies manifest with tissue-specific defects and sometimes increased cancer susceptibility, but few treatments target the underlying cause. By highlighting new research in the field, we review current hypotheses for the basis of this tissue specificity. Based on new work, we broaden our understanding of the role of ribosome biogenesis in diverse tissue types throughout embryonic development. We also pose the question of whether previously described human conditions such as aging can be at least partially attributed to defects in making ribosomes.

  • Advances Using Single-Particle Trajectories to Reconstruct Chromatin Organization and Dynamics
    Trends Genet. (IF 10.627) Pub Date : 2019-07-29
    O. Shukron, A. Seeber, A. Amitai, D. Holcman

    Chromatin organization remains complex and far from understood. In this article, we review recent statistical methods of extracting biophysical parameters from in vivo single-particle trajectories of loci to reconstruct chromatin reorganization in response to cellular stress such as DNA damage. We look at methods for analyzing both single locus and multiple loci tracked simultaneously and explain how to quantify and describe chromatin motion using a combination of extractable parameters. These parameters can be converted into information about chromatin dynamics and function. Furthermore, we discuss how the timescale of recurrent encounter between loci can be extracted and interpreted. We also discuss the effect of sampling rate on the estimated parameters. Finally, we review a polymer method to reconstruct chromatin structure using crosslinkers between chromatin sites. We list and refer to some software packages that are now publicly available to simulate polymer motion. To conclude, chromatin organization and dynamics can be reconstructed from locus trajectories and predicted based on polymer models.

  • Coordinated Control of rRNA Processing by RNA Polymerase I
    Trends Genet. (IF 10.627) Pub Date : 2019-07-26
    Catherine E. Scull, David A. Schneider

    Ribosomal RNA (rRNA) is co- and post-transcriptionally processed into active ribosomes. This process is dynamically regulated by direct covalent modifications of the polymerase that synthesizes the rRNA, RNA polymerase I (Pol I), and by interactions with cofactors that influence initiation, elongation, and termination activities of Pol I. The rate of transcription elongation by Pol I directly influences processing of nascent rRNA, and changes in Pol I transcription rate result in alternative rRNA processing events that lead to cellular signaling alterations and stress. It is clear that in divergent species, there exists robust organization of nascent rRNA processing events during transcription elongation. This review evaluates the current state of our understanding of the complex relationship between transcription elongation and rRNA processing.

  • Nucleolar DNA Double-Strand Break Responses Underpinning rDNA Genomic Stability
    Trends Genet. (IF 10.627) Pub Date : 2019-07-25
    Marjolein van Sluis, Brian McStay

    Nucleoli, the sites of ribosome biogenesis, form around ribosomal gene (rDNA) arrays termed nucleolar organiser regions (NORs). These are the most transcriptionally active regions of the human genome and specialised responses have evolved to ensure their genomic stability. This review focuses on nucleolar responses to DNA double-strand breaks (DSBs) introduced into rDNA arrays using sequence-specific endonucleases, including CRISPR/Cas9. Repair of rDNA DSBs is predominantly carried out by the homology-directed repair (HDR) pathway that is facilitated by inhibition of transcription by RNA polymerase-I (Pol-I) and ensuing dramatic nucleolar reorganisation. Additionally, we review evidence that nucleoli can sense and respond to DSBs elsewhere in the genome.

  • Potential of Genome Editing to Improve Aquaculture Breeding and Production
    Trends Genet. (IF 10.627) Pub Date : 2019-07-19
    Remi L. Gratacap, Anna Wargelius, Rolf Brudvik Edvardsen, Ross D. Houston

    Aquaculture is the fastest growing food production sector and is rapidly becoming the primary source of seafood for human diets. Selective breeding programs are enabling genetic improvement of production traits, such as disease resistance, but progress is limited by the heritability of the trait and generation interval of the species. New breeding technologies, such as genome editing using CRISPR/Cas9 have the potential to expedite sustainable genetic improvement in aquaculture. Genome editing can rapidly introduce favorable changes to the genome, such as fixing alleles at existing trait loci, creating de novo alleles, or introducing alleles from other strains or species. The high fecundity and external fertilization of most aquaculture species can facilitate genome editing for research and application at a scale that is not possible in farmed terrestrial animals.

  • Nucleolus and rRNA Gene Chromatin in Early Embryo Development
    Trends Genet. (IF 10.627) Pub Date : 2019-07-18
    Jelena Kresoja-Rakic, Raffaella Santoro

    The nucleolus is the largest substructure in the nucleus and forms around the nucleolar organizer regions (NORs), which comprise hundreds of rRNA genes. Recent evidence highlights further functions of the nucleolus that go beyond ribosome biogenesis. Data indicate that the nucleolus acts as a compartment for the location and regulation of repressive genomic domains and, together with the nuclear lamina, represents the hub for the organization of the inactive heterochromatin. In this review, we discuss recent findings that have revealed how nucleolar structure and rRNA gene chromatin states are regulated during early mammalian development and their contribution to the higher-order spatial organization of the genome.

  • A New Portrait of Constitutive Heterochromatin: Lessons from Drosophila melanogaster
    Trends Genet. (IF 10.627) Pub Date : 2019-07-15
    René M. Marsano, Ennio Giordano, Giovanni Messina, Patrizio Dimitri

    Constitutive heterochromatin represents a significant portion of eukaryotic genomes, but its functions still need to be elucidated. Even in the most updated genetics and molecular biology textbooks, constitutive heterochromatin is portrayed mainly as the ‘silent’ component of eukaryotic genomes. However, there may be more complexity to the relationship between heterochromatin and gene expression. In the fruit fly Drosophila melanogaster, a model for heterochromatin studies, about one-third of the genome is heterochromatic and is concentrated in the centric, pericentric, and telomeric regions of the chromosomes. Recent findings indicate that hundreds of D. melanogaster genes can ‘live and work’ properly within constitutive heterochromatin. The genomic size of these genes is generally larger than that of euchromatic genes and together they account for a significant fraction of the entire constitutive heterochromatin. Thus, this peculiar genome component in spite its ability to induce silencing, has in fact the means for being quite dynamic. A major scope of this review is to revisit the ‘dogma of silent heterochromatin’.

  • The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease
    Trends Genet. (IF 10.627) Pub Date : 2019-07-10
    Yann Aubert, Shaun Egolf, Brian C. Capell

    Epigenetic regulation is critical for the precise control of cellular fate and developmental programs. Disruption of epigenetic information is increasingly appreciated as a potential driving mechanism in both developmental disorders as well as ubiquitous diseases such as cancer. Consistent with this, mutations in histone modifying enzymes are amongst the most frequent events in all of human cancer. While early studies have focused on the canonical enzymatic functions involved in catalyzing modifications to histones, more recent studies have uncovered a new layer of critical nonenzymatic roles in transcriptional regulation for these proteins. Here, we provide an overview of these surprising, yet exciting, noncanonical, noncatalytic roles, and highlight how these revelations may have important implications for understanding disease and the future of epigenome-targeting therapies.

  • Templated Insertions: A Smoking Gun for Polymerase Theta-Mediated End Joining
    Trends Genet. (IF 10.627) Pub Date : 2019-07-08
    Joost Schimmel, Robin van Schendel, Johan T. den Dunnen, Marcel Tijsterman

    A recognized source of disease-causing genome alterations is erroneous repair of broken chromosomes, which can be executed by two distinct mechanisms: non-homologous end joining (NHEJ) and the recently discovered polymerase theta-mediated end joining (TMEJ) pathway. While TMEJ has previously been considered to act as an alternative mechanism backing up NHEJ, recent work points to a role for TMEJ in the repair of replication-associated DNA breaks that are excluded from repair through homologous recombination. Because of its mode of action, TMEJ is intrinsically mutagenic and sometimes leaves behind a recognizable genomic scar when joining chromosome break ends (i.e., ‘templated insertions’). This review article focuses on the intriguing observation that this polymerase theta signature is frequently observed in disease alleles, arguing for a prominent role of this double-strand break repair pathway in genome diversification and disease-causing spontaneous mutagenesis in humans.

  • SOXopathies: Growing Family of Developmental Disorders Due to SOX Mutations
    Trends Genet. (IF 10.627) Pub Date : 2019-07-06
    Marco Angelozzi, Véronique Lefebvre

    The SRY-related (SOX) transcription factor family pivotally contributes to determining cell fate and identity in many lineages. Since the original discovery that SRY deletions cause sex reversal, mutations in half of the 20 human SOX genes have been associated with rare congenital disorders, henceforward called SOXopathies. Mutations are generally de novo, heterozygous, and inactivating, revealing gene haploinsufficiency, but other types, including duplications, have been reported too. Missense variants primarily target the HMG domain, the SOX hallmark that mediates DNA binding and bending, nuclear trafficking, and protein–protein interactions. We here review key clinical and molecular features of SOXopathies and discuss the prospect that the disease family likely involves more SOX genes and larger clinical and genetic spectrums than currently appreciated.

  • Transcriptional Control by Premature Termination: A Forgotten Mechanism
    Trends Genet. (IF 10.627) Pub Date : 2019-06-15
    Kinga Kamieniarz-Gdula, Nick J. Proudfoot

    The concept of early termination as an important means of transcriptional control has long been established. Even so, its role in metazoan gene expression is underappreciated. Recent technological advances provide novel insights into premature transcription termination (PTT). This process is frequent, widespread, and can occur close to the transcription start site (TSS), or within the gene body. Stable prematurely terminated transcripts contribute to the transcriptome as instances of alternative polyadenylation (APA). Independently of transcript stability and function, premature termination opposes the formation of full-length transcripts, thereby negatively regulating gene expression, especially of transcriptional regulators. Premature termination can be beneficial or harmful, depending on its context. As a result, multiple factors have evolved to control this process.

  • The Nuclear Pore Complex in Cell Type-Specific Chromatin Structure and Gene Regulation
    Trends Genet. (IF 10.627) Pub Date : 2019-06-15
    Jiayu Sun, Yuming Shi, Eda Yildirim

    Nuclear pore complex (NPC)-mediated nucleocytoplasmic trafficking is essential for key cellular processes, such as cell growth, cell differentiation, and gene regulation. The NPC has also been viewed as a nuclear architectural platform that impacts genome function and gene expression by mediating spatial and temporal coordination between transcription factors, chromatin regulatory proteins, and transcription machinery. Recent findings have uncovered differential and cell type-specific expression and distinct chromatin-binding patterns of individual NPC components known as nucleoporins (Nups). Here, we examine recent studies that investigate the functional roles of NPCs and Nups in transcription, chromatin organization, and epigenetic gene regulation in the context of development and disease.

  • The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases
    Trends Genet. (IF 10.627) Pub Date : 2019-06-11
    Heini Natri, Angela R. Garcia, Kenneth H. Buetow, Benjamin C. Trumble, Melissa A. Wilson

    We hypothesize that, ancestrally, sex-specific immune modulation evolved to facilitate survival of the pregnant person in the presence of an invasive placenta and an immunologically challenging pregnancy – an idea we term the 'pregnancy compensation hypothesis' (PCH). Further, we propose that sex differences in immune function are mediated, at least in part, by the evolution of gene content and dosage on the sex chromosomes, and are regulated by reproductive hormones. Finally, we propose that changes in reproductive ecology in industrialized environments exacerbate these evolved sex differences, resulting in the increasing risk of autoimmune disease observed in females, and a counteracting reduction in diseases such as cancer that can be combated by heightened immune surveillance. The PCH generates a series of expectations that can be tested empirically and that may help to identify the mechanisms underlying sex differences in modern human diseases.

  • The Impact of Centromeres on Spatial Genome Architecture
    Trends Genet. (IF 10.627) Pub Date : 2019-06-11
    Héloïse Muller, José Gil, Ines Anna Drinnenberg

    The development of new technologies and experimental techniques is enabling researchers to see what was once unable to be seen. For example, the centromere was first seen as the mediator between spindle fiber and chromosome during mitosis and meiosis. Although this continues to be its most prominent role, we now know that the centromere functions beyond cellular division with important roles in genome organization and chromatin regulation. Here we aim to share the structures and functions of centromeres in various organisms beginning with the diversity of their DNA sequence anatomies. We zoom out to describe their position in the nucleus and ultimately detail the different ways they contribute to genome organization and regulation at the spatial level.

  • Poly(ADP-Ribosylation) in Age-Related Neurological Disease
    Trends Genet. (IF 10.627) Pub Date : 2019-06-07
    Leeanne McGurk, Olivia M. Rifai, Nancy M. Bonini

    A central and causative feature of age-related neurodegenerative disease is the deposition of misfolded proteins in the brain. To devise novel approaches to treatment, regulatory pathways that modulate these aggregation-prone proteins must be defined. One such pathway is post-translational modification by the addition of poly(ADP-ribose) (PAR), which promotes protein recruitment and localization in several cellular contexts. Mounting evidence implicates PAR in seeding the abnormal localization and accumulation of proteins that are causative of neurodegenerative disease. Inhibitors of PAR polymerase (PARP) activity have been developed as cancer therapeutics, raising the possibility that they could be used to treat neurodegenerative disease. We focus on pathways regulated by PAR in neurodegenerative disease, with emphasis on amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).

  • Phase Separation as a Melting Pot for DNA Repeats
    Trends Genet. (IF 10.627) Pub Date : 2019-05-31
    Amanda C. Hall, Lauren A. Ostrowski, Karim Mekhail

    Genome expression and stability are dependent on biological processes that control repetitive DNA sequences and nuclear compartmentalization. The phase separation of macromolecules has recently emerged as a major player in the control of biological pathways. Here, we summarize recent studies that collectively reveal intersections between phase separation, repetitive DNA elements, and nuclear compartments. These intersections modulate fundamental processes, including gene expression, DNA repair, and cellular lifespan, in the context of health and diseases such as cancer and neurodegeneration.

  • Beneficial Noncancerous Mutations in Liver Disease
    Trends Genet. (IF 10.627) Pub Date : 2019-05-28
    Miryam Müller, Stuart J. Forbes, Thomas G. Bird

    Chronic liver disease results in fibrosis and cancer. While injury is associated with mutational burden, a recent study (Zhu et al. Cell 2019;177:608–621) highlights that not all positively selected mutations in the liver are precancerous. Indeed, some may be beneficial to the ability of the liver to not only withstand injury , but also to regenerate.

  • High-Diversity Mouse Populations for Complex Traits
    Trends Genet. (IF 10.627) Pub Date : 2019-05-24
    Michael C. Saul, Vivek M. Philip, Laura G. Reinholdt, Elissa J. Chesler

    Contemporary mouse genetic reference populations are a powerful platform to discover complex disease mechanisms. Advanced high-diversity mouse populations include the Collaborative Cross (CC) strains, Diversity Outbred (DO) stock, and their isogenic founder strains. When used in systems genetics and integrative genomics analyses, these populations efficiently harnesses known genetic variation for precise and contextualized identification of complex disease mechanisms. Extensive genetic, genomic, and phenotypic data are already available for these high-diversity mouse populations and a growing suite of data analysis tools have been developed to support research on diverse mice. This integrated resource can be used to discover and evaluate disease mechanisms relevant across species.

  • The Many Roles of Cohesin in Drosophila Gene Transcription
    Trends Genet. (IF 10.627) Pub Date : 2019-05-23
    Dale Dorsett

    The cohesin protein complex mediates sister chromatid cohesion to ensure accurate chromosome segregation, and also influences gene transcription in higher eukaryotes. Modest deficits in cohesin function that do not alter chromosome segregation cause significant birth defects. The mechanisms by which cohesin participates in gene regulation have been studied in Drosophila, revealing that it is involved in gene activation by transcriptional enhancers and epigenetic gene silencing mediated by Polycomb group proteins. Recent studies reveal that early DNA replication origins are important for determining which genes associate with cohesin, and suggest that cohesin at replication origins is important for establishing both sister chromatid cohesion and enhancer–promoter communication.

Contents have been reproduced by permission of the publishers.
上海纽约大学William Glover