Reviews & Analysis

This Review describes our latest understanding of the range of functions of tRNAs. Emerging roles include the tight regulation of tRNA biogenesis to meet the translational needs of different cell types, cleavage and covalent modification of tRNAs in stress signalling, and diverse mechanistic links to various diseases.

Transposable elements are key drivers of evolutionary innovation across many species. This Opinion article proposes evolutionary scenarios in which transposable elements have acted on innate immunity loci to generate adaptive immune systems and discusses striking parallels between the evolution of different adaptive immune systems: CRISPR–Cas in bacteria and archaea, and V(D)J recombination in vertebrates.

Large-scale genetic perturbation screens have been central to many biological discoveries. This Review outlines the recent advances in the quantification of various perturbations across large numbers of single cells simultaneously and describes the use of genetic perturbation screens to infer functional interactions between genes and phenotypes.

Preserving spatial information in gene expression analyses is key for interpreting the single-cell tissue context (and even subcellular environments) of RNAs to achieve a more complete understanding of the underlying physiology. This Innovation article describes the emerging technologies of and biological insights from spatially resolved transcriptomics technologies, and how they set the stage for comprehensive investigations using complementary omic approaches.

Mendelian conditions, which are caused by dysfunction of a single gene, illustrate how the availability of the human genome sequence and tools for interrogating individual genomes can provide insights into disease. In this Review, cystic fibrosis is presented as an example of how genetics can continuously inform clinical research and practice.

Relatedness has traditionally been defined using pedigree-based measures, but these have serious deficiencies. With genome-wide data, SNP-based measures can now be used to directly measure genome similarity, a more useful concept than relatedness. This Review outlines ways to evaluate measures of genome similarity.

The RNA World concept is the idea that billions of years ago — before current life based on DNA, RNA and proteins — the primary living substance was RNA or something chemically similar. This Review highlights the challenges and solutions of this point of view, particularly for the synthesis and replication of RNA, and how various types of molecular cooperation probably had important roles.

Various small molecules, including numerous anticancer agents, act by targeting DNA or protein components of chromatin. This Review describes how various complementary technologies use high-throughput sequencing to delineate drug responses, from identifying the genomic binding sites of drugs or their targets, to the ensuing changes to chromatin states and gene expression. These insights should facilitate the rational use of these therapies.

The resolution of epigenomic profiling has been vastly augmented with the adoption of new approaches to interrogate varied features of the epigenome. This Review describes these techniques and outlines the ways in which these genome-wide tools can be used to examine the epigenome.

This Review provides insights obtained from comparative transcriptomic studies of mammalian species. The dynamics of gene expression evolution in coding and non-coding genes, as well as the regulatory basis of transcriptome evolution and future research avenues, are discussed.

Various bacterial and eukaryotic microorganisms engage in interactions with plant hosts, ranging from co-evolutionary arms races between phytopathogens and their hosts to the beneficial effects of mutualistic microorganisms. This Review discusses how next-generation sequencing of microbial isolates and environmental samples has provided insights into the mechanisms and genome-wide evolution of pathogenesis in phytopathogens, as well as a more global understanding of plant-associated microbial communities.

This Review describes how whole-genome sequencing of pooled DNA from many individuals (Pool-seq) is an economical alternative to sequencing the genomes of individuals separately. The authors outline the strengths and pitfalls of Pool-seq, and provide example applications across diverse species and biological questions.

Next-generation sequencing methods can be used to examine features of chromatin biology, although the outputs of these methods can be subject to various potential biases. This Review describes the ways in which biases can be introduced to such experiments and outlines methods to detect and mitigate their effect.

Genome-wide association studies have been extensively used to uncover genetic variants that independently influence complex traits, including diseases. This Review describes advances in computational approaches to detect interactions (epistasis) between genetic variants underlying complex traits, including the different promises and pitfalls of the methods. Additionally, the authors summarize current empirical evidence on how pervasive epistasis is in complex traits and its wider biological implications.

This Review provides insights into the use of eusocial insect species as models to study the role of epigenetic processes in regulating behaviour.

Recent developments and refinements to DNA methylation assays have led to the availability of several methods to detect and quantify cytosine modifications. This Review discusses the principles behind the newly developed techniques, compares the strengths and weaknesses of the different methods, and provides guidelines for selecting the most appropriate methods for particular experimental contexts.

Forward genetic screens have a long history of uncovering the genetic mutations underlying phenotypes of interest. This Review describes how next-generation sequencing technology can be integrated into forward genetic screens not only to enhance their efficiency but also to allow them to be carried out using expanded repertoires of species, populations and experimental strategies.

RNA-binding proteins (RBPs) influence alternative splicing in a highly context-sensitive and combinatorial manner, and it is therefore difficult to predict their actions on the basis of genomic sequence. However, recent progress in understanding alternative splicing, particularly using global approaches, has revealed new sets of rules for deciphering these patterns. This Review outlines the function of RBPs at different levels and describes the emerging rules of alternative splicing.

Single-cell sequencing of uncultivated microbial species is rapidly providing a wealth of new information. Here, the authors provide an update on recent progress in capturing novel genomes, large-scale environmental studies and research relating to human health, as well as recent methodological improvements and remaining technical challenges.

Understanding disease pathogenesis and developing potential therapies require accurate and genetically tractable models. This Review discusses how human stem cells — including embryonic stem cells, adult stem cells and induced pluripotent stem cells — can provide informative models of diverse human diseases. Such methods can also be extended through gene editing, co-culture or infectious agent approaches.