Review Articles

Regulatory circuits of gene expression can be represented as gene regulatory networks (GRNs) that are useful to understand cellular identity and disease. Here, the authors review the computational methods used to infer GRNs — in particular from single-cell multi-omics data — as well as the biological insights that they can provide, and methods for their downstream analysis and experimental assessment.

This Review discusses the range of methods used for assessing the growth and fitness of SARS-CoV-2 variants, from classic population genetics to phylogenetics and epidemiological data, and describes future perspectives for surveillance of SARS-CoV-2.

This Review discusses how transposable elements contribute to mammalian genome evolution and gene regulation through their ability to both maintain and reshape 3D genome structure.

The authors review genetic studies of sensorineural hearing impairment (SNHI) and their resulting insights into the molecular mechanisms underlying auditory system function. They also discuss preclinical studies of inner-ear gene therapy and key translational opportunities and challenges for treating monogenic forms of SNHI and associated balance disorders.

Recent systems biology and single-cell approaches have revealed the impact of the microenvironment, lineage specification and cell identity, and the genome on epithelial–mesenchymal plasticity (EMP). In addition, cell memory (hysteresis) and cellular noise can drive stochastic transitions between cell states. The authors review these forces and the regulatory mechanisms that stabilize EMP states or facilitate epithelial–mesenchymal transitions (EMTs).

Hook and Timp describe increasingly flexible ways in which single-molecule sequencing technologies are being used to analyse genomes. Examples include targeted genome sequencing, analysis of chromatin state and protein–DNA interactions, and sequencing of short reads.

In this Review, Gaulton et al. discuss how single-cell epigenomic methods generate cell type-, subtype- and state-resolved maps of candidate cis-regulatory elements in heterogeneous human tissues that can help to interpret the genetic basis of common traits and diseases.

Differences in facial morphology distinguish vertebrates. Here, Selleri and Rijli discuss advances in multi-omics and single-cell technologies linking genes, transcriptional networks and epigenetic landscapes to the establishment of facial patterning and its variation, with an emphasis on normal and abnormal craniofacial morphogenesis.

In this Review, the authors describe the emerging field of single-cell genetics, which lies at the intersection of single-cell genomics and human genetics. They review the first single-cell expression quantitative trait loci studies, which combine single-cell information with genotype data at the population scale and thereby link genetic variation to the cellular processes underpinning key aspects of human biology and disease.

Mutations that affect primary cilia cause ciliopathies with variable severity and expressivity. The diversity of cilia across cell types, tissues and developmental stages enables their function as versatile signalling hubs but may underlie the disconnect between genotype and phenotype. This Review examines the structural and functional diversity of primary cilia, their dynamic regulation in different cellular and developmental contexts and their disruption in disease.

Variant calling is the process of identifying genetic variants, which is important for characterizing population genetic diversity and for identifying disease-associated variants in clinical sequencing projects. In this Review, the authors discuss the state-of-the-art in variant calling, focusing on challenging types of genetic variants, advances in both sequencing technologies and computational pipelines, and benchmarking strategies to assess the robustness of variant-calling strategies.

In this Review, the authors discuss our growing knowledge of the underlying genetics of amyotrophic lateral sclerosis (ALS; also known as motor neuron disease). They discuss how this information provides insight into causal disease mechanisms and translational opportunities for developing clinical therapeutics.

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.