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The mitochondrial transcription factor A is excluded from the mitochondria in spermatozoa by virtue of phosphorylation of the mitochondrial presequence. This is associated with transport to the nucleus and loss of mitochondrial DNA (mtDNA) from the mitochondria, providing a mechanistic basis for uniparental inheritance of mtDNA in humans.
Genome-wide association meta-analysis across individuals of diverse ancestries identifies risk loci for nonalcoholic fatty liver disease. The associated variants implicate plausible biological pathways and improve estimates of disease risk.
Somatic SLC30A1 mutations altering the zinc efflux transporter ZnT1 cause primary aldosteronism. These mutations result in membrane depolarization and opening of voltage-gated calcium channels, stimulating CYP11B2 expression and aldosterone production.
Mouse models of lung and colorectal cancer with sporadic DNA mismatch repair deficiency clarify that the intratumor heterogeneity and clonal architecture rather than tumor mutational burden are powerful determinants of immunotherapy response.
A survey of the fitness effects conferred by mosaic chromosomal alterations (mCAs) in UK Biobank shows that most mCAs—despite being relatively infrequent—are associated with increased fitness. Mosaic loss of the sex chromosomes was more common but these events afforded only small fitness gains.
Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
Resequencing of 2,839 hybrid rice cultivars and 9,839 F2 individuals from 18 elite crosses is used to characterize the genetics underlying a range of grain yield-related traits, providing insights into heterosis during breeding and a predictive model.
Asymmetric segregation of parental histones H3 and H4 in MCM2-mutant embryonic stem cells impacts mitotic inheritance of histone modifications and genome regulation. MCM2-2A mutation perturbs exit from pluripotency and differentiation.
Mcm2 mutation or Pole3 deletion in mouse embryonic stem cells leads to asymmetric parental histone distribution and impaired neural differentiation. Mutation of the Mcm2 histone-binding domain causes defects in pre-implantation development and embryonic lethality.
Single-cell multi-omic analyses show that chronic inflammation contributes to myeloproliferative neoplasm transformation to secondary acute myeloid leukemia by enhancing tumor protein 53 (TP53) mutant cell fitness and genetic evolution.
Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.
High-quality genome assemblies of four Solanum Americanum accessions lead to the identification of three NLR-encoding genes, Rpi-amr4, R02860 and R04373, that recognize potato late blight pathogen Phytophthora infestans effectors.
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.
GATK-gCNV uses a probabilistic model and inference framework to discover rare copy number variants (CNVs) from sequencing read-depth information. This algorithm is used to generate a reference catalog of rare coding CNVs in exome sequencing data from UK Biobank.
Meta-analysis of three large whole-exome sequencing datasets highlights protein-truncating and rare missense variants associated with breast cancer susceptibility.
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.