News & Views

Quantifying whether different populations share similar effect sizes of common causal variants is vital to understand the genetic basis of disease and build better prediction models. A new study proposes a method leveraging admixture to estimate the correlation of causal genetic variants and finds they are largely similar across ancestry backgrounds.

Current risk assessment and treatment strategies for venous thromboembolism (VTE) consider genetic factors only in a limited way. New work shows a more pervasive role of common variants in VTE risk, inspiring genetic predictors that surpass and complement individual clinical risk factors and monogenic thrombophilia testing.

Multi-omic profiling of lesions at autopsy reveals a plethora of resistance mechanisms present within individual patients with ovarian cancer. This highlights the extreme challenge faced in treating end-stage disease and underscores the need for new methods of early detection and intervention.

A major challenge in human genetics is the prioritization of causal genes in common complex diseases. A genome-wide CRISPR screen for intracellular insulin content in a human β-cell line has now identified a new candidate gene for type 2 diabetes, demonstrating the utility of this screening approach in β-cells.

CRISPR cell and gene therapy have been designed largely with respect to a single reference human genome. A new study reveals how human genetic diversity could lead to off-target effects and presents a new tool to identify these risks.

5-hydroxymethylcytosine (5hmC) accumulates in transcribed gene regions (called ‘gene bodies’) and near enhancers, but its biological role has remained mysterious. A new study demonstrates that 5hmC serves to counteract inappropriate, spurious intragenic transcription in airway smooth muscle cells and by doing so, this DNA base functions in the prevention of chronic inflammation in the lung and an asthma-like phenotype.

Previous genome-wide association studies of coronary artery disease (CAD) have discovered multiple susceptibility loci but have largely failed to uncover causal genes. A new study identifies hundreds of likely causal genes underlying the genetic risk for CAD.

For plants, the decision to germinate is a gamble on their subsequent survival. Xu et al. have now discovered a mechanism that determines the choice between germination and dormancy by regulating the level of ABA.

K27M mutation of histone H3 has been identified as a driver event in diffuse midline glioma. Two studies used comprehensive multi-model single-cell genomic, epigenomic and chromatin structure analysis to characterize the cell of origin and find a distinct etiology of H3K27M between pontine and thalamic tumors, and show that pontine gliomas harbor more immature oligodendrocyte-precursor-like cells.

Few genetic alterations have been linked to metastasis, during which cancer cells acquire abnormal migratory behavior. A new study sheds light on how loss of NECTIN1 leads to melanoma dissemination after local depletion of IGF1.

The evolutionary benefits of ongoing endogenous retrovirus (ERV) mobility in animals are largely unknown. A new paradigm suggests activation of the ERV family mdg4 at the fruitfly pupal stage may bolster adult antiviral defenses.

Mutations in the sodium channel NALCN promote epithelial cell shedding and dissemination independent of oncogenic transformation. This observation suggests that metastasis may not uniformly represent the end stage of carcinogenesis but can occur before oncogenic transformation.

A new study identifies prolyl hydroxylation of histone H3 as a signal for the recruitment of KDM5A, altering H3K4me3 and gene expression. H3P16oh is independent of the HIF hypoxia-sensing pathway and provides a further layer of complexity to oxygen-sensitive chromatin modifications.

Genetic risk factors for autism include both rare and common variants. A study shows that rare copy number variants and common variants across 16p that contribute to autism risk functionally converge to downregulate the expression of a large group of neuronally expressed genes in the 16p subtelomeric region.

KCNK3 mutations identified in sleep apnea probands affect TASK-1 X-gate function. These changes lead to an increase in potassium current and open probability, as well as impaired sensitivity to G-protein-coupled receptor inhibitors.

Clonal expansion of DNMT3A-mutant hematopoietic stem cells is a risk factor for myeloid malignancies and other morbidities. A new study uses multi-modal single-cell genomics to characterize the myeloid differentiation bias of DNMT3A-mutated clones, and finds preferential hypomethylation of binding motifs for key transcriptional regulators.

In this issue, Deng and colleagues show that the RNA m⁶A modification reader FXR1 recruits DNA 5-methylcytosine dioxygenase TET1 to genomic regions in order to demethylate DNA, which highlights a crosstalk between RNA methylation and DNA methylation in chromatin.

A new study uses single-cell and spatial transcriptomics to provide a systematic characterization of the recurrent gene-expression programs that control neoplastic cell states in diverse cancers.

The impact of endogenous retrovirus silencing during mammalian development is poorly understood. A new study shows that their abnormal reactivation in pluripotent cells dismantles key gene regulatory networks by perturbing transcriptional condensates linked to super-enhancer function.

A machine-learning model produces summarized sequence representations of genomic regulatory activity, and provides a functional view of regulatory DNA variation in the human genome, with the aim of better understanding the role of sequence variation in health and disease.