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Many precision cancer therapies function by inhibiting oncogenic signaling pathways. A new study describes the counterintuitive finding that forced hyperactivation of the same pathways can also enable selective tumor targeting.
Genetic studies have associated thousands of non-coding variants with Alzheimer’s disease (AD), yet the functions of these variants remain elusive. We conducted cell-type-specific genetic fine mapping of AD variants and performed extensive functional characterization to unravel the causal variants that contribute to transcriptional regulation and ADrelated phenotypes in microglia.
CT-SLEB, a powerful and scalable method, improves the performance of multiancestry polygenic prediction by generating polygenic risk scores based on GWAS summary statistics in diverse populations.
Gain-of-function perturbation screens across 488 barcoded cell lines identify context-specific activation lethalities. The authors show that cells with MAPK, PI3K and WNT pathway activation are vulnerable to mutations that lead to further activation, suggesting a new strategy for treating tumors driven by these oncogenic pathways.
Genetic fine-mapping and CRISPRi screens identify functional variants and their target genes associated with Alzheimer’s disease in microglia. The variant rs7922621 modulates AD risk through control of TSPAN14 expression in this cell type.
APOBEC3B interacts with R-loops and helps mediate their resolution in a deamination-dependent way. This association also renders R-loops susceptible to enhanced APOBEC3B-dependent mutagenesis.
We re-sequenced and phenotyped 2,839 rice hybrid cultivars and 9,839 F2 individuals from elite hybrids. Based on the dataset, the genetic improvement during rice hybrid breeding was investigated, and the genetic basis underlying strong heterosis was quantitatively evaluated. Furthermore, a genomic selection model was constructed to optimize heterotic combinations.
Simulations and applications to real data show that adjustment of genome-wide association analyses for polygenic scores increases the statistical power for discovery across all ancestries, suggesting an analytical strategy for future studies in underrepresented populations.
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.
Using data from the UK Biobank, we reveal the roles of selection and mutation in shaping the genetic diversity of mosaic chromosomal alterations in healthy blood.
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.
