Long-read sequencing is becoming more accessible and more accurate. In this Review, Logsdon et al. discuss the currently available platforms, how the technologies are being applied to assemble and phase human genomes, and their impact on improving our understanding of human genetic variation.
October 2020 marks the 20th anniversary of the launch of Nature Reviews Genetics. To celebrate this milestone, we have delved into our archives to curate a Collection of cutting-edge articles, historical pieces and thought-provoking commentaries and opinions. Featuring a range of article types, including Reviews, Perspectives, Viewpoints and Comments, this Collection provides a glimpse of the genetics and genomics field over the past two decades.
Data sharing can maximize the benefit and reach of genomics research. However, sharing must occur in a responsible manner, particularly when there are privacy risks to human participants. In this Review, the authors discuss the principles of data sharing, strategies for assessing and mitigating privacy risks, as well as practical guidelines for researchers and wider stakeholders.
Gene expression is typically measured at the level of either mRNAs or proteins. In this Review, Buccitelli and Selbach discuss how large-scale comparative studies are characterizing the degree to which mRNA and protein levels correlate. They discuss technical and biological reasons why mRNA and protein levels may be particularly concordant or disconnected, as well as the different biological information provided by these non-redundant readouts of gene expression.
In this Review, Gasperini, Tome and Shendure discuss the evolving definitions of transcriptional enhancers, as well as diverse modern experimental tools to identify them. The authors describe how these diverse mindsets and methods provide differing but complementary insights into enhancers, each with notable strengths and caveats. They discuss how such views and approaches might be combined in a comprehensive catalogue of functional enhancers.
Understanding evolutionary relationships between species requires the generation of accurate phylogenetic trees. In this Review, Kapli, Yang and Telford discuss the principles, steps and computational tools for phylogenetic tree building. They describe the impact of burgeoning genomic datasets as well as the diverse sources of errors and how they can be mitigated.
This Review describes different deep learning techniques and how they can be applied to extract biologically relevant information from large, complex genomic data sets.
To map the full extent of structural variation in the human genome, detection methods are needed that improve on short-read approaches. This Review discusses how ensemble algorithms and emerging sequencing technologies are helping to resolve the full spectrum of structural variations.
Activating transcriptional regulatory elements have traditionally been categorized into promoters, which define transcription start sites, and enhancers, which act distally to stimulate transcription. In this Review, Andersson and Sandelin discuss the latest findings from methodologies for profiling and testing transcriptional regulatory elements at scale. They explain how the data support an updated, nuanced model that accounts for the numerous overlapping molecular properties of promoters and enhancers.
This Review discusses advances in RNA-sequencing technologies and methods over the past decade and outlines adaptations that are enabling a fuller understanding of RNA biology, from when and where an RNA is expressed to the structures it adopts.
Adeno-associated virus (AAV) vector-mediated gene delivery has had long-term therapeutic effects for several diseases, including haemophilia and Duchenne muscular dystrophy. Genetically modifying AAV vectors to increase their transduction efficiency, vector tropism and ability to avoid the host immune response may further increase the success of AAV gene therapy.
Although single reference genomes are valuable resources, they do not capture genetic diversity among individuals. Sherman and Salzberg discuss the concept of ‘pan-genomes’, which are reference genomes that encompass the genetic variation within a given species. Focusing particularly on large eukaryotic pan-genomes, they describe the latest progress, the varied methodological approaches and computational challenges, as well as applications in fields such as agriculture and human disease.
Understanding developmental trajectories has recently been enabled by progress in modern lineage-tracing methods that combine genetic lineage analysis with omics-based characterization of cell states (particularly transcriptomes). In this Review, Wagner and Klein discuss the conceptual underpinnings, experimental strategies and analytical considerations of these approaches, as well as the biological insights gained.
How chromosomes are positioned and folded within the nucleus has implications for gene regulation. In this Review, Kempfer and Pombo describe and evaluate methods for studying chromosome architecture and outline the insights they are providing about nuclear organization.
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.
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.
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.
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.
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.
Despite the remarkable throughput of next-generation sequencing technologies, standard techniques are limited by the difficulty in distinguishing sequencing errors from genuine low-frequency DNA variants within heterogeneous cellular or molecular populations. This Review discusses sequencing methodologies and bioinformatic strategies that have been devised for the reliable detection of rare mutations and describes various important applications in diverse fields including cancer, ageing and metagenomics.
Loss-of-function (LOF) approaches are powerful experimental tools for characterizing gene functions. However, emerging discrepancies when genes are investigated using different tools or organisms has triggered debate about how such LOF results should be biologically interpreted. In this Review, experts from varied fields discuss how understanding the underlying features of each LOF approach can provide explanations for different experimental outcomes and can guide their optimal and reliable application.
Comment & Opinion
As Nature Reviews Genetics turns 20 years, the editors embrace the opportunity to pause and reflect on the past, take stock of the present and look to the future. Please join us in celebrating our Anniversary issue.
To celebrate the first 20 years of Nature Reviews Genetics, we asked 12 leading scientists to reflect on the key challenges and opportunities faced by the field of genetics and genomics.
Thirty years on from the launch of the Human Genome Project, Richard Gibbs reflects on the promisesthat this voyage of discovery bore. Its success should be measured by how this project transformed the rules of research, the way of practising biological discovery and the ubiquitous digitization of biological science.
To celebrate the first 10 years ofNature Reviews Genetics, we asked eight leading researchers for their views on the key developments in genetics and genomics in the past decade and the prospects for the future.
For genomics to fulfil its potential of improving human health, diversity and inclusion must be recognized as essential catalysts of research success.
Just as humans thrive from being part of a community, genetics and genomics benefit from interdisciplinary collaboration and knowledge integration.
In this Perspective article, the authors discuss how Indigenous Peoples' desires for greater involvement and oversight when participating in genomic research projects can be balanced against calls for unrestricted data access. They provide practical recommendations for the handling and sharing of Indigenous genomic data, with the aim of achieving mutual benefit for the research community and participating Indigenous communities.
Including diverse populations in genomic studies has the potential to improve the use of genomic data in the clinic. Here, members of the National Human Genome Research Institute review the benefits of increasing diversity, the challenges to overcome and key recommendations for how to achieve this goal.
High-resolution studies of chromosome conformation are revealing that the 3D genome is organized into smaller structural features than was previously supposed and is primarily composed of compartmental domains and CTCF loops. In this Perspectives article Rowley and Corces describe the latest views on the organizational drivers and principles of the 3D genome, and the interplay between genome activity and organization.
In this Perspective article, Cheetham, Faulkner and Dinger describe our latest understanding of pseudogenes, which are typically defined as defective copies of regular genes. They argue that being open minded about potential functionality, as well as carefully designing functional studies, will lead to a growing appreciation of emerging functional roles of these understudied elements.
Seven leading geneticists express their views about where the unidentified components of the heritability for complex human diseases might lie and how this could affect the underlying genetic architecture, as well as offering suggestions of how genomic research could be targeted to address this key issue.
Advances in genome sequencing, editing and synthetic biology have enhanced the feasibility of large-scale genome engineering, termed genome writing. In this Opinion article, Chari and Church discuss the strengths and limitations of diverse strategies for genome writing, including extensively modifying existing genomes versus synthesizing genomesde novo, and they provide future visions for writing large genomes.
The data from genome-wide association studies can be applied to genotype data to predict the phenotype of a complex trait. Here the authors discuss the potential pitfalls of such analyses and the inherent limitations of the method.
The authors argue that ancient whole-genome duplications might be linked to major ecological upheavals and extinction. When established, polyploidy might lead to increased vigour, species diversity and phenotypic novelties, and could therefore contribute to the evolutionary success of a lineage.
Evo–devo is now a mature field encompassing a wide range of research areas. The author offers his assessment of its main theoretical implications and challenges for the immediate future.
Four leading researchers contribute their personal opinions on recent progress and current challenges in induced pluripotent stem cell research. Their varied perspectives suggest that for clinical applications there is cause for optimism, tempered with caution, and they highlight exciting recent advances in reprogramming and differentiation.
The ability to generate personalized genomic information for large numbers of people is rapidly becoming a reality. Four experts provide their opinions on how useful this information is likely to be and how it should best be put to use.
This Comment discusses how data from smartphones or wearables could be used for behavioural phenotyping, knowledge that may help to reveal the genetic and environmental contributions to disease-related behavioural variation.
Genome-wide sequencing (GWS) is the most sensitive test available for detecting pathogenic genetic variants but it generates complex results. It is important, therefore, that individuals undergoing GWS are offered both pre-test and post-test genetic counselling.
From The Archive
Over the past few decades, epigenetics has evolved from a collection of curious biological phenomena to a functionally dissected research field. In this article, the authors provide a personal perspective on the advances of research into epigenetics — from its historical origins to its modern era — with a focus on molecular breakthroughs.
Discoveries over the past decade portend a paradigm shift in molecular biology; evidence suggests that RNA is not only functional as a messenger between DNA and protein but also involved in the regulation of genome organization and gene expression. This Timeline article surveys the emergence of the previously unsuspected world of regulatory RNA from a historical perspective.
Single-cell genome sequencing can provide detailed insights into the composition of single genomes that are not readily apparent when studying bulk cell populations. This Review discusses the considerable technical challenges of amplifying and interrogating genomes from single cells, emerging innovative solutions and various applications in microbiology and human disease, in particular in cancer.
Our understanding of the function of DNA methylation is developing now that we are able to look beyond CpG-rich regions at transcriptional start sites. The emerging picture is of a complex relationship between DNA methylation and transcription and of possible additional roles of methylation.
Exome sequencing is a powerful approach for accelerating the discovery of the genes underlying Mendelian disorders and, increasingly, of genes underlying complex traits. This Review describes the experimental and analytical options for applying exome sequencing and the key challenges in using this approach.
Advances in DNA sequencing technologies have led to vast increases in the diversity of sequencing-based applications and in the amount of data generated. This Review discusses the current state-of-the-art technologies in both short-read and long-read DNA sequencing, their underlying mechanisms, relative strengths and limitations, and emerging applications.
Genome-wide association studies have led to an improved understanding of the genetic basis of common diseases. Following the first wave of such studies, this Review takes a critical look at progress so far and considers how future studies can be optimized.
The transcription regulation networks that control gene expression consist of a series of recurring logical wiring patterns — network motifs. By understanding the properties of these simple motifs we can start to understand the complexity of whole networks.
Gene expression is regulated by an intricate interplay of many factors at different levels. To understand how the currently observed expression patterns have evolved, we need to understand the evolution of the individual regulators and the complex regulatory networks that they form.
Batch effects can lead to incorrect biological conclusions but are not widely considered. The authors show that batch effects are relevant to a range of high-throughput 'omics' data sets and are crucial to address. They also explain how batch effects can be mitigated.
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.
Genetic variation in gene expression among individuals is an important contributor to differences in organismal phenotypes. This Review describes key concepts of such variation and provides an update on recent research on the effects of regulatory variants on the transcriptome, proteome and complex traits, including human disease risk.
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.
MicroRNAs (miRNAs) repress gene expression both through initiating mRNA degradation and through translational repression. This Review describes how molecular studies and structural data are revealing key insights into both mechanisms of miRNA-mediated gene repression in animals, including their intricate interplay, and are posing new questions for future research.
A growing understanding of the relationship between the microbiome and human health is made possible by advances in sequencing technologies and computational tools. These studies highlight how the composition and function of the microbiome varies across individuals and anatomical sites, over time, and also in disease.
Transposable elements (TEs) are widely known for their deleterious consequences of selfish propagation and mutagenesis. However, as described in this Review, TEs also provide hosts with rich, beneficial gene-regulatory machinery in the form of regulatory DNA elements and TE-derived gene products. The authors highlight the diverse regulatory contributions of TEs to organismal physiology and pathology, provide a framework for responsibly assigning functional roles to TEs and offer visions for the future.