Review Articles

  • Review Article |

    In most human genes, RNA 3ʹ end cleavage and polyadenylation can occur at multiple, alternative sites, enabling the expression of distinct transcripts. Novel techniques to sequence RNA 3ʹ ends, coupled with innovative computational methods for studying the list of polyadenylation sites that they generate, have uncovered the roles of alternative cleavage and polyadenylation in both health and disease.

    • Andreas J. Gruber
    •  & Mihaela Zavolan
  • Review Article |

    Global genomic diversity can provide new opportunities for discovery and translation into therapies, as well as a better understanding of population disease risks. This Review considers the value of examining diverse populations to better understand genetic contributors to disease risk and trait variation.

    • Deepti Gurdasani
    • , Inês Barroso
    • , Eleftheria Zeggini
    •  & Manjinder S. Sandhu
  • Review Article |

    Somatic genetic rescue (SGR) occurs when an acquired somatic mutation counteracts the effects of a germline mutation at a cellular level. The increasing number of SGR events reported for Mendelian haematopoietic diseases have important diagnostic, therapeutic and clinical consequences.

    • Patrick Revy
    • , Caroline Kannengiesser
    •  & Alain Fischer
  • Review Article |

    In this Review, van Rheenen et al. outline how improved methodologies have enabled genetic correlations to be estimated for almost any trait pair. Genetic correlations can improve our understanding of the shared biology and causal relationships between traits.

    • Wouter van Rheenen
    • , Wouter J. Peyrot
    • , Andrew J. Schork
    • , S. Hong Lee
    •  & Naomi R. Wray
  • Review Article |

    Enabled by genome-wide profiling approaches, there is growing appreciation for the prevalence and functional importance of various types of chromatin-associated RNAs. As Li and Fu describe in this Review, these RNAs can either be retained in cis at their site of transcription or recruited in cis to other loci, and they have diverse roles in gene regulation, genome organization, nuclear body formation and phase-separation events.

    • Xiao Li
    •  & Xiang-Dong Fu
  • Review Article |

    This Review discusses the current status of expanded carrier screening, including existing recommendations and limitations. The author reviews the framework that is needed for successful comprehensive carrier screening programmes for all autosomal recessive disorders in various populations.

    • Stylianos E. Antonarakis
  • Review Article |

    Gene expression is subjected to various random processes (referred to as ‘noise’) that contribute to variability in molecular phenotypes. As Eling, Morgan and Marioni describe, there are various challenges to studying this variability, such as disentangling its multilayered sources, distinguishing it from deterministic influences on cellular variability, modelling it with appropriate statistical methods and understanding its practical consequences.

    • Nils Eling
    • , Michael D. Morgan
    •  & John C. Marioni
  • Review Article |

    For appropriate control of gene expression, enhancers must communicate with the right target genes at the right time, typically over large genomic distances. In this Review, Schoenfelder and Fraser discuss our latest understanding of long-range enhancer–promoter crosstalk, including target-gene specificity, interaction dynamics, protein and RNA architects of interactions, roles of 3D genome organization and the pathological consequences of regulatory rewiring.

    • Stefan Schoenfelder
    •  & Peter Fraser
  • Review Article |

    Throughout evolution, DNA has been the primary medium of biological information storage. In this article, Ceze, Nivala and Strauss discuss how DNA can be adopted as a storage medium for custom data, as a potential future complement to current data storage media such as computer hard disks, optical disks and tape. They discuss strategies for coding, decoding and error correction and give examples of implementation both in vitro and in vivo.

    • Luis Ceze
    • , Jeff Nivala
    •  & Karin Strauss
  • Review Article |

    Despite the success of human genome-wide association studies (GWAS) in associating genetic variants and complex diseases or traits, criticisms of the usefulness of this study design remain. This Review assesses the pros and cons of GWAS, with a focus on the cardiometabolic field.

    • Vivian Tam
    • , Nikunj Patel
    • , Michelle Turcotte
    • , Yohan Bossé
    • , Guillaume Paré
    •  & David Meyre
  • Review Article |

    This article reviews recent advances in ancient pathogen genomics, from methodological improvements in retrieving whole genomes to evolutionary analyses of ancient pathogens that remain relevant to public health. Focusing on the evolutionary history of the plague pathogen Yersinia pestis, the authors present unique insights afforded by the study of ancient pathogen genomes.

    • Maria A. Spyrou
    • , Kirsten I. Bos
    • , Alexander Herbig
    •  & Johannes Krause
  • Review Article |

    Clinical metagenomic next-generation sequencing (mNGS) is rapidly moving from bench to bedside. This Review discusses the clinical applications of mNGS, including infectious disease diagnostics, microbiome analyses, host response analyses and oncology applications. Moreover, the authors review the challenges that need to be overcome for mNGS to be successfully implemented in the clinical laboratory and propose solutions to maximize the benefits of clinical mNGS for patients.

    • Charles Y. Chiu
    •  & Steven A. Miller
  • Review Article |

    Recent next-generation sequencing studies have captured the spatial and temporal evolutionary patterns that shape cancer. This Review provides an overview of the theoretical models of tumour evolution and discusses what to consider when inferring evolutionary dynamics from genomic data.

    • Samra Turajlic
    • , Andrea Sottoriva
    • , Trevor Graham
    •  & Charles Swanton
  • Review Article |

    Eukaryotes differ substantially from bacteria and archaea owing to their nucleosome-based packaging of DNA. In this Review, Talbert, Meers and Henikoff place gene regulation in an evolutionary context by discussing how the emergence and diversification of eukaryotic chromatin provided both challenges and opportunities for intricate mechanisms of gene regulation in eukaryotes.

    • Paul B. Talbert
    • , Michael P. Meers
    •  & Steven Henikoff
  • Review Article |

    Next-generation sequencing has improved the identification and characterization of antimicrobial resistance. Focusing on sequence-based discovery of antibiotic resistance genes, this Review discusses computational strategies and resources for resistance gene identification in genomic and metagenomic samples, including recent deep-learning approaches.

    • Manish Boolchandani
    • , Alaric W. D’Souza
    •  & Gautam Dantas
  • Review Article |

    Transposable elements (TEs) need to be tightly regulated in genomes to prevent the detrimental consequences of transposition. In this Review, Deniz, Frost and Branco discuss how DNA methylation dynamics play a central role in the multilayered epigenetic mechanisms regulating TEs. Beyond roles for 5-methylcytosine (5mC), they discuss TET-mediated oxidation products of 5mC, as well as ongoing debates about the functional relevance of adenine methylation.

    • Özgen Deniz
    • , Jennifer M. Frost
    •  & Miguel R. Branco
  • Review Article |

    Enthusiasm for patient-specific therapies based on induced pluripotent stem cells (iPSCs) has risen in parallel with rapid advances in genome editing. This Review summarizes the progress in iPSC-based disease modelling over the past decade, with a focus on 3D organoid systems and chimeric models being exploited for new therapeutic approaches.

    • R. Grant Rowe
    •  & George Q. Daley
  • Review Article |

    The functional interpretation of single-cell RNA sequencing (scRNA-seq) data can be enhanced by integrating additional data types beyond RNA-based gene expression. In this Review, Stuart and Satija discuss diverse approaches for integrative single-cell analysis, including experimental methods for profiling multiple omics types from the same cells, analytical approaches for extracting additional layers of information directly from scRNA-seq data and computational integration of omics data collected across different cell samples.

    • Tim Stuart
    •  & Rahul Satija
  • Review Article |

    Chromatin accessibility comprises the positions, compaction and dynamics of nucleosomes, as well as the occupancy of DNA by other proteins such as transcription factors. In this Review, the authors discuss diverse methods for characterizing chromatin accessibility, how accessibility is determined and remodelled in cells and the regulatory roles of accessibility in gene expression and development.

    • Sandy L. Klemm
    • , Zohar Shipony
    •  & William J. Greenleaf
  • Review Article |

    Disruption of genomic imprinting can lead to disease. Recent studies suggest that interactions between the genome, the epigenome and the environment in germ cells and early embryos have an impact on developmental outcomes and on the heritability of imprinting disorders.

    • David Monk
    • , Deborah J. G. Mackay
    • , Thomas Eggermann
    • , Eamonn R. Maher
    •  & Andrea Riccio
  • Review Article |

    Comparing the microbiomes of great apes enables an evolutionary perspective on microbial communities. This approach is revealing not only new insights about humans and what differentiates us from our closest relatives but also the factors that influence microbiome composition and the ways in which microbiomes diverge.

    • Alex H. Nishida
    •  & Howard Ochman
  • Review Article |

    Single-cell RNA sequencing (scRNA-seq) enables transcriptome-based characterization of the constituent cell types within a heterogeneous sample. However, reliable analysis and biological interpretation typically require optimal use of clustering algorithms. This Review discusses the multiple algorithmic options for clustering scRNA-seq data, including various technical, biological and computational considerations.

    • Vladimir Yu Kiselev
    • , Tallulah S. Andrews
    •  & Martin Hemberg
  • Review Article |

    Understanding the fundamental impact of sex and gender on human health and disease is crucial for optimizing precision medicine. In this Review, Khramtsova, Davis and Stranger discuss the roles of sex in the genetics of complex traits, including genomic evidence for sex-dependent genetic architecture, models and molecular mechanisms of sexually differentiated phenotypes and implications for health care.

    • Ekaterina A. Khramtsova
    • , Lea K. Davis
    •  & Barbara E. Stranger
  • Review Article |

    The maternal-to-zygotic transition (MZT) is the process by which the transcriptionally silent embryonic genome is gradually activated. The mechanisms underlying the MZT are not fully understood, but recent work indicates that transcriptional activators have an important role.

    • Katharine N. Schulz
    •  & Melissa M. Harrison
  • Review Article |

    DNA methylation is the primary epigenetic modification in bacteria, but a lack of suitable methods has hampered its study. Now, new sequencing technologies, including single-molecule, real-time sequencing and nanopore sequencing, are providing new opportunities for studying bacterial methylomes.

    • John Beaulaurier
    • , Eric E. Schadt
    •  & Gang Fang
  • Review Article |

    Improvements to livestock genetics will be critical to tackling the looming food crisis. Achieving this goal will require implementation of improved genomic technologies and better use of a wider range of genomic information.

    • Michel Georges
    • , Carole Charlier
    •  & Ben Hayes
  • Review Article |

    Disruptions to the epigenome occur during the pathogenesis of various human diseases. In this Review, Berdasco and Esteller describe the challenges and progress of harnessing epigenetic changes for clinical application, including for diagnostics, disease classification and therapeutics. They discuss applications to diverse diseases, such as cancer, neurological disease, immune disorders and viral infections.

    • María Berdasco
    •  & Manel Esteller
  • Review Article |

    PIWI-interacting RNAs (piRNAs) have numerous crucial biological roles, particularly transposon silencing in the germ line. In this Review, the authors describe our latest understanding of piRNA biogenesis and functions across diverse species, highlighting how, despite the universal importance of transposon control, different species have evolved intriguingly distinct mechanistic routes to achieve this.

    • Deniz M. Ozata
    • , Ildar Gainetdinov
    • , Ansgar Zoch
    • , Dónal O’Carroll
    •  & Phillip D. Zamore
  • Review Article |

    Liquid biopsies enable non-invasive, longitudinal analysis of tumour components (including circulating tumour cells and circulating tumour DNA) in bodily fluids such as blood. However, their analytical and clinical validity must be rigorously demonstrated before they are adopted for precision oncology.

    • Ellen Heitzer
    • , Imran S. Haque
    • , Charles E. S. Roberts
    •  & Michael R. Speicher
  • Review Article |

    Transcriptome profiling in different brain regions has revealed distinct patterns of gene and non-coding RNA expression, as well as alternative splicing, in autism spectrum disorder (ASD). The authors review these ASD-associated signatures and the resulting mechanistic insights into ASD.

    • Mathieu Quesnel-Vallières
    • , Robert J. Weatheritt
    • , Sabine P. Cordes
    •  & Benjamin J. Blencowe
  • Review Article |

    Lysine acetyltransferases (KATs) act at the interface of the cellular environment and transcription to modify levels of acetylation on target proteins. This Review highlights the roles of KATs beyond chromatin regulation, as detectors of metabolic intermediates and as integrators of signalling pathways, which enable cells to respond to and directly meet their homeostatic needs.

    • Bilal N. Sheikh
    •  & Asifa Akhtar
  • Review Article |

    In this article, Payne and Wagner discuss how recent experimental studies are complementing theoretical work to enhance our understanding of the evolvability of diverse biological systems. They highlight phenotypic heterogeneity, robustness and adaptive landscape topography as causes of evolvability, and they additionally discuss evidence for whether evolvability itself can evolve.

    • Joshua L. Payne
    •  & Andreas Wagner
  • Review Article |

    Recent technological advances are enabling new views of the 3D genome within the space of the nucleus. These studies are beginning to reveal the ways cells co-opt the structures and components of the nuclear periphery for genome organization and gene regulation.

    • Abigail Buchwalter
    • , Jeanae M. Kaneshiro
    •  & Martin W. Hetzer
  • Review Article |

    Genome editing through direct editing of bases holds promise for achieving precise genomic changes at single-nucleotide resolution while minimizing the occurrence of potentially mutagenic double-strand DNA breaks. In this Review, Rees and Liu provide a comprehensive account of the state of the art of base editing of DNA and RNA, including the progressive improvements to methodologies, understanding and avoiding unintended edits, cellular and organismal delivery of editing reagents and diverse applications in research and therapeutic settings.

    • Holly A. Rees
    •  & David R. Liu
  • Review Article |

    The virulence of viruses is a major determinant of the health burden of viral infections in humans and other species. In this article, Geoghegan and Holmes discuss how largely disparate research fields — theoretical modelling of virulence evolution and experimental dissection of genetic virulence determinants in laboratory model systems — can be bridged by considering real genomic data of viral evolution in a phylogenetic context. They describe the underlying principles of virulence evolution and how they apply to real-world viral infections and outbreaks of global importance.

    • Jemma L. Geoghegan
    •  & Edward C. Holmes
  • Review Article |

    CRISPR–Cas genome editing and next-generation sequencing are driving advances in cancer modelling and functional cancer genomics. Their application to autochthonous mouse models of human cancer to generate and analyse multiplexed and/or combinatorial alterations in vivo is reviewed here.

    • Ian P. Winters
    • , Christopher W. Murray
    •  & Monte M. Winslow
  • Review Article |

    In this Review, Sheth and Wang describe emerging synthetic biology approaches for using DNA as a memory device for recording cellular events, including the various methodological steps from detecting diverse signals, converting them into DNA alterations and reading out and interpreting the recorded information. Furthermore, they discuss potential applications as biotechnological and environmental biosensors.

    • Ravi U. Sheth
    •  & Harris H. Wang
  • Review Article |

    The repetitive nature of transposable elements (TEs) creates bioinformatic challenges that frequently result in them being disregarded (‘masked’) in analyses. As physiological and pathological roles for TEs become increasingly appreciated, this Review discusses bioinformatics tools dedicated to TE analysis, including for genomic annotation, TE classification, identifying polymorphisms and assessing likely functional impacts.

    • Patricia Goerner-Potvin
    •  & Guillaume Bourque
  • Review Article |

    Organoids are 3D structures derived from stem cells that recapitulate some key characteristics of real organs. The authors review recent progress in organoid derivation and applications and outline how advances in other disciplines might lead to more physiologically relevant organoids.

    • Giuliana Rossi
    • , Andrea Manfrin
    •  & Matthias P. Lutolf
  • Review Article |

    The genomes of East African cichlid fish have yielded new insights into adaptive radiation and suggest that specific genomic features underlie their propensity for explosive diversification. The author reviews these findings and the challenges of reconstructing the evolutionary history of rapidly diversifying clades.

    • Walter Salzburger
  • Review Article |

    This Review discusses how stem cell bioengineering can advance regenerative medicine by giving insight into the design principles that underlie different levels of stem cell systems — from the inner circuitry in single cells and the stem cell niche to systemic interactions between organs and tissues.

    • Mukul Tewary
    • , Nika Shakiba
    •  & Peter W. Zandstra
  • Review Article |

    High-throughput sequencing technology is enabling the structures of RNA to be determined on an unprecedented scale, providing insights into the relationship between the structures adopted by RNAs and the functions they perform in the cell.

    • Eric J. Strobel
    • , Angela M Yu
    •  & Julius B. Lucks
  • Review Article |

    Eukaryotic cells must regulate not only their nuclear genomes but also the intimate functional interplay with organelle genomes, such as those in mitochondria and plastids. This Review discusses the functional and evolutionary implications of cellular genomes being partitioned between the nucleus and organelles, including the translocation of genes and gene products, chimeric enzyme complexes and insights into molecular co-evolution.

    • Daniel B. Sloan
    • , Jessica M. Warren
    • , Alissa M. Williams
    • , Zhiqiang Wu
    • , Salah E. Abdel-Ghany
    • , Adam J. Chicco
    •  & Justin C. Havird
  • Review Article |

    High-throughput sequencing technologies have enabled comparative analysis of large numbers of diverse bacterial genomes. Such studies are providing insights into the genomic changes that accompany changes in host specificity, with possible implications for controlling transmission of pathogenic bacteria.

    • Samuel K. Sheppard
    • , David S. Guttman
    •  & J. Ross Fitzgerald
  • Review Article |

    Various types of observational studies can provide statistical associations between factors, such as between an environmental exposure and a disease state. This Review discusses the various genetics-focused statistical methodologies that can move beyond mere associations to identify (or refute) various mechanisms of causality, with implications for responsibly managing risk factors in health care and the behavioural and social sciences.

    • Jean-Baptiste Pingault
    • , Paul F. O’Reilly
    • , Tabea Schoeler
    • , George B. Ploubidis
    • , Frühling Rijsdijk
    •  & Frank Dudbridge
  • Review Article |

    Genomic technologies are helping researchers to understand the natural genetic variation that exists in wild and cultivated rice populations. Harnessing this genetic variation will be key to developing Green Super Rice varieties with high yield and low environmental costs.

    • Rod A. Wing
    • , Michael D. Purugganan
    •  & Qifa Zhang
  • Review Article |

    Fine-mapping is the process by which a trait-associated region from a genome-wide association study (GWAS) is analysed to identify the particular genetic variants that are likely to causally influence the examined trait. This Review discusses the diverse statistical approaches to fine-mapping and their foundations, strengths and limitations, including integration of trans-ethnic human population data and functional annotations.

    • Daniel J. Schaid
    • , Wenan Chen
    •  & Nicholas B. Larson
  • Review Article |

    Virtually all studies depend on annotations, maps of the genome that catalogue gene loci and the sequences of their transcripts. This Review discusses the state of currently available long non-coding RNA annotations and the impact of emerging technologies such as long-read sequencing.

    • Barbara Uszczynska-Ratajczak
    • , Julien Lagarde
    • , Adam Frankish
    • , Roderic Guigó
    •  & Rory Johnson
  • Review Article |

    Polygenic risk profiling can lead to actionable outcomes for individuals at high risk of developing a subset of common adult-onset polygenic diseases. The authors review recent studies that have demonstrated the utility of polygenic risk scores for disease risk stratification and their potential impact on early disease detection, prevention, therapeutic intervention and life planning.

    • Ali Torkamani
    • , Nathan E. Wineinger
    •  & Eric J. Topol