来自杂志 Nature Genetics 的文献。
当前共找到 8 篇文献分享。
1.
孤舟蓑笠翁
(2025-06-26 19:48):
#paper 【doi】10.1038/s41588-025-02237-8；【发表年份】2025年；【期刊】Nature Genetics；【标题】Single-cell eQTL analysis identifies genetic variation underlying metabolic dysfunction-associated steatohepatitis。【内容总结】这篇研究想搞清楚为什么不同人得脂肪肝的程度不一样，科学家怀疑和基因有关。他们用了一种叫单细胞RNA测序（snRNA-seq）的高科技方法，分析了48个人的肝脏细胞（包括健康人和不同程度的脂肪肝患者），结合基因组数据找到了3500多个影响基因表达的遗传变异位点（eQTL），特别是发现了一个叫EFHD1的基因在特定基因型（rs13395911:TT）的人中会被FOXO1蛋白调控，当肝脏代谢异常时这个保护机制会失效，导致脂肪肝恶化。主要方法包括单细胞转录组测序、Poisson混合效应模型（PME）找eQTL、细胞状态互作分析（ieQTL）、染色质状态分析和功能验证实验（如电泳迁移实验和类器官模型）。结果不仅验证了已知脂肪肝相关基因HSD17B13的调控机制，还首次揭示了EFHD1通过维持线粒体功能和减少内质网应激来保护肝脏，这些发现为个性化治疗提供了新靶点。
2.
孤舟蓑笠翁
(2025-06-25 21:22):
#paper 【doi】10.1038/s41588-025-02212-3；【发表年份】2025年；【期刊】Nature Genetics；【标题】Using large-scale population-based data to improve disease risk assessment of clinical variants。【内容总结】这篇论文想解决医学中基因变异风险评估不准的问题，特别是传统方法把变异简单分成"致病"或"无害"的缺陷。作者发现当前ClinVar数据库里的分类存在误差——有些标为"致病"的变异在普通人群里其实风险很低。他们主要做了两件事：一是提出新的贝叶斯统计框架，把基因功能数据和真实人群健康记录结合起来计算变异致病概率和实际发病率（称为外显率）；二是建议改进ClinVar数据库，要求增加年龄分层、多族裔数据和高优先级表型信息，还提议建立专门的外显率数据库。结果显示，整合人群数据后，像BRCA2基因的某个变异从"致病"降级为"无害"，避免了不必要的医疗干预。简单说，就是用海量普通人健康数据给基因变异风险"纠偏"，让基因诊断更靠谱。
Nature Genetics,
2025-6-23.
DOI: 10.1038/s41588-025-02212-3
Abstract:
No abstract available.
3.
孤舟蓑笠翁
(2025-06-25 21:15):
#paper 【doi】10.1038/s41588-025-02233-y；【发表年份】2025年；【期刊】Nature Genetics；【标题】Predicting resistance to chemotherapy using chromosomal instability signatures。【内容总结】这篇论文想解决化疗药物效果预测难题，开发了基于染色体不稳定性特征(CIN)的生物标志物来预测患者对三种常见化疗药物(铂类、紫杉烷类和蒽环类)的耐药性。简单说就是通过分析肿瘤DNA的拷贝数变异模式来预测哪种化疗会失效。主要方法包括：1)用全基因组测序数据计算17种CIN特征活性值；2)在细胞系和患者来源类器官中验证特征与药物敏感性的关系；3)用真实世界临床数据模拟临床试验评估预测效果。研究发现这些特征能准确预测耐药，比如在卵巢癌中紫杉烷类耐药患者的治疗失败风险比敏感患者高7.44倍。更详细地说，研究者先通过TCGA数据库和细胞实验确定了与三种化疗药物耐药相关的特定CIN特征组合，然后在840例真实患者数据中验证，结果显示该方法能跨癌种应用，且适用于临床常用的基因检测技术如TSO500 panel测序，部分病例甚至能用血液检测代替组织活检。
Nature Genetics,
2025-6-23.
DOI: 10.1038/s41588-025-02233-y
Abstract:
Abstract Chemotherapies are often given without precision biomarkers, exposing patients to toxic side effects without guaranteed benefit. Here we present chromosomal instability signature biomarkers that identify resistance to platinum-, taxane- …
>>>
Abstract Chemotherapies are often given without precision biomarkers, exposing patients to toxic side effects without guaranteed benefit. Here we present chromosomal instability signature biomarkers that identify resistance to platinum-, taxane- and anthracycline-based treatments using a single genomic test. In retrospectively emulated randomized-control biomarker clinical trials using real-world cohorts (n = 840), predicted resistant patients had elevated treatment failure risk for taxane (hazard ratio (HR) of 7.44) and anthracycline (HR of 1.88) in ovarian, taxane (HR of 3.98) and anthracycline (HR of 3.69) in metastatic breast and taxane (HR of 5.46) in metastatic prostate. Nonrandomized emulations showed predictive capacity for platinum resistance in ovarian (HR of 1.46) and anthracycline in sarcoma (HR of 3.59). We demonstrate feasibility using whole-genome sequencing, capture-panel sequencing and cell-free DNA. Our findings highlight the clinical value of chromosomal instability signatures in predicting resistance to chemotherapies across multiple cancer types, with the potential to transform the one-size-fits-all chemotherapy approach into precise, tailored treatment.
<<<
翻译
4.
孤舟蓑笠翁
(2025-06-21 11:32):
#paper 【doi】10.1038/s41588-025-02193-3；【发表年份】2025年；【期刊】Nature Genetics；【标题】High-definition spatial transcriptomic profiling of immune cell populations in colorectal cancer。【内容总结】本研究的目标是探索结肠癌中免疫细胞的空间分布和功能，使用高分辨率空间转录组学技术来理解肿瘤微环境的复杂性，以改善诊断和治疗策略；方法包括Visium HD空间转录组学（提供单细胞尺度分辨率）、单细胞RNA测序（创建参考数据集）、Xenium原位基因表达分析（用于验证）、空间距离分析（如肿瘤边界50微米范围）、差异基因表达以及配体-受体相互作用预测；结果识别了两个巨噬细胞亚群（SELENOP+和SPP1+），它们在空间上分离并富集于不同通路，表明各自在促进肿瘤进展中的作用，例如SPP1+巨噬细胞与TGFBI+肿瘤细胞和基质细胞共定位促进侵袭，而SELENOP+巨噬细胞与特定肿瘤细胞相互作用抑制免疫反应，同时通过Xenium验证发现克隆扩增的T细胞与表达趋化因子的巨噬细胞共定位，揭示潜在抗肿瘤微环境。简言之，研究证明了Visium HD的高分辨率和准确性，揭示了结肠癌中免疫细胞的异质性空间组织和功能互作，为靶向治疗提供新见解。
5.
白鸟
(2025-03-31 14:35):
#paper：doi：doi.org/10.1038/s41588-024-01883-8, MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution Nat Genet(2024).
通过HLA分子呈递肿瘤新生抗原对于实现肿瘤免疫治疗至关重要。但肿瘤的免疫识别可能会因HLA分子被破坏而受到抑制。HLA被破坏的不同类型（突变、LOH、抑制和可变剪接）在癌症中很常见。
1.检测工具：作者开发了一个工具 MHC Hammer，检测MHC杂合性缺失（LOH） 、等位基因特异性突变及测量HLA表达和抑制。
2.肿瘤HLA变化：肺癌和乳腺癌队列中破坏性的HLA突变很少见，但HLA等位基因的LOH、抑制和肿瘤富集的可变剪接却很普遍。这突出了HLA转录组损坏的程度及其重要性，和HLA抑制和可变剪接在癌症进化中的作用。
3.HLA抑制与甲基化：HLA抑制和替代剪接事件的潜在机制可能是表观遗传。发现甲基化和HLA基因表达之间存在很强的关联。
4.展望：HLA替代剪接和抑制在多大程度上代表一种泛癌症免疫逃避机制需要更多的研究。
Nature Genetics,
2024-10.
DOI: 10.1038/s41588-024-01883-8
Abstract:
AbstractDisruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation …
>>>
AbstractDisruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.
<<<
翻译
6.
惊鸿
(2025-03-16 16:46):
#paper Hyperactive histone genes fuel cancer
Pub Date : 2025-03-13
DOI : 10.1038/s41588-025-02145-x
许多癌症类型在整个基因组中表现出非常高水平的转录，这与不良的临床结果相关。为了更好地了解这种现象，Henikoff 等人在靶向可及染色质 （CUTAC） 方法下使用福尔马林固定石蜡包埋 （FFPE） 切割来研究多种癌症样本中 RNA 聚合酶 II （Pol II） 在全基因组范围内的结合。他们在小鼠神经胶质瘤和各种人类肿瘤（乳腺癌、结肠癌、肝脏癌、直肠癌和胃癌）中观察到 Pol II 整体升高。局部 Pol II 增加对应于乳腺癌和结肠癌中的新发 ERBB2 （也称为 HER2） 扩增。有趣的是，在脑膜瘤中发现了 S 期依赖性组蛋白基因的高 Pol II 水平，并与世界卫生组织 （WHO） 等级、快速复发率和全臂染色体丢失相关。脑膜瘤和乳腺癌组蛋白基因 Pol II 的增加表明组蛋白水平可能对 S 期进展至关重要。作者推测，组蛋白基因高转录可能会促进癌细胞的异常增殖，并且过量的 H3 组蛋白可能与着丝粒处的 CENP-A 组蛋白竞争，最终导致癌症中的高非整倍体发生率。
Nature Genetics,
2025-3.
DOI: 10.1038/s41588-025-02145-x
Abstract:
No abstract available.
7.
颜林林
(2025-02-24 21:06):
#paper doi:10.1038/s41588-024-02050-9, Nature Genetics, 2025, Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes. 这篇是今年1月份新发表在Nature Genetics的文章，对391例人脑（208患者 vs. 183对照，死后的组织样本）进行snRNA-seq（单核测序）和SNP芯片检测，单核测序能够分析得到不同细胞类型的每个基因的表达量，于是可以鉴别出特定细胞的eQTL，即只在某个细胞类型中才会对基因表达量产生影响的那些突变。这个研究逻辑（鉴别特定细胞的eQTL），在此之前已经有不止一篇文章做过了。本文的重要创新点在于，构建了三个模型（M0、M1、M2），分别表示用临床信息协变量、协变量+基因型、协变量+基因型x疾病来预测表达量，接着，M1 对 M0，M2 对 M1 分别做似然比检验（likelihood ratio test），可以筛选出那些仅影响基因表达量但不直接影响疾病表型的突变，这正好用于后续的孟德尔随机化分析，从而在基因（表达量）与表型之间建立起因果关系（而不仅仅是相关关系）。之后文章还使用大规模的蛋白组数据，在蛋白水平进行了相应验证。
Nature Genetics,
2025-2.
DOI: 10.1038/s41588-024-02050-9
Abstract:
Abstract Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is …
>>>
Abstract Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is unclear. Using 2,348,438 single-nuclei profiles from 391 disease-case and control brains, we report 13,939 genes whose expression correlated with genetic variation, of which 16.7–40.8% (depending on cell type) showed disease-dependent allelic effects. Across 501 colocalizations for 30 CNS traits, 23.6% had a disease dependency, even after adjusting for disease status. To estimate the unconfounded effect of genes on outcomes, we repeated the analysis using nondiseased brains (n = 183) and reported an additional 91 colocalizations not present in the larger mixed disease and control dataset, demonstrating enhanced interpretation of disease-associated variants. Principled implementation of single-cell Mendelian randomization in control-only brains identified 140 putatively causal gene–trait associations, of which 11 were replicated in the UK Biobank, prioritizing candidate peripheral biomarkers predictive of CNS outcomes.
<<<
翻译
8.
白鸟
(2024-12-31 14:20):
#paper doi：10.1038/s41588-024-01819-2 Mapping spatially resolved transcriptomes in human and mouse pulmonary fibrosis.
这是一篇肺纤维化的空间转录组文献。文献基于前人单细胞文献的结果，对人患者IPF和小鼠BLM的肺部病变组织取样，分析病理纤维化生态位，探讨病变机制问题。
单细胞文献发现病变跟KRT5−/KRT17+基底细胞样 (AbBa) 上皮细胞群，Krt8+肺泡分化中间 (ADI) 细胞群有关。
文献的两个分析点是：
1.空转的分析非完全创新，而是基于单细胞的两类病变细胞群，在空间分析两类细胞与纤维化的关联；
2.Visium空转的一个鸡肋问题是：spot的细胞类型是混沌的，即使用单细胞的解卷积推测出来，也很难说明其准确性。
文献的核心是NMF非负矩阵因子，单个spot包含三层定义：NMF因子，手动病理注释，解卷积细胞类型推断；证明三层定义的一致性；能较好的规避单用解卷积推断偏差；后续的分析在此基础上进一步推断...
Nature Genetics,
2024-8.
DOI: 10.1038/s41588-024-01819-2
Abstract:
AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and …
>>>
AbstractIdiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. Here we generated spatially resolved transcriptome maps of human IPF (n = 4) and bleomycin-induced mouse pulmonary fibrosis (n = 6) to address these limitations. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by transforming growth factor beta signaling alongside predicted regulators, such as TP53 and APOE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.
<<<
翻译