News & Views

The exact relationship between 3D chromatin interactions and enhancer function is unclear. By probing three-dimensional enhancer interactions in developing embryos, two studies now show nuanced dynamics in tissue-specific contexts and reveal how moderately increased enhancer–promoter interactions coincide with functionality.

Mutational signatures help to deconvolve the different processes that shape cancer genomes. A new tool now alleviates some of the persistent challenges in the field.

Gestational diabetes is a complex metabolic condition thought to have a strong genetic predisposition. A large genome-wide association study of participants from Finland sheds light on the genetic contributors, opening avenues for research into mechanisms that underlie glucose regulation in pregnancy to improve the health of mothers and babies.

Spatial omics enables the molecular profiling of cells with the tissue context preserved. A new analytic approach shows how cellular neighborhood analysis and feature augmentation can spatially connect and cluster millions of cells into higher-order functional units.

A common architectural feature of the genome in many organisms is chromatin domains. A synthetic biology approach now builds chromatin domains from scratch and identifies some of the minimal components needed for their formation.

An open-source automated algorithm called DeepFlow enables large-scale derivation of aortic flow measurements, and genetic analysis of aortic flow, structural and functional traits demonstrates a causal relationship between aortic size and aortic valve regurgitation.

Understanding clinical heterogeneity in attention deficit hyperactivity disorder (ADHD) is important for improving personalized care and long-term outcomes. A study exploits the large scale and breadth of phenotyping of the iPSYCH cohort to link clinical heterogeneity to genetic heterogeneity in ADHD.

The spatial biology revolution promises deep insights into tissue organization, but deriving this knowledge from diverse, complex data remains a major obstacle. Data-driven discovery of the multicellular organization of tissues is now achieved by transforming multimodal spatial imaging data using deep learning.

A new study combining experimental treatments of human blood cells from thousands of individuals with flow-cytometry-based phenotyping and then genome-wide association analyses identifies genetic loci associated with non-resting cell states. Integrating the results with disease association signals yields insights into the underlying biology.

New research reports that paused RNA polymerase II (RNAPII) enhances the targeting and activity of BAF chromatin remodelers. These findings suggest a new paradigm for understanding how the collaborative action of chromatin remodelers and the transcriptional machinery govern cell-type-specific chromatin accessibility.

CX-5461 (also known as pidnarulex), currently in phase 1/2 trials, induces selective killing of homologous-recombination-deficient or BRCA1- or BRCA2-mutated tumors in preclinical models. New work confirms these findings but shows it to be a remarkably potent mutagen that induces extensive genetic changes in cultured human cells with or without BRCA1/2 mutations, raising substantial safety issues.

Long segments of the genome that are shared ‘identical by descent’ (IBD) demonstrate recent relatedness between individuals. A new computational method robustly identifies shared IBD segments in human ancient DNA data, providing insights into the mobility and demography of prehistoric human societies.

Deep learning shows promise for predicting gene expression levels from DNA sequences. However, recent studies show that current state-of-the-art models struggle to accurately characterize expression variation from personal genomes, limiting their usefulness in personalized medicine.

Variants in the HLA region on chromosome 6 are strongly associated with many immune-related diseases. A method to construct personalized HLA genomes from single-cell RNA sequencing data, coupled with single-cell HLA expression quantitative trait loci modeling, identifies how genetic variants influence HLA gene expression across cell states.

The pancreas is an essential organ present in all vertebrates, and human pancreatic agenesis is an extremely rare disorder of largely unknown genetic determinants. A study now demonstrates that a primate-specific regulatory network controlled by the KRAB zinc-finger protein ZNF808 is essential for pancreas development.

Brain somatic mosaicism is linked to several neurological disorders and is thought to arise post-zygotically. A study suggests that pre-zygotic aneuploidy followed by post-zygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy.

The mechanisms of many disease-associated variants are uncertain because of limited power to detect their modest effects on gene expression. This study finds that natural selection leads to preferential detection of disease-associated versus expression-associated variants.

DNA mismatch repair deficiency (MMRd) is associated with elevated tumor mutational burden (TMB) and exceptional immunotherapy responses, yet some patients experience no clinical benefit. Recent work proposes that high intra-tumoral heterogeneity can offset immunogenicity in sporadic MMRd, suggesting a potential mechanism of immunotherapy failure.

Many precision cancer therapies function by inhibiting oncogenic signaling pathways. A new study describes the counterintuitive finding that forced hyperactivation of the same pathways can also enable selective tumor targeting.

Transformation of a myeloproliferative neoplasm to a secondary acute myeloid leukemia is rare but devastating. Single-cell, multi-omic characterization of hematopoietic stem and progenitor cells now shows the role of inflammation in transformation driven by mutations in TP53, with effects on the mutant clone but also non-mutant counterparts.