Reviews & Analysis

New statistical and machine learning techniques to understand, quantify and correct for the impact of biases in genomic data are emerging. The authors review how the choice of analytical methods used to process, analyse and interpret genomic data can influence genomic research, as well as existing methodological approaches to promote equity and fairness in genomics.

Cell-type deconvolution methods are often needed to analyse spatial transcriptomic data to recover cell-type distributions. In this Review, the authors describe the process of cell-type deconvolution, contrast the tools available and highlight important considerations for which tool to use.

Barbadilla-Martínez et al. review recent progress in deep-learning-based sequence-to-expression models, which predict gene expression levels solely from DNA sequence. These models are providing new insights into the complex combinatorial logic underlying cis-regulatory control of gene expression.

Differences in X chromosome sequence content can trigger competitive interactions between clones that may alter organismal development and skew the representation of X-linked sequence variants in a cell-type-specific manner. The authors review this recently described phenomenon of X-linked competition and map out the implications for X-linked human diseases.

Genomic advances have enhanced our understanding of schizophrenia, bipolar disorder and major depressive disorder, revealing genetic architectures and risk mechanisms through large-scale genome-wide association studies and sequencing, which could address limitations in current diagnostic frameworks and treatment strategies in the future.

In this Review, Shao et al. discuss experimental and computational advances in single-cell DNA sequencing, insights into somatic genetic variation during normal development and in disease, and the potential use of single-cell somatic mutations for lineage tracing, diagnostics and biomarkers.

Transcriptional condensates are membraneless organelles that concentrate molecules involved in gene regulation. In this Perspective, the authors outline how transcriptional condensates could serve as temporal signal decoders that transmit information through gene regulatory networks governing cellular responses.

ADAR1-mediating RNA editing enables the cell to distinguish between endogenous and viral RNA. Li and Walkley review findings from human and mouse genetics that have revealed the mechanisms of ADAR1-mediated RNA editing, which are now providing insights for the development of potential therapies that target these mechanisms.

Post-transcriptional splicing has emerged as a key layer of gene expression regulation but is challenging to differentiate from co-transcriptional splicing. The authors review methodologies to detect post-transcriptional splicing, the mechanisms controlling splicing timing and how the temporal regulation of splicing affects gene expression.

Genetic factors that influence human height encompass rare monogenic variants as well as common and rare polygenic variants. In this Review, Bicknell et al. summarize our current understanding of the genetic underpinnings of human stature and link these genes to common developmental and cellular pathways that affect skeletal growth.

Upon fertilization and during early mammalian development, major changes in cellular plasticity occur. This is accompanied by large-scale epigenome remodelling, as has been recently highlighted by the application of genomics techniques to this developmental period.

In this Review, Della Valle et al. discuss the role of retrotransposable elements (RTEs) in the onset and progression of ageing and ageing-related disease, including evidence that environmental stressors act through RTEs to shift the trajectory towards unhealthy ageing.

Advances in long-read sequencing are driving the implementation of these technologies for transcriptome profiling. The authors provide a comprehensive guide to long-read RNA sequencing, including experimental and computational tools, current applications, challenges and opportunities.

Long-read sequencing technologies can directly profile methylation modifications across the genome. In this Review, Fu et al. overview the long-read computational tools to identify and compare methylation signals, as well as tools that use these methylation signals to analyse cell-type diversity and gain additional genomic insights.

This Review explores how experimental models of metastasis, such as mouse models and cell cultures, can complement the (multi)omics analysis of human metastasis samples, thereby filling knowledge gaps left by model studies and validating the findings from human sequencing data.

Differences between humans and experimental models create a translational gap that makes it difficult to extrapolate research findings. The authors review systems-focused approaches to identify and control the translational distance between a complex disease process being studied and the experimental model used for testing.

In this Review, Isomura and Kageyama discuss how advances in live imaging, stem cell technologies and synthetic approaches are providing insights into the mechanisms underlying synchronization and species-specific periodicity of the mammalian segmentation clock during somitogenesis.

Intrinsically disordered domains (IDRs) are increasingly appreciated as important components of protein function. This Perspective discusses the emerging evidence for IDRs from transcription factors as contributors to the transcription factor target search process, as well as the challenges associated with studying these regions.

In this Review, Dowdle and Lykke-Andersen discuss advances in our understanding of the machinery and mechanisms involved in the control of cytoplasmic mRNA decay and comment on implications for the design of therapeutic mRNAs.

Collins and Talkowski provide a broad overview of structural variation in the human genome that covers their mutational properties, the dynamics of population genetics and functional consequences in disease as well as promising directions for future research.