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Linkage disequilibrium graphical models (LDGMs) derived from genome-wide genealogies provide an efficient representation of LD, yielding large improvements in runtime for LD matrix computations. LDGMs will enable methods that scale to millions of variants and individuals.
An analysis of UK Biobank participants shows that the risk of developing different types of myeloid neoplasms can be inferred years before diagnosis. The authors integrate somatic gene mutations with blood test parameters into a predictive model, which could guide future strategies for early detection and prevention of these diseases.
Genome-wide association analyses of magnetic resonance imaging data describe the genetic architecture of 13 cortical phenotypes at both global and regional levels, implicating neurodevelopmental and constrained genes.
Bulk ex vivo and single-cell in vivo CRISPR knockout screens are used to characterize 680 chromatin factors during mouse hematopoiesis, highlighting lineage-specific and normal and leukemia-specific functions.
Tissue co-regulation score regression (TCSC) infers causal tissues and partitions trait heritability into tissue-specific components using a transcriptome-wide association study framework. Applying TCSC to 78 complex traits and diseases identifies biologically plausible tissue–trait relationships.
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.