Reviews & Analysis

In this Review, Senft and Macfarlan discuss the diverse ways by which transposable elements (TEs) contribute to mammalian development and evolution, including direct contributions through TE-derived regulatory elements, RNAs and proteins, as well as indirect effects through the evolution of a TE repression system, the Krüppel-associated box zinc finger proteins (KRAB-ZFPs).

In this Review, the authors discuss computational methods for interpreting the molecular and clinical effects of genetic variants. They focus on methods leveraging machine learning, including those that characterize the effects on wider molecular networks.

Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases. The authors review approaches that leverage GWAS to identify opportunities for repurposing existing drugs, including single-loci mapping to drug targets, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization and polygenic scoring.

Synthetic biology has enabled the development of engineered cells that can serve as ex vivo or in vivo diagnostic tools or therapeutic delivery systems. This Review discusses preclinical and clinical applications of bacterial and mammalian theranostic cells as well as their underlying biological designs and remaining hurdles to their successful clinical application.

In this Review, Gelernter and Polimanti discuss how recent large-scale studies have provided insights into the genetics and biology of substance use and abuse. By considering a range of addictive substances (both legal and illegal), they describe the genetic commonalities and distinctions among use and dependency phenotypes for these substances.

McLaren and Fellay review our current understanding of the effects of human genetic variation on HIV infection and disease progression and how this knowledge is contributing to preventative and therapeutic approaches.

Genome-scale sequencing data have revealed statistical properties of mutagenesis in humans. Statistical analyses that interpret these patterns and incorporate knowledge on DNA replication and repair pathways can provide mechanistic models that shed light on the origin of spontaneous human mutation in the germ line.

Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics can localize transcriptionally characterized single cells within their native tissue context. This Review discusses methodologies and tools to integrate scRNA-seq with spatial transcriptomics approaches, and illustrates the types of insights that can be gained.

Omics methods can be used to mine the genomes of diverse organisms, from microorganisms to plants and animals, for the discovery of natural products and their biosynthetic genes. In this Review, the authors review the why, what, where and how of genome mining.

Differences of sex development (DSD) are under-diagnosed, partly because of the complexity of conditions included under this umbrella terminology. This Review discusses the potential of genomic approaches to improve variant detection, molecular diagnosis and outcomes for individuals with DSD.

Long-read sequencing at the population scale presents specific challenges but is becoming increasingly accessible. In this Review, Sedlazeck and colleagues discuss the major platforms and analytical tools, considerations in project design and challenges in scaling long-read sequencing to populations.

Silver, Bick and Savona discuss our latest understanding of clonal haematopoiesis (CH), which is an expansion of blood cell populations with shared somatic mutations. They focus on human germline risk variants and on how these are linked to different forms of CH and their associated disease pathologies.

This Review outlines how approaches from physics can be used to simplify and understand complex patterning events during development. In particular, wavefronts, genetic oscillators and genetic timers are discussed in the context of illustrative developmental processes.

Population-scale testing is an essential component of responses to the COVID-19 pandemic and is likely to become increasingly important in public health. Here, Mercer and Salit describe the roles of testing during the COVID-19 pandemic, including in genomic surveillance, contact tracing and environmental testing.

In this Perspective article, Oh and Petronis discuss emerging evidence of time-dependent patterns of DNA modification and describe how incorporating this ‘chrono-epigenetic’ perspective could add value and interpretability in human disease studies.

In this Perspective, Teschendorff and Feinberg describe how single-cell analysis methods based on statistical mechanics can provide valuable insights into developmental phenomena, such as differentiation potency and lineage trajectories, as well as disruption of these processes in cancer.

In this Review, Neafsey, Taylor and MacInnis discuss how population genomics approaches are currently used to study malaria parasites and mosquito vectors. They explore information that can be derived from such genomics approaches and discuss the use of relatedness-based measures of population variation to understand parasite and vector dynamics at highly resolved spatiotemporal scales.

The authors review the evidence for a biological role of RNA as a form of cell–cell communication in mammals as well as proposed roles for extracellular RNAs in health and disease. Moreover, this Review emphasizes and provides guidance on the experimental rigor that is required to definitively show that extracellular RNAs are functional in recipient cells in vivo.

Stapornwongkul and Vincent review models for morphogen gradient formation. They propose that hindered diffusion, in which interactions between morphogens and extracellular binders modulate gradient shape and dynamics, could form robust morphogen gradients in a variety of tissue contexts.

Profiling tumours by next-generation sequencing can improve diagnostic accuracy, assess for heritable cancer risk and guide treatment selection. The authors review efforts to enhance the clinical utility of cancer genomic profiling through integrative analyses of tumour and germline variants, as well as by characterizing allelic context and mutational signatures that influence therapy response.