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A modified framework leveraging a protein language model (ESM1b) is used to predict all possible 450 million missense variant effects in the human genome and shows potential for generalizing to more complex genetic variations such as indels and stop-gains.
Analysis of exome sequencing data identifies a burden of rare coding variants in 19 genes associated with bone mineral density. Integrated analyses show convergence of common- and rare-variant signals and highlight likely effector genes influencing osteoporosis risk.
Genome-wide association analysis of a binge eating disorder phenotype derived from a supervised machine-learning model applied to electronic medical records identifies three risk loci for this disorder and implicates iron metabolism in its etiology.
SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant (SF3B1MUT) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.
Saccharomyces cerevisiae Reference Assembly Panel (ScRAP) comprising telomere-to-telomere assemblies of 142 strains representing phylogenetic and ecological diversity of the species characterizes its genome structural landscape.
Single-cell RNA- and ATAC-seq analysis of human scalp biopsies characterizes the regulatory programs of heterogeneous cell types. Integration with genome-wide association studies of hair and skin diseases implicates critical cell types, transcription factors and candidate causal variants.
Somatic mutations are identified from circulating cell-free DNA using a single-molecule-based lowpass whole-genome sequencing method. The regional distribution of mutations can identify a tumor-specific mutational profile in patients with cancer and can be used to monitor patients through treatment.
Depletion of cohesin subunit RAD21 increases DNA breaks genome-wide, leading to translocations at cancer-mutated hotspot genes. RAD21 depletion leads to dormant origin firing and induces irregular replication timing.
GY3 encodes a LOG-like protein that acts as a 5′-ribonucleotide phosphohydrolase in cytokinin synthesis. A Gypsysolo-LTR insertion downregulates GY3 expression and shows the potential to enhance grain yield in rice.
CRISPRi-based screen identifies enhancers that nonlinearly regulate lineage-specifying transcription factors during definitive endoderm differentiation. A new CTCF-loop-constrained Interaction Activity (CIA) model is better at predicting functional enhancers than previous Hi-C-based enhancer–promoter contact frequency models.
The N6-methyladenosine reader YTHDC2 recruits TET1 to remove 5-methylcytosine from LTR7/HERV-H loci in human embryonic stem cells. The YTHDC2/LTR7 pathway inhibits neural fate commitment.
Polygenic Priority Score (PoPS) prioritizes candidate effector genes at complex trait loci by integrating genome-wide association summary statistics with other data types. Combining PoPS with methods that leverage local genetic signals further improves the performance.
Perturbation of RNA polymerase II (Pol II) via chemical inhibition or dTAG-induced degradation and analysis using Micro-C and run-on sequencing show that enhancer–promoter contacts are dependent on transcription and stabilized by paused RNA Pol II.
Slide-seq profiling of mouse embryos at the onset of organogenesis (embryonic days 8.5–9.5) coupled with a new three-dimensional reconstruction and visualization tool (sc3D) provides high-resolution maps of spatiotemporal gene expression dynamics.
A comparison of fetal hemoglobin gene editing strategies using human sickle cell disease donor cells and in vivo transplantation finds that adenine base editing of the –175A>G site in the γ-globin gene promoters results in durable and potent expression.
G4access is a nuclease-based method for identifying DNA G-quadruplex forming regions genome-wide in open chromatin using sequencing. Application across a range of cell types and species highlights associations of G-quadruplexes with various epigenetic and regulatory features.
Single-cell analyses of immune cells from patients with pathogenic, single large-scale mitochondrial DNA (mtDNA) deletions including Pearson syndrome describe heteroplasmy dynamics consistent with purifying selection, as well as T-cell state-specific regulatory mechanisms and metabolic vulnerabilities.
GATA2 regulatory mutations are associated with hereditary congenital facial paresis in humans. A genetically engineered mouse model recapitulates the human phenotype, showing altered neuron-specific Gata2 expression and a bias in formation of inner-ear efferent neurons over facial branchial motor neurons.
Multitrait genome-wide association analyses identify hundreds of risk loci for primary open-angle glaucoma. Integration with other data types highlights potential new drug targets, including proteins likely to act via the optic nerve.
Transcriptomic analysis of BCR-ABL1 lymphoblastic leukemia identifies three subgroups, each associated with a maturation arrest at a specific stage of B-cell progenitor differentiation and distinct genetic and clinical features.