Reviews & Analysis

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  • 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.

    • Paul L. Auer
    News & Views
  • We developed a CRISPR-based functional assay for genetic sequence variants found in human disease, probing their effects on cell proliferation, survival, motility and any physiological or pathological process measurable by fluorescence-activated cell sorting (FACS). The assay accurately assessed variant pathogenicity, drug responsiveness or resistance and mechanistic role in disease, in vitro and in vivo.

    Research Briefing
  • 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.

    • Xiao-Nan Li
    News & Views
  • 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.

    • Jaume Barcelo
    • Victoria Sanz-Moreno
    News & Views
  • 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.

    • Ana Rita Nobre
    • Adrienne Boire
    News & Views
  • 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.

    • James A. Nathan
    News & Views
  • Adult human kidney organoids or tubuloids are derived from an epithelial CD24+ subpopulation in the proximal nephron and can be utilized for advanced disease modeling of the most common hereditary kidney disease: autosomal dominant polycystic kidney disease.

    Research Briefing
  • Genome sequencing and analysis of public epigenomic data enabled the identification of disease-causing variants in a non-coding regulatory region of hexokinase 1 (HK1) in individuals with congenital hyperinsulinism. These variants caused inappropriate HK1 expression within pancreatic β-cells, which led to increased insulin secretion and hypoglycemia.

    Research Briefing
  • Cancer cells frequently amplify oncogenes on DNA molecules outside of chromosomes — extrachromosomal DNA. A technique adapted for isolation of extrachromosomal DNA, termed CRISPR-CATCH, enables analyses of its genetic and epigenetic compositions, which provides insights into its origin, structural diversity and mechanism of oncogene activation in cancer.

    Research Briefing
  • We present a high-resolution genomic variation map that greatly expands the sequence information for maize and its wild relatives in the Zea genus. Population genetics of Zea spp. provide a vast trove of adaptive alleles that are absent in maize, with the potential for accelerating future breeding by reintroducing genetic diversity.

    Research Briefing
  • 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.

    • Hyejung Won
    • Guillaume Huguet
    • Sébastien Jacquemont
    News & Views
  • This Perspective addresses next steps to investigate the predictions that inhibition of APOBEC3-mediated mutagenesis may limit tumor heterogeneity, metastasis and drug resistance in a broad range of cancer types by highlighting gaps in our understanding of APOBEC3 biology in cancer and in healthy tissues and strategies to address them.

    • Mia Petljak
    • Abby M. Green
    • Matthew D. Weitzman
    Perspective
  • The ability to predict gene-expression landscapes at single-cell resolution has long been a challenge in the field of genomics. We mapped whole-body single-cell transcriptomic landscapes of zebrafish, Drosophila, and earthworm using Microwell-seq. We propose the first sequence-based model, Nvwa, that can predict gene expression at single-cell resolution directly from genomic sequences.

    Research Briefing
  • 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.

    • Tatum S. Simonson
    • Esteban A. Moya
    • Atul Malhotra
    News & Views
  • Oncogenes commonly amplify on circular extrachromosomal DNA (ecDNA) molecules in cancer. We show that ecDNA shapes each of the foundational principles of Darwinian evolution — random inheritance by descent, enhanced variation through random segregation, and selection — and thereby promotes rapid genome change, treatment resistance and poor outcomes for patients with cancer.

    Research Briefing
  • 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.

    • Richard A. Voit
    • Vijay G. Sankaran
    News & Views