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EasySci, a scalable single-cell profiling technique, uncovered over 300 mammalian brain cell states, revealing molecular features and dynamics of rare cell states linked to aging and Alzheimer’s disease. This work offers insights into cell states that expand (rare astrocytes and vascular leptomeningeal cells in the olfactory bulb, reactive microglia, and oligodendrocytes) or are depleted (neuronal progenitors, neuroblasts and committed oligodendrocyte precursors) during normal and pathological aging.
Combined analysis of genome-wide association studies and epigenetic data has identified certain immune cell types as drivers of autoimmune disease, but current methods have not been able to pinpoint key effector immune cell states. Using single-cell data from inflammatory tissues, we identified effector cell states embedded within inflammatory tissues — including T peripheral helper cells and tissue regulatory T cells — that capture disproportionate disease heritability.
We present a model to predict the chance of each possible de novo mutation in the human genome informed by recent insights into determinants of mutagenesis. Predictions were applied to refine demographic models, identify constrained genes, and uncover mutagenic effects of polymerase III transcription and transcription factor binding in testis.
Deep learning shows promise for predicting gene expression levels from DNA sequences. However, recent studies show that current state-of-the-art models struggle to accurately characterize expression variation from personal genomes, limiting their usefulness in personalized medicine.
Variants in the HLA region on chromosome 6 are strongly associated with many immune-related diseases. A method to construct personalized HLA genomes from single-cell RNA sequencing data, coupled with single-cell HLA expression quantitative trait loci modeling, identifies how genetic variants influence HLA gene expression across cell states.
This Perspective article explores complex synthetic lethal relationships in cancer, which can involve several partners. Understanding this complexity presents challenges and opportunities for the development of therapeutics that target these interactions.
Whole-genome sequencing data of individuals from the UK Biobank and Iceland and a somatic mutation barcoding strategy enabled detection of clonal hematopoiesis at scale. This comprehensive study provides insights into the epidemiology, somatic and germline genetics, and disease associations of clonal hematopoiesis.
Previous studies reported an effect of N6-methyladenosine (m6A) of super-enhancer RNAs (seRNAs) on chromatin accessibility and gene transcription. We investigated seRNA m6A levels in pancreatic ductal adenocarcinoma (PDAC) and found that aberrantly increased m6A methylation promoted local chromatin accessibility, resulting in increased transcription of oncogenes acting in PDAC progression.
We present an analysis that shows that although nearly half of the human genome comprises repetitive sequences, recombination between homologous repeats has a minor role in cancer chromosomal evolution.
The pancreas is an essential organ present in all vertebrates, and human pancreatic agenesis is an extremely rare disorder of largely unknown genetic determinants. A study now demonstrates that a primate-specific regulatory network controlled by the KRAB zinc-finger protein ZNF808 is essential for pancreas development.
Whole-exome and genome sequencing in consanguineous families with unsolved lipodystrophy identified biallelic pathogenic loss-of-function variants in the phospholipase gene PLAAT3. Multi-omics and functional analyses in human and mouse PLAAT3-deficient adipose tissue and adipose stem cells revealed an adipocyte differentiation defect that is mediated by an altered gene network downstream of the adipogenesis master regulator PPARγ.
This Review discusses how embryonic transcriptional programs, such as epithelial–mesenchymal plasticity and stemness, may be harnessed in adult tissues to drive processes and diseases such as regeneration and cancer.
Brain somatic mosaicism is linked to several neurological disorders and is thought to arise post-zygotically. A study suggests that pre-zygotic aneuploidy followed by post-zygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy.
The mechanisms of many disease-associated variants are uncertain because of limited power to detect their modest effects on gene expression. This study finds that natural selection leads to preferential detection of disease-associated versus expression-associated variants.
We developed a computational, age-dependent topic model to identify longitudinal comorbidity patterns from hospital diagnosis data. The inferred comorbidity patterns are robust across UK and US populations and identify disease subtypes with distinct genetic profiles.
Genome-wide association analyses of placental weight identify 40 association signals, partially overlapping with birth weight genetics. We find parent-of-origin effects and connections to placental development and morphology, and transport of amino acids and antibodies. Mendelian randomization reveals a fetal contribution to preeclampsia and implicates fetal insulin in the regulation of placental growth.
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.
