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A new study shows that re-expressing PKD genes early in the course of the disease can fully reverse polycystic kidney disease in mice. These results reveal an unexpected ability of the kidney to regenerate following genetic rescue of polycystin function.
The genomes of cells across human tissues are riddled by changes to their DNA1–3. Many of these mutations do not alter the properties of a cell, and are neutral passengers. However, a small proportion can change a cell’s fitness, and increase or decrease the progeny that originate from the mutated cell4. How many of these alterations under positive selection (drivers) exist in total is unknown. Whether the current list of drivers is almost complete, or whether large proportions of positively selected drivers in the human genome remain undetected is yet to be determined.
FastGWA-GLMM is a fast, scalable generalized linear mixed model method for genetic association testing for binary traits in large cohorts that is robust to variant frequency and case–control imbalance.
Synonymous passenger mutations are used to measure levels of positive selection in healthy blood and esophagus. This approach can quantify missing selection due to unidentified drivers.
SNP rs17713054 in the 3p21.31 COVID-19 risk locus is identified as a probable causative variant for disease association. Chromatin conformation and gene expression data indicate that LZTFL1 is impacted by rs17713054 in pulmonary epithelial cells.
Open Targets Genetics is a community resource that provides systematic fine mapping at human GWAS loci, enabling users to prioritize genes at disease-associated regions and assess their potential as drug targets.
Mutational signatures can shed light onto mechanisms of carcinogenesis and reveal the mutagenic impact of novel and established environmental risk factors. A new study examines the mutational spectra of esophageal squamous cell cancer together with exposure information in regions of high and low incidence of the disease, and demonstrates both the limitations and potential of mutational signature analyses.
Automated and single-cell CUT&Tag is used to characterize the effects of KMT2A fusion proteins on chromatin in human primary leukemia samples, identifying oncogenic networks and fusion-specific therapeutic vulnerabilities.
The incidence of esophageal squamous cell carcinoma varies significantly across different geographical regions. Mutational signature analysis of tumors sampled from high- and low-incidence areas suggests that these variations may not be explained by mutagenic exposures.
A deep-learning framework interprets multiomic data across epidermal differentiation, identifying cooperative DNA sequence rules that regulate gene modules. Massively parallel reporter assay analysis validates temporal dynamics and cis-regulatory logic.
Re-expression of Pkd genes in cystic kidneys results in rapid reversal of autosomal dominant polycystic kidney disease phenotypes in mice, revealing an unexpected capacity for renal plasticity under the control of Pkd gene function.
Depletion of BRD4 reduces the chromatin occupancy of NIPBL, resulting in aberrant genome folding. Loss of BRD4 impedes neural crest differentiation, which can be rescued by depletion of WAPL.
Genome-wide association and Mendelian randomization analyses in the UK Biobank identify genetic variants associated with leukocyte telomere length and highlight putative causal links between telomere length and biomedical phenotypes.
A high-resolution reference panel based on whole-genome sequencing data enables accurate imputation of HLA alleles across diverse populations and fine-mapping of HLA association signals for HIV-1 host response.
Heterogeneity in brain tumors has been viewed through many lenses—from microscopes and experimental models to ‘omic’ analysis at the tissue and single-cell levels. Two studies now characterize patterns of DNA methylation and gene expression in single cells to reveal epigenomic underpinnings of cellular heterogeneity and plasticity in exquisite detail, including mechanistic insight into cellular transitions between stem-like and differentiated-like states.