Reviews & Analysis

In this Review, the authors discuss the latest advances in profiling multiple molecular modalities from single cells, including genomic, transcriptomic, epigenomic and proteomic information. They describe the diverse strategies for separately analysing different modalities, how the data can be computationally integrated, and approaches for obtaining spatially resolved data.

This Review discusses the importance of understanding the mechanisms by which specific allelic variants and allelic combinations cause disease for accurately diagnosing, treating and counselling individuals with genetic disorders.

In this Review, the authors discuss our latest understanding of evolutionary genetic changes that are specific to humans, which might endow uniquely human traits and capabilities. They describe how new cellular and molecular approaches are helping to decipher the functional implications of these human-specific changes.

Environmental pollutants have been shown to disrupt molecular mechanisms underlying common complex diseases. The authors review the interplay of environmental stressors with the human genome and epigenome as well as other molecular processes, such as production of extracellular vesicles, epitranscriptomic changes and mitochondrial changes, through which the environment can exert its effects.

In this Review, Munir Pirmohamed provides an overview of the current state of the pharmacogenomics field, using examples of clinically relevant drug–gene associations, before outlining the steps needed for implementation of pharmacogenomics into clinical practice. The role of pharmacogenomics in drug discovery and development is also considered.

The ability to map DNA and RNA modifications has improved our understanding of these marks, but in some cases inconsistent results have been problematic. Here, Kong et al. discuss how to recognize and resolve issues associated with commonly used sequencing-based approaches to minimize mapping errors.

Macroautophagy and microautophagy involve characteristic membrane dynamics regulated by autophagy-related proteins to degrade cytoplasmic material in lysosomes. In this Review, the authors summarize recent progress in elucidating these highly conserved processes, the pathological relevance of autophagy-related genes in Mendelian and complex diseases, and the evolution of the autophagy pathway.

The vast combinatorial sequence space of RNAs has prohibited quantitative mapping from nucleotide sequence to structure and function. New biochemical methods in vitro, which carry out measurements on hundreds of thousands of molecules at the same time, are now beginning to solve this issue.

In this Review, the authors describe how advances in comparative primate genomics — complemented by multi-layered omic resources and primate cell systems — are providing insights into the evolution of primates and the genetic underpinnings of key traits of developmental and biomedical importance.

Alternative splicing of pre-mRNAs is key for cellular function and underpins the aetiology of numerous diseases. Here, we review major advances in understanding the structures and functions of the splicing machinery and its regulation, and in harnessing this knowledge for the design of novel therapies.

In this Review, the authors discuss our latest understanding of the spatial aspects of cancer evolution, including the roles of cancer subclonal structure, tissue architecture, and interactions between cancer cells and diverse cell types of the microenvironment at local and distant sites.

In this Review, Berger and Yu discuss how the sheer amounts of sequence data create bottlenecks in downstream analytical pipelines that must be overcome by new analysis strategies, each with their own trade-offs for properties such as speed, accuracy and applicability.

This Review surveys the known mechanisms of communication between RBPs and their effectors and their roles in reducing the complexity of RNA networks. The authors review the emerging roles of RBP–effector interactions in the control of RNA processing and regulation of biological outcomes, and their contribution to human health and disease.

In this Review, Spitale and Incarnato discuss how the application of sequencing-based RNA structure mapping methods to entire transcriptomes in living cells is providing insight into the RNA structurome, the dynamics of RNA ensembles and how RNA structure regulates cellular processes.

In this Review, Chen and Liu discuss the latest developments in prime editing systems, including improvements to their editing efficiency and capabilities, as well as diverse emerging applications in research and preclinical therapeutic studies.

Non-B DNA secondary structures, such as G quadruplexes, H-DNA or Z-DNA, have key roles in genetic instability and disease aetiology. The authors review the impact of non-B DNA on transcription, replication, recombination and DNA damage and repair, the mechanisms of non-B DNA-induced mutagenesis and the role of non-B DNA sequences in human disease.

In this Perspective, Harden reviews the terms genetic determinism, genetic essentialism and genetic reductionism to provide consensus and clarity about the meaning of these terms. She discusses common misconceptions, illustrates examples and concludes with recommendations for science communication.

Boulias and Greer review the functions of N⁶-methyladenosine (m⁶A) in RNA at the molecular, genomic and organismal level. They describe the impact of m⁶A deposition on RNA substrates, chromatin architecture, epigenetic regulation of gene expression and genome stability, as well as key roles of m⁶A in stem-cell differentiation, neurogenesis and immunity.

Microbiome epidemiology associates microbial community features with health outcomes, traits or exposures in human host populations. In this Review, the authors discuss ways in which various microbiome features at varying levels of resolution (community, strain, pathway or gene) influence human health using established examples of microbiome-associated changes linked with host outcomes.

In this Review, the authors describe advances in deep learning approaches in genomics, whereby researchers are moving beyond the typical ‘black box’ nature of models to obtain biological insights through explainable artificial intelligence (xAI).