Reviews & Analysis

Understanding the fundamental impact of sex and gender on human health and disease is crucial for optimizing precision medicine. In this Review, Khramtsova, Davis and Stranger discuss the roles of sex in the genetics of complex traits, including genomic evidence for sex-dependent genetic architecture, models and molecular mechanisms of sexually differentiated phenotypes and implications for health care.

The maternal-to-zygotic transition (MZT) is the process by which the transcriptionally silent embryonic genome is gradually activated. The mechanisms underlying the MZT are not fully understood, but recent work indicates that transcriptional activators have an important role.

DNA methylation is the primary epigenetic modification in bacteria, but a lack of suitable methods has hampered its study. Now, new sequencing technologies, including single-molecule, real-time sequencing and nanopore sequencing, are providing new opportunities for studying bacterial methylomes.

Improvements to livestock genetics will be critical to tackling the looming food crisis. Achieving this goal will require implementation of improved genomic technologies and better use of a wider range of genomic information.

Disruptions to the epigenome occur during the pathogenesis of various human diseases. In this Review, Berdasco and Esteller describe the challenges and progress of harnessing epigenetic changes for clinical application, including for diagnostics, disease classification and therapeutics. They discuss applications to diverse diseases, such as cancer, neurological disease, immune disorders and viral infections.

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.

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.

Lysine acetyltransferases (KATs) act at the interface of the cellular environment and transcription to modify levels of acetylation on target proteins. This Review highlights the roles of KATs beyond chromatin regulation, as detectors of metabolic intermediates and as integrators of signalling pathways, which enable cells to respond to and directly meet their homeostatic needs.

Transcriptome profiling in different brain regions has revealed distinct patterns of gene and non-coding RNA expression, as well as alternative splicing, in autism spectrum disorder (ASD). The authors review these ASD-associated signatures and the resulting mechanistic insights into ASD.

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.

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.

Recent technological advances are enabling new views of the 3D genome within the space of the nucleus. These studies are beginning to reveal the ways cells co-opt the structures and components of the nuclear periphery for genome organization and gene regulation.

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.

The virulence of viruses is a major determinant of the health burden of viral infections in humans and other species. In this article, Geoghegan and Holmes discuss how largely disparate research fields — theoretical modelling of virulence evolution and experimental dissection of genetic virulence determinants in laboratory model systems — can be bridged by considering real genomic data of viral evolution in a phylogenetic context. They describe the underlying principles of virulence evolution and how they apply to real-world viral infections and outbreaks of global importance.

CRISPR–Cas genome editing and next-generation sequencing are driving advances in cancer modelling and functional cancer genomics. Their application to autochthonous mouse models of human cancer to generate and analyse multiplexed and/or combinatorial alterations in vivo is reviewed here.

In this Review, Sheth and Wang describe emerging synthetic biology approaches for using DNA as a memory device for recording cellular events, including the various methodological steps from detecting diverse signals, converting them into DNA alterations and reading out and interpreting the recorded information. Furthermore, they discuss potential applications as biotechnological and environmental biosensors.

The repetitive nature of transposable elements (TEs) creates bioinformatic challenges that frequently result in them being disregarded (‘masked’) in analyses. As physiological and pathological roles for TEs become increasingly appreciated, this Review discusses bioinformatics tools dedicated to TE analysis, including for genomic annotation, TE classification, identifying polymorphisms and assessing likely functional impacts.

Organoids are 3D structures derived from stem cells that recapitulate some key characteristics of real organs. The authors review recent progress in organoid derivation and applications and outline how advances in other disciplines might lead to more physiologically relevant organoids.

The genomes of East African cichlid fish have yielded new insights into adaptive radiation and suggest that specific genomic features underlie their propensity for explosive diversification. The author reviews these findings and the challenges of reconstructing the evolutionary history of rapidly diversifying clades.

This Review discusses how stem cell bioengineering can advance regenerative medicine by giving insight into the design principles that underlie different levels of stem cell systems — from the inner circuitry in single cells and the stem cell niche to systemic interactions between organs and tissues.