Volume 55 Issue 10, October 2023

DNA mismatch repair deficiency (MMRd) is associated with elevated tumor mutational burden (TMB) and exceptional immunotherapy responses, yet some patients experience no clinical benefit. Recent work proposes that high intra-tumoral heterogeneity can offset immunogenicity in sporadic MMRd, suggesting a potential mechanism of immunotherapy failure.

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.

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.

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.

Polygenic risk scores (PRSs) are increasingly able to predict complex traits; however, they perform suboptimally in populations not of European ancestry. We present CT-SLEB, a powerful method that enables the calculation of PRSs from multi-ancestry samples and provides insights into the opportunities and challenges of enhancing polygenic risk prediction across populations of diverse ancestry.

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.

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.

Multi-ancestry genome-wide association meta-analysis identifies new risk loci for CAC. Functional evidence implicates candidate causal genes as regulators of smooth muscle cell-mediated calcification.

Analysis of H3K27ac genome-wide maps across 387 brain, heart, muscle and lung samples, along with eQTL and genome-wide association studies (GWAS) data integration, identifies tissue-specific genetically influenced active regulatory regions and target genes that potentially mediate disease etiology.

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.

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.

Multi-omic analysis of 579 patients with hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2⁻) breast cancer identifies subgroups of the disease with distinct biological and clinical features.

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.

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.

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.

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.

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.

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.