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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.
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.
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.
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.
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.
Transformation of a myeloproliferative neoplasm to a secondary acute myeloid leukemia is rare but devastating. Single-cell, multi-omic characterization of hematopoietic stem and progenitor cells now shows the role of inflammation in transformation driven by mutations in TP53, with effects on the mutant clone but also non-mutant counterparts.
The symmetric inheritance of histone modifications by the nascent chromatin fibers during DNA replication is essential for proper developmental progression. Two new studies using mouse embryonic stem cells further illuminate the role of histone inheritance in early cell fate decisions.
In this issue of Nature Genetics, Lara-Astiaso et al. systematically characterized the functional roles of several chromatin factors in hematopoiesis by combining functional CRISPR screens with single-cell transcriptomics and chromatin accessibility profiling, revealing lineage biases and relationships with important transcription factors.
A novel pipeline that expands the utility of the protein language model ESM1b has provided variant effect predictions for more than 40,000 protein isoforms. This strategy outperformed several state-of-the-art methods over multiple benchmarks.
Identifying genetic risk factors for binge-eating disorder (BED) is vital to understand its etiology and develop effective prevention and intervention strategies. To overcome under-reporting of clinical BED diagnosis, a new study uses machine learning to identify genetic variants associated with quantitative BED risk scores and finds evidence for a pathological role of heme metabolism.
Incidence of keratinocyte skin cancer varies markedly between populations living in different areas of the world. A detailed analysis of somatic mutations in the normal skin of individuals from the UK and Singapore reveals different patterns of clonal mutational landscapes that could contribute to differential risk.
Across multiple cancer types, hotspot mutations in SF3B1 confer selective sensitivity to multiple clinically available PARP inhibitors. This sensitivity is due to reduced levels of CINP specifically in SF3B1-mutant cells, which leads to a loss of the canonical replication stress response after challenge with PARP inhibitors.
Through whole-genome sequencing of single molecules of circulating cell-free DNA, we found that tumor-derived mutations in cancer genomes are associated with regions of late replication timing and other chromatin features. These genome-wide analyses identified altered regional mutation profiles in people with cancer that distinguished them from people without cancer and reflected tumor burden during therapy.
Matched single-cell transcriptomic and epigenomic profiles obtained from human scalp reveal gene regulatory maps of diverse cell types in the hair follicle niche. Integrating these data with existing genome-wide association studies enabled prioritization of cell types, genes, and causal variants implicated in the pathobiology of androgenetic alopecia, eczema, and other complex traits.
How the chromatin states of transposable elements (TEs) are controlled in development and disease is unclear. We present CARGO-BioID, a CRISPR-based proteomic approach to identify TE-associated proteins, and reveal an interplay between RNA N6-methyladenosine (m6A) and DNA methylation that is crucial for regulating TE activation and human embryonic stem cell (hESC) fate.
The three-dimensional organization of mammalian chromosomes can regulate transcription. Whether transcription itself influences genome structure has remained a source of debate. Using sensitive genome-wide readouts, two recent studies describe the involvement of transcription on genome architecture by different mechanisms.
Identifying the ways that a study sample is not representative is essential for maximizing the generalizability of findings to the population. A new method proposes discerning non-representativeness in large-scale genetic studies by comparing the genotypes of closely related participants.
Single large-scale mitochondrial DNA deletions cause a spectrum of disease with differing severities and tissue expressivity. Quantification of single-cell deletion levels with multi-modal cellular readouts provides insights into hematopoietic cell fate and disease manifestation.
Cross-ancestry genome-wide association meta-analyses of neuroimaging genetics data from European and East Asian populations identified 339 genetic variant–hippocampal volumetric trait associations (23 new). Further cross-ancestry analyses revealed similar genetic effects on hippocampal volumetric traits between ancestries, with improved fine-mapping precision and predictive accuracy of polygenic scores in the under-represented East Asian population.
