Reviews & Analysis

The mammalian inactive X chromosome shows unusual folding dominated by large-scale structures. A study finds a megadomain structure with a boundary at the Xist locus, preceding the well-known Dxz4-separated megadomains in somatic cells.

Primary cell cultures need to be frequently passaged, which limits the study of long-term biological processes, such as how mutant clones colonize aging epithelia. Esophageal epithelioids self-maintain for months, recapitulating progenitor cell behavior in vivo. Epithelioid CRISPR–Cas9 screens reveal genes encoding molecules that control cell fitness.

We identified methylated tandem repeat expansions that resemble the FMR1 CGG repeat that causes fragile X syndrome and investigated their association with traits in the UK Biobank. AFF3 expansion carriers had a 2.4-fold reduced probability of completing secondary education and were enriched in a cohort of individuals with intellectual disability.

A co-factor for the androgen receptor, NSD2, provides insights into context-specific functions of the androgen receptor and is a new target for intervention.

This study presents a spatial transcriptomic analysis of matched primary tumors, liver metastases and lymph node metastases from patients with pancreatic ductal adenocarcinoma. Using a tumor ecosystem approach, we uncovered notable tumor microenvironmental heterogeneity and marked differences between primary and metastatic samples, providing key insights into metastatic pancreatic cancer.

Somatic mutations accrue with age as patches of mutant clones arise in otherwise histologically normal tissue. The clones’ persistence, expansion and roles in physiology and tumorigenesis are unclear. New work on the behavior of Pik3caH1047R mutant esophageal clones shows that host-dependent metabolic features underpin their expansion.

Blockade of primary genomic binding sites with small molecules causes redistribution of the transcription factor PU.1 to alternative binding sites; its transcriptional activity at these sites activates secondary gene networks that drive myeloid cell differentiation.

Epigenetic therapy triggers myriad transposable elements to generate new antigens that could prime tumor cells for immunotherapy. A study of glioblastoma discovers indiscriminate activation in healthy cells as well, and presents a more selective strategy for potential therapeutic targeting.

Precision oncology has just received a boost: a report on the prevalence of mutations in cancer driver genes based on whole genome sequencing of 10,000 clinical cases. The challenge ahead lies in how to explore the data to accelerate new discoveries in cancer biology while advancing precision oncology.

A new single-cell multiomic technique, GAGE-seq, pushes the frontier of single-cell 4D genome analysis by enabling analysis of rare cell populations in complex tissues.

Here we describe an open collaborative effort termed the ‘Ruminant T2T Consortium’. It aims to generate complete diploid assemblies for many species of ruminants to examine chromosomal evolution in the context of natural selection and domestication.

The clinical use of current polygenic risk scores (PRSs) might widen global health disparities, as their portability to diverse groups is limited, emphasizing the need for global collaboration to develop PRSs that perform equitably across the world.

A new analysis of clinical trials that were stopped early generates insights on the role of genetics in drug development and provides a new resource for researchers aiming to improve success rates of clinical trials.

This Review discusses gene regulatory networks in plants and their function across evolution and highlights how their manipulation with synthetic biology and gene editing can promote plant productivity in the face of climate change.

This Perspective explores challenges in calculating the penetrance of monogenic disease-associated variants in the context of large-scale population sequencing cohorts.

As we age, our cells acquire DNA mutations, resulting in cell-to-cell genomic heterogeneity. We characterized the landscape of mitochondrial DNA (mtDNA) heterogeneity in healthy human cells. Our observations provide deeper insight into the frequency of new mitochondrial mutations and the mechanisms that propagate low-level mutations in mtDNA over a lifetime.

Nearly 50% of the sequence of mammalian genomes is derived from mobile elements that inserted into the genome over millions of years of evolution. A recent mobile element insertion, found only in some individuals with European genetic ancestry, contributes to decreased skin pigmentation and increased sunburn frequency and skin cancer risk.

We present a multi-omic map of the human kidney in health and disease, using single-cell RNA, single-nuclei RNA, single-nuclei assay for transposase-accessible chromatin sequencing, spot-based and single-cell spatial transcriptomics. This comprehensive approach enables an in-depth understanding of the microenvironments in the diseased kidney.

This Review explores the challenges and strategies for developing gapless telomere-to-telomere genome assemblies to enhance our understanding of genome organization and improve crops through genome-assisted breeding or gene editing.

Genetic constraint identifies genes under selection against loss-of-function, but existing methods are inaccurate for shorter genes. A new study overcomes this key limitation to ascribe more confident predictions to all human protein-coding genes.