【Nature Genetics】2024年12月刊论文导读

期刊介绍：

Nature Genetics创刊于1992年，由NATURE RESEARCH出版商出版，发表最高质量的遗传学研究。它包括对人类和植物性状以及其他模式生物的遗传和功能基因组研究。目前的重点是通过扰动实验研究常见和复杂疾病的遗传基础以及基因网络的功能机制、结构和进化。在行业领域中学术影响力很大，属于国际一流期刊，影响因子指数41.307。

Volume 56 Issue 12, December 2024

在2024年12月，Nature Genetics共发表40篇文章，其中包括1篇Turning Points，2篇Correspondence，1篇Comment，4篇Research Highlights，4篇News & Views，7篇Research Briefings，2篇Review Articles，1篇Letters，15篇Articles，1篇Technical Reports，2篇Amendments & Corrections。

1. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

全基因组关联分析深入揭示扩张型心肌病的分子病因

英国帝国理工学院、伦敦大学、丹麦奥胡斯大学等机构合作发表

Abstract

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

摘要：

扩张型心肌病（DCM）是导致心力衰竭和心脏移植的主要原因。该研究报告了一项全基因组关联研究以及对DCM（14,256 例）和三种左心室特征（36,203名英国生物库参与者）的多特征分析。确定了80个基因组风险位点，并对62个可能的效应基因进行了优先排序，其中包括几个与DCM相关的罕见变异基因（MAP3K7、NEDD4L和SSPN）。利用单核转录组学，确定了驱动发病机制的细胞状态、生物通路和细胞内通讯。研究结果证明，多基因评分可预测普通人群中的DCM，并可改变罕见DCM变异携带者的外显率。该研究结果可为设计包含多基因背景的基因检测策略提供参考。研究结果还提供了对DCM分子病因学的见解，这可能会促进靶向疗法的开发。

2.Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries

全基因组关联分析确定了不同血统老年性黄斑变性的不同基因结构

美国VA医疗保健系统、博思艾伦咨询公司、西奈山伊坎医学院等机构合作发表

Abstract

To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.

摘要：

要在全球范围内有效减少老年性黄斑变性（AMD）造成的视力损失，就必须了解其在不同人群中的遗传结构。其中一个关键因素，即非洲裔和西班牙裔/拉丁美洲裔的AMD风险概况，在很大程度上仍不为人所知。该研究将 “百万退伍军人计划”（Million Veteran Program）中的数据与其他五个队列的数据相结合，首次开展了AMD的多血统全基因组关联研究，发现了63个基因位点（30个新位点）。在主要风险位点观察到明显的跨种属异质性，尤其是在非洲种属人群中，他们在主要组织相容性复合体II类单倍型中显示出主要信号，而在已确定的CFH和ARMS2/HTRA1位点则显示出风险降低。在对混血个体的当地血统进行分析时，发现非洲血统单倍型中CFH风险等位基因的边际效应显著较小。将祖先不同的人群纳入研究范围有助于发现以祖先依赖性方式增加风险的基因和通路，这些基因和通路是纠正疗法的潜在靶点。

3.Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease

人类脑脊液的蛋白质基因组分析确定了与神经系统相关的调控，并揭示了阿尔茨海默病的病因蛋白

美国华盛顿大学医学院、埃默里大学医学院、西班牙加泰罗尼亚国际大学等机构合作发表

Abstract

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer’s disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

摘要：

事实证明，将定量性状位点（QTL）与疾病全基因组关联研究（GWAS）相结合，可以成功地优先确定疾病相关位点的候选基因。QTL图谱主要针对多组织表达QTL或血浆蛋白QTL（pQTL）。该研究通过测量3,506份样本中的6,361种蛋白质，生成了脑脊液（CSF）pQTL 图谱。确定了1,883个蛋白质的3,885个关联，其中包括2,885个新的pQTLs，显示了脑脊液中独特的遗传调控。在OSTN附近的染色体(chr)3q28和APOE附近的chr19q13.32上发现了CSF富集的多向性区域，这些区域富集了神经元特异性和神经系统发育。该研究通过全蛋白质组关联研究（PWAS）、共定位和孟德尔随机化，整合了与阿尔茨海默病（AD）的关联，并确定了38种推测的致病蛋白，其中15种已有药物可用。最后，该研究建立了一个基于蛋白质组学的AD预测模型，该模型优于基于遗传学的模型。这些发现将有助于进一步了解生物学，并确定大脑和神经特征的因果蛋白和药物靶点。

4.Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits

脑脊液和大脑代谢物水平的遗传结构以及代谢物与人类特征的遗传共定位

美国华盛顿大学医学院、巴罗神经学研究所、西班牙加泰罗尼亚国际大学等机构合作发表

Abstract

Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or urine. We integrated the metabolite quantitative trait loci (MQTLs) with 23 neurological, psychiatric and common human traits and diseases through colocalization to identify metabolites and biological processes implicated in these phenotypes. Combining CSF and brain, we identified 71 metabolite–trait associations, such as glycerophosphocholines with Alzheimer’s disease, O-sulfo-l-tyrosine with Parkinson’s disease, glycine, xanthine with waist-to-hip ratio and ergothioneine with inflammatory bowel disease. Our study expanded the knowledge of MQTLs in the central nervous system, providing insights into human traits.

摘要：

脑代谢紊乱可导致性状改变和疾病。该研究对脑脊液（CSF）和脑代谢物水平进行了全基因组关联研究，为139种脑脊液代谢物确定了205个独立关联（47.3%为新信号，包含11个新位点），为31种脑代谢物确定了32个独立关联（43.8%为新信号，包含4个新位点）。其中，96.9%（脑脊液）和 71.4%（大脑）的新信号属于先前分析过的血液或尿液中的代谢物。通过共定位将代谢物定量性状位点（MQTLs）与23种神经、精神和人类常见性状和疾病结合起来，以确定与这些表型有关的代谢物和生物过程。结合脑脊液和大脑，研究发现了71种代谢物与性状的关联，如甘油磷酸胆碱与阿尔茨海默病的关联，O-硫代-l-酪氨酸与帕金森病的关联，甘氨酸、黄嘌呤与腰臀比的关联，麦角硫因与炎症性肠病的关联。该研究拓展了人们对中枢神经系统中MQTLs的认识，为理解人类的性状提供了新视角。

5.Pervasive biases in proxy genome-wide association studies based on parental history of Alzheimer’s disease

基于父母阿尔茨海默病病史的代理全基因组关联研究中普遍存在的偏差

美国威斯康星大学、华盛顿大学

Abstract

Almost every recent Alzheimer’s disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and nonrandom participation in parental illness surveys, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that the current AD GWAX provide highly misleading genetic correlations between AD risk and higher education, which subsequently affects a variety of genetic epidemiological applications involving AD and cognition. Our study sheds light on potential issues in the design and analysis of middle-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.

摘要：

几乎所有最新的阿尔茨海默病（AD）全基因组关联研究（GWAS）都进行了荟萃分析，将临床诊断为AD的研究与使用基于父母疾病史的替代表型的研究结合起来。该研究报告了目前通过代理进行GWAS（GWAX）研究的主要局限性，这些局限性是由于未校正的生存偏倚和非随机参与的父母疾病调查造成的，它们导致了AD GWAS和GWAX结果之间的巨大差异。研究结果证明，目前的AD GWAX在AD风险与高等教育程度之间提供了极具误导性的遗传相关性，进而影响了涉及AD和认知的各种遗传流行病学应用。该研究揭示了中年生物库队列的设计和分析中可能存在的问题，并强调在解释基于近亲报告的父母疾病史的遗传关联结果时需要谨慎。

6.Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s disease

遗传性和散发性阿尔茨海默病的空间和单核转录组分析

美国加州大学

Abstract

The pathogenesis of Alzheimer’s disease (AD) depends on environmental and heritable factors, with its molecular etiology still unclear. Here we present a spatial transcriptomic (ST) and single-nucleus transcriptomic survey of late-onset sporadic AD and AD in Down syndrome (DSAD). Studying DSAD provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. We identified transcriptomic changes that may underlie cortical layer-preferential pathology accumulation. Spatial co-expression network analyses revealed transient and regionally restricted disease processes, including a glial inflammatory program dysregulated in upper cortical layers and implicated in AD genetic risk and amyloid-associated processes. Cell–cell communication analysis further contextualized this gene program in dysregulated signaling networks. Finally, we generated ST data from an amyloid AD mouse model to identify cross-species amyloid-proximal transcriptomic changes with conformational context.

摘要：

阿尔茨海默病（AD）的发病机制取决于环境因素和遗传因素，其分子病因尚不清楚。该研究对晚发散发性阿兹海默症和唐氏综合征相关阿兹海默症（DSAD）进行了空间转录组（ST）和单核转录组调查。研究DSAD为增进对先天性痴呆症转录组的了解提供了一个机会，从而有可能缩小遗传小鼠模型与散发性先天性痴呆症之间的差距。研究发现了可能导致皮质层特异性病理积累的转录组变化。空间共表达网络分析揭示了瞬时性和区域局限性的疾病过程，包括皮质上层失调的神经胶质炎症程序，该程序与AD遗传风险和淀粉样蛋白相关过程有关。细胞间通讯分析进一步将这一基因程序与失调的信号网络联系起来。最后，该研究从淀粉样蛋白AD小鼠模型中获得了ST数据，以在构象背景下确定跨物种淀粉样蛋白邻近转录组的变化。

7.A temporal cortex cell atlas highlights gene expression dynamics during human brain maturation

颞叶皮层细胞图谱突显人脑成熟过程中的基因表达动态

荷兰鹿特丹伊拉斯谟大学、德国马尔堡大学、芬兰赫尔辛基大学等机构合作发表

Abstract

The human brain undergoes protracted postnatal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell-type-specific gene expression dynamics. Here, using single-nucleus RNA sequencing on temporal lobe tissue, including samples of African ancestry, we build a joint pediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between pediatric and adult cell subtypes, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including the LTK and FREM subtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in pediatric tissue. The resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map.

摘要：

人脑在基因表达动态变化的引导下经历了漫长的产后成熟过程。大多数探索这些过程的研究都使用了大块组织分析，这掩盖了细胞类型特异性基因表达的动态变化。该研究利用对颞叶组织（包括非洲血统样本）的单核RNA测序，建立了75种细胞亚型的儿童和成人联合图谱，并通过空间转录组学进行了验证。研究探索了小儿和成人细胞亚型之间的差异，揭示了大脑成熟过程中发生变化的基因和通路。研究结果突显了兴奋性神经元亚型，包括LTK和FREM亚型，在小儿脑组织中显示出与认知和突触可塑性相关基因的高表达。该研究介绍的资源增进了对大脑发育过程的了解，并有助于全球努力构建一个包容性脑细胞图谱。

8.Consensus prediction of cell type labels in single-cell data with popV

利用popV对单细胞数据中的细胞类型标签进行共识预测

美国加州大学伯克利分校、麻省理工学院

Abstract

Cell-type classification is a crucial step in single-cell sequencing analysis. Various methods have been proposed for transferring a cell-type label from an annotated reference atlas to unannotated query datasets. Existing methods for transferring cell-type labels lack proper uncertainty estimation for the resulting annotations, limiting interpretability and usefulness. To address this, we propose popular Vote (popV), an ensemble of prediction models with an ontology-based voting scheme. PopV achieves accurate cell-type labeling and provides uncertainty scores. In multiple case studies, popV confidently annotates the majority of cells while highlighting cell populations that are challenging to annotate by label transfer. This additional step helps to reduce the load of manual inspection, which is often a necessary component of the annotation process, and enables one to focus on the most problematic parts of the annotation, streamlining the overall annotation process.

摘要：

细胞类型分类是单细胞测序分析的关键步骤。人们提出了各种方法，将细胞类型标签从注释参考图集转移到未注释的查询数据集。现有的细胞类型标签转移方法缺乏对结果注释的不确定性估计，从而限制了可解释性和实用性。为了解决这个问题，该研究提出了流行投票（popV），这是一种基于本体投票方案的预测模型集合。popV可实现准确的细胞类型标注，并提供不确定性分数。在多个案例研究中，popV能可靠地标注大多数细胞，同时突出难以通过标签转移标注的细胞群。这一额外步骤有助于减轻人工检查的负担（人工检查通常是注释过程的必要组成部分），并使人们能够专注于注释中最有问题的部分，从而简化整个注释过程。

9.Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases

外周血单细胞RNA测序将细胞类型特异性剪接调控与自身免疫性疾病和炎症性疾病联系起来

新加坡国立大学、韩国三星基因组研究所、日本大阪大学等机构合作发表

Abstract

Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5′ splice site of TCHP exon 4 that putatively modulates the risk of Graves’ disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution.

摘要：

替代剪接有助于形成复杂的性状，但在不同遗传祖先的性状相关细胞类型中是否存在差异尚不清楚。该研究描述了来自亚洲免疫多样性图谱（Asian Immune Diversity Atlas）的474名健康捐献者的约100万个外周血单核细胞中的细胞特异性、性别差异和祖先差异的替代剪接。研究发现了广泛的基于性别和祖先的差异剪接，其中大部分具有细胞类型特异性。发现了11,577个独立的顺式剪接定量性状位点（sQTL）、607个反式基因和107个动态sQTL。顺式-eQTL和反式-sQTL 之间的共定位揭示了HNRNPLL和PTPRC之间的细胞特异性调控关系。研究观察到顺式-sQTL效应在自身免疫性和炎症性疾病遗传性中的富集。具体来说，从功能上验证了一个亚洲特异的sQTL，它破坏了TCHP第4外显子的5′剪接位点，可能会调节东亚人群患巴塞杜氏病的风险。该工作凸显了祖先的多样性对剪接的影响，并为以单细胞分辨率剖析剪接在复杂疾病中的作用提供了路线图。

10.Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations

BRCA1或BRCA2基因突变携带者和非携带者的乳腺上皮细胞均存在常见的乳腺癌拷贝数改变

美国纪念斯隆凯特琳癌症中心、哈佛医学院、加拿大哥伦比亚大学等机构合作发表

Abstract

The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples (n = 28). In BRCA1/BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles. These CNAs, common in malignant tumors, are enriched in luminal cells but absent in basal myoepithelial cells. Allele-specific analysis of prevalent CNAs reveals that they arose by independent mutational events, consistent with convergent evolution. BRCA1/BRCA2 carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, BRCA1/BRCA2 LOH and multiple breast cancer-associated CNAs. Our findings suggest that CNAs arising in normal luminal breast epithelium are precursors to clonally expanded tumor genomes.

摘要：

人们对乳腺上皮细胞中体细胞拷贝数改变（CNA）的发生率和性质及其在肿瘤发生和进化中的作用仍然知之甚少。该研究通过对BRCA1和BRCA2携带者或野生型个体的上皮细胞进行单细胞DNA测序（49,238个细胞），发现了几乎所有样本（n = 28）中的存在于罕见细胞群中的复发性CNA（例如，1q-gain和7q、10q、16q和22q-loss）。在BRCA1/BRCA2携带者中，这些情况发生在野生型等位基因的杂合性丢失（LOH）之前。这些在恶性肿瘤中常见的CNA在管腔细胞中富集，但在基底肌上皮细胞中却不存在。对普遍存在的CNA进行等位基因特异性分析后发现，它们是通过独立的突变事件产生的，与趋同进化一致。BRCA1/BRCA2携带者中含有一小部分极度非整倍体细胞，其特点是TP53缺失、BRCA1/BRCA2 LOH和多种乳腺癌相关CNA。该研究结果表明，正常管腔乳腺上皮细胞中出现的CNA是肿瘤基因组克隆扩增的前体。

11.Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer

在遗传性乳腺癌小鼠模型中，Brca1单倍体缺失会促进肿瘤的早期发生和表观遗传学改变

美国哈佛医学院、Dana-Farber 癌症研究所、麻省理工学院

Abstract

Germline BRCA1 mutation carriers face a high breast cancer risk; however, the underlying mechanisms for this risk are not completely understood. Using a new genetically engineered mouse model of germline Brca1 heterozygosity, we demonstrate that early tumor onset in a Brca1 heterozygous background cannot be fully explained by the conventional ‘two-hit’ hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1 heterozygous state. Single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1 heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells. Transcription factor analyses identify loss of ELF5 and gain of AP-1 sites in these epigenetically primed regions; in vivo experiments further implicate AP-1 and Wnt10a as strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1 haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies.

摘要：

胚系BRCA1基因突变携带者面临着很高的乳腺癌风险；然而，这种风险的内在机制尚未完全明了。该研究利用一种新的基因工程小鼠胚系BRCA1杂合模型证明，传统的“two-hit二次打击”假说不能完全解释BRCA1杂合背景下肿瘤的早期发病，这表明在BRCA1杂合状态下存在固有的促肿瘤改变。单细胞RNA测序和转座酶可及染色质检测与测序分析在表面正常的Brca1杂合子乳腺上皮细胞中发现了一组独特的可及染色质区域，它们不同于野生型细胞，部分模拟了肿瘤细胞中染色质和RNA水平的变化。转录因子分析确定了这些表观遗传启动区中ELF5位点的缺失和AP-1位点的增殖；体内实验进一步表明AP-1和Wnt10a是Brca1相关乳腺癌的强启动子。这些发现揭示了Brca1单倍体缺乏症在加速肿瘤发生方面以前未被认识到的表观遗传学效应，加深了对机理的理解，并为潜在的治疗策略提供了信息。

12.JAK/STAT signaling maintains an intermediate cell population during prostate basal cell fate determination

JAK/STAT信号在前列腺基底细胞命运决定过程中维持中间细胞群

中国科学院、南京医科大学第一附属医院、美国约翰霍普金斯大学、上海科技大学

Abstract

Unipotent basal and luminal stem cells maintain prostate homeostasis, with an intermediate cell population emerging during prostate inflammation or cancer. However, the identities of basal stem cell and intermediate cell population remain unclear. Here we identified a rare intermediate cell population expressing luminal markers (termed Basal-B) with enhanced organoid formation capacity, and a larger basal population (termed Basal-A). Genetic lineage tracing revealed Basal-B cells represented a transient basal stem cell state during prostate homeostasis and androgen-mediated regeneration. Activated JAK/STAT signaling was identified in Basal-B cells, and its inhibition significantly reduced Basal-B markers expression. Inflammation increased Basal-B-to-luminal cell transdifferentiation, but JAK/STAT inhibition notably attenuated this effect. Pten gene deletion increased Nkx3.1-expressing Basal-B-like cell population and led to neoplasia. In humans, h-Basal-B cells were more prevalent in benign prostate hyperplasia. This study reveals the identities of intermediate Basal-B cells and underscores the role of JAK/STAT signaling in prostate cell fate determination.

摘要：

单能基底干细胞和管腔干细胞维持前列腺的稳态，中间细胞群在前列腺炎症或癌症期间出现。然而，基底干细胞和中间细胞群的身份仍不清楚。该研究发现了一个罕见的表达管腔标记的中间细胞群体（称为Basal-B），它具有增强的类器官形成能力，以及一个更大的基底细胞群体（称为Basal-A）。基因谱系追踪显示，在前列腺稳态和雄激素介导的再生过程中，Basal-B细胞代表了一种短暂的基底干细胞状态。在Basal-B细胞中发现了活化的JAK/STAT信号，抑制该信号可显著减少Basal-B标志物的表达。炎症增加了基底-B细胞向腔细胞的转分化，但抑制JAK/STAT可明显减弱这种效应。Pten基因缺失会增加Nkx3.1表达的Basal-B样细胞数量并导致肿瘤。在人类良性前列腺增生中，h-Basal-B细胞更为普遍。这项研究揭示了中间Basal-B细胞的特性，并强调了JAK/STAT信号在前列腺细胞命运决定中的作用。

13.Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype

单细胞多组学分析揭示复杂核型急性髓性白血病的动态克隆进化和靶向表型

德国癌症研究中心、海德堡大学、韩国汉阳大学等机构合作发表

Abstract

Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage–fusion–bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug–response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.

摘要：

染色体不稳定性是瘤内异质性（ITH）的主要驱动因素，可促进肿瘤进展。该研究将结构变异的发现和核小体占位谱分析与单细胞的转录组学和免疫表型变化相结合，研究了复杂核型急性髓性白血病（CK-AML）中的ITH。在CK-AML患者的单个细胞中观察到了复杂的结构变异景观，其特征是线性和环状断裂-融合-桥接循环以及染色体三分裂。在确诊或救治阶段的CK-AML患者中发现了三种克隆进化模式（单克隆、线性和分支多克隆），其中75%的患者携带多个亚克隆，这些亚克隆经常表现出持续的核型重塑。利用源自患者的异种移植，证实了白血病干细胞（LSC）的不同克隆演变，并进一步剖析了亚克隆特异性药物反应谱，以确定针对LSC的疗法，包括BCL-xL抑制剂。在配对的纵向患者样本中进一步揭示了基因进化和细胞类型可塑性作为疾病进展机制的作用。通过剖析CK-AML的动态基因组、表型和功能复杂性，该研究结果为描述和靶向疾病驱动的LSC提供了临床相关的途径。

Volume 57 Issue 1, January 2025

在2025年1月，Nature Genetics共发表30篇文章，其中包括1篇Obituary，4篇Research Highlights，2篇News & Views，2篇Research Briefings，2篇Review Articles，17篇Articles，1篇Analysis，1篇Technical Reports。

1.Fine-mapping causal tissues and genes at disease-associated loci

在疾病关联位点精细定位因果组织和基因

美国哈佛大学、卡内基梅隆大学、加州大学

Abstract

Complex diseases often have distinct mechanisms spanning multiple tissues. We propose tissue–gene fine-mapping (TGFM), which infers the posterior inclusion probability (PIP) for each gene–tissue pair to mediate a disease locus by analyzing summary statistics and expression quantitative trait loci (eQTL) data; TGFM also assigns PIPs to non-mediated variants. TGFM accounts for co-regulation across genes and tissues and models uncertainty in cis-predicted expression models, enabling correct calibration. We applied TGFM to 45 UK Biobank diseases or traits using eQTL data from 38 Genotype–Tissue Expression (GTEx) tissues. TGFM identified an average of 147 PIP > 0.5 causal genetic elements per disease or trait, of which 11% were gene–tissue pairs. Causal gene–tissue pairs identified by TGFM reflected both known biology (for example, TPO–thyroid for hypothyroidism) and biologically plausible findings (for example, SLC20A2–artery aorta for diastolic blood pressure). Application of TGFM to single-cell eQTL data from nine cell types in peripheral blood mononuclear cells (PBMCs), analyzed jointly with GTEx tissues, identified 30 additional causal gene–PBMC cell type pairs.

摘要：

复杂的疾病往往具有跨越多个组织的不同机制。该研究提出了组织-基因精细定位（TGFM），它通过分析汇总统计和表达定量性状位点（eQTL）数据，推断出每个基因-组织配对介导疾病位点的后纳入概率（PIP）；TGFM还为非介导变体分配PIP。TGFM考虑了跨基因和组织的共调控，并对顺式预测表达模型中的不确定性进行建模，从而实现了正确的校准。利用来自38个基因型-组织表达(GTEx)组织的eQTL数据，将TGFM应用于45种英国生物库疾病或性状。TGFM为每种疾病或性状平均鉴定出147个PIP > 0.5的因果遗传因子，其中11%是基因-组织对。TGFM发现的因果基因-组织对既反映了已知的生物学特性（如甲状腺功能减退症的TPO-甲状腺），也反映了生物学上合理的发现（如舒张压的SLC20A2-主动脉）。将TGFM应用于外周血单核细胞（PBMCs）中九种细胞类型的单细胞eQTL数据，并与GTEx组织联合分析，发现了另外30对因果基因-PBMC细胞类型。

2.The impact of common and rare genetic variants on bradyarrhythmia development

常见和罕见基因变异对缓性心律失常发生的影响

美国麻省总医院、麻省理工学院和哈佛大学、赫尔辛基大学等机构合作发表

Abstract

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias.

摘要：

为了深入理解对缓慢性心律失常和传导疾病，该研究对多达130万人进行了常见变体全基因组关联分析，并对46万人进行了窦房结功能障碍（SND）、远端传导疾病（DCD）和起搏器（PM）植入的罕见变体负荷测试。该研究分别为SND、DCD和PM确定了13、31和21个常见变异位点。四个已知的基因位点（SCN5A/SCN10A、CCDC141、TBX20和CAMK2D）是SND和DCD的共有基因位点，而其他基因位点则对SND或DCD更具特异性。SND和DCD显示出中等程度的遗传相关性（rg = 0.63）。心肌细胞表达的基因对DCD遗传性有丰富的贡献。罕见变异分析表明，LMNA与所有缓性心律失常表型有关，SMAD6和SCN5A与DCD有关，TTN、MYBPC3和SCN5A与PM有关。这些结果表明，多种遗传途径（如离子通道功能、心脏发育程序、肉瘤结构和细胞稳态）的变异似乎对缓慢性心律失常的发生至关重要。

3.Blood DNA virome associates with autoimmune diseases and COVID-19

血液 DNA 病毒组与自身免疫性疾病和 COVID-19 有关

日本大阪大学、东京大学、RIKEN综合医学科学中心等机构合作发表

Abstract

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases.

摘要：

对病毒病原体的异常免疫反应是疾病发生的重要机制，但对人类病毒组（尤其是在人群范围内）中病毒引起的病理免疫反应的了解仍然有限。该研究分析了6321名日本人的全基因组测序数据集，其中包括自身免疫性疾病（寻常型银屑病、类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、肺泡蛋白病（PAP）或多发性硬化症）和冠状病毒病2019（COVID-19）患者或健康对照组。系统地量化了血液DNA病毒组的两种成分，即内源性HHV-6（eHHV-6）和anellovirus。eHHV-6B阳性者患系统性红斑狼疮和PAP的风险较高；前者在All of Us中得到了验证。全基因组关联研究和长读长测序绘制了HHV-6B基因组整合到染色体22q上的一个位点。表位图谱和单细胞RNA测序显示，eHHV-6B对系统性红斑狼疮患者具有独特的免疫诱导作用。此外，高anellovirus载量与系统性红斑狼疮、RA和COVID-19状态密切相关。该研究分析揭示了人类病毒组与自身免疫性疾病和传染性疾病之间的关系。

4.Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions

通过对192个风险区域进行多祖先精细定位分析，完善乳腺癌遗传风险和生物学特性

美国范德堡大学、耶鲁大学、国立卫生研究院等机构合作发表

Abstract

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses.

摘要：

全基因组关联研究发现了约200个乳腺癌遗传风险位点，但大部分的因果变异和目标基因尚不清楚。该研究利用来自172,737例女性乳腺癌病例和242,009例非洲、亚洲和欧洲血统对照的全基因组关联研究数据，对所有已知的乳腺癌风险位点进行精细定位分析。发现了332个独立的乳腺癌风险关联信号，其中包括131个以前未报道过的信号；对于其中的50个信号，将可信的因果变异缩小到了单个变异。整合功能基因组学数据的分析确定了195个候选易感基因，这些基因富集在PI3K/AKT、TNF/NF-κB、p53和Wnt/β-catenin通路中。单细胞RNA测序或体外实验数据为105个基因提供了额外的功能证据。该研究发现了大量乳腺癌关联信号和候选易感基因，揭示了乳腺癌遗传学和生物学，并证实了在精细定位分析中纳入多家系细胞数据的价值。

5.ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip

ZIC1是菱形唇中环境依赖性髓母细胞瘤的驱动因子

加拿大多伦多大学、多伦多病童医院、美国麻省总医院和哈佛医学院等机构合作发表

Abstract

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1 mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1 is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1 as an exquisitely context-dependent driver gene in medulloblastoma.

摘要：

转录因子是常见的癌症驱动基因，根据精确的起源细胞表现出显著的特异性。该研究证明，ZIC1在第4组（G4）髓母细胞瘤中通过复发性点突变、亚染色体缺失和单等位表观遗传抑制（占G4髓母细胞瘤的 60%）表现出功能缺失（LOF）体细胞事件。相比之下，高度相似的SHH髓母细胞瘤则表现出截然相反的功能增益突变和拷贝数增加（20%的SHH髓母细胞瘤）。过表达ZIC1可抑制第3组髓母细胞瘤模型的生长，而促进SHH髓母细胞瘤前体细胞的增殖。与野生型ZIC1相比，SHH髓母细胞瘤ZIC1突变体显示出更高的活性，而G4髓母细胞瘤ZIC1突变体则表现出LOF表型。不同的ZIC1突变以截然相反的方式影响菱形唇细胞，这表明ZIC1在正常和转化的菱形唇细胞中都是一个关键的发育转录调控因子，并确定ZIC1是髓母细胞瘤中一个极其依赖环境的驱动基因。

6.Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER

用SPRINTER表征单细胞克隆中癌症增殖的进化动态

英国伦敦大学、英国癌症研究中心、加拿大哥伦比亚大学

Abstract

Proliferation is a key hallmark of cancer, but whether it differs between evolutionarily distinct clones co-existing within a tumor is unknown. We introduce the Single-cell Proliferation Rate Inference in Non-homogeneous Tumors through Evolutionary Routes (SPRINTER) algorithm that uses single-cell whole-genome DNA sequencing data to enable accurate identification and clone assignment of S- and G2-phase cells, as assessed by generating accurate ground truth data. Applied to a newly generated longitudinal, primary-metastasis-matched dataset of 14,994 non-small cell lung cancer cells, SPRINTER revealed widespread clone proliferation heterogeneity, orthogonally supported by Ki-67 staining, nuclei imaging and clinical imaging. We further demonstrated that high-proliferation clones have increased metastatic seeding potential, increased circulating tumor DNA shedding and clone-specific altered replication timing in proliferation- or metastasis-related genes associated with expression changes. Applied to previously generated datasets of 61,914 breast and ovarian cancer cells, SPRINTER revealed increased single-cell rates of different genomic variants and enrichment of proliferation-related gene amplifications in high-proliferation clones.

摘要：

增殖是癌症的一个重要标志，但肿瘤内共存的不同进化克隆之间是否存在差异尚不清楚。该研究介绍了通过进化途径推断非均质肿瘤中的单细胞增殖率（SPRINTER）算法，该算法使用单细胞全基因组DNA测序数据来准确识别和分配S期和G2期细胞的克隆，并通过生成准确的基准真值数据进行评估。将SPRINTER应用于新生成的由14994个非小细胞肺癌细胞组成的纵向、原发-转移匹配数据集，发现了广泛的克隆增殖异质性，Ki-67染色、核成像和临床成像均支持这种异质性。研究进一步证明，高增殖克隆具有更高的转移播种潜力，更高的循环肿瘤 DNA 释放量，以及与表达变化相关的增殖或转移相关基因的克隆特异性复制时间发生改变。将SPRINTER应用于之前生成的61,914个乳腺癌和卵巢癌细胞数据集，发现高增殖克隆中不同基因组变异的单细胞率增加，增殖相关基因扩增丰富。

7.Comprehensive genomic characterization of early-stage bladder cancer

早期膀胱癌的全面基因组特征描述

丹麦奥胡斯大学、哥本哈根大学、奥尔堡大学等机构合作发表

Abstract

Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification.

摘要：

了解非肌层浸润性膀胱癌（NMIBC）的分子图谱对于改进风险评估和治疗方案至关重要。该研究使用全外显子组测序（438例）、浅层全基因组测序（362例）和总RNA测序（414例）对NMIBC患者进行了全面的基因组分析。在NMIBC中观察到大量基因组变异，并与不同的分子亚型相关。在FGFR3和TP53发生突变的肿瘤中，分别发现了FGFR3和17p（影响TP53）的频繁杂合性缺失。在15%的肿瘤中观察到了全基因组倍增（WGD），这与较差的预后有关。出现全基因组倍增的肿瘤基因组不稳定，细胞周期相关基因发生改变，免疫组成也发生改变。最后，多组学数据的综合聚类突显了基因组不稳定性和免疫细胞衰竭在疾病侵袭性中的重要作用。这些发现加深了对与NMIBC疾病侵袭性相关的基因组差异的理解，并可能最终改善对患者的分层。

8.Multi-omic profiling highlights factors associated with resistance to immuno-chemotherapy in non-small-cell lung cancer

多组学分析凸显非小细胞肺癌免疫化疗耐药性的相关因素

上海同济大学、中国科学院大学

Abstract

Although immune checkpoint blockade (ICB) therapies have shifted the treatment paradigm for non-small-cell lung cancer (NSCLC), many patients remain resistant. Here we characterize the tumor cell states and spatial cellular compositions of the NSCLC tumor microenvironment (TME) by analyzing single-cell transcriptomes of 232,080 cells and spatially resolved transcriptomes of tumors from 19 patients before and after ICB–chemotherapy. We find that tumor cells and secreted phosphoprotein 1-positive macrophages interact with collagen type XI alpha 1 chain-positive cancer-associated fibroblasts to stimulate the deposition and entanglement of collagen fibers at tumor boundaries, obstructing T cell infiltration and leading to poor prognosis. We also reveal distinct states of tertiary lymphoid structures (TLSs) in the TME. Activated TLSs are associated with improved prognosis, whereas a hypoxic microenvironment appears to suppress TLS development and is associated with poor prognosis. Our study provides novel insights into different cellular and molecular components corresponding to NSCLC ICB–chemotherapeutic responsiveness, which will benefit future individualized immuno-chemotherapy.

摘要：

尽管免疫检查点阻断（ICB）疗法改变了非小细胞肺癌（NSCLC）的治疗模式，但许多患者仍有耐药性。该研究通过分析ICB化疗前后19位患者232,080个细胞的单细胞转录组和肿瘤的空间分辨转录组，描述了NSCLC肿瘤微环境（TME）的肿瘤细胞状态和空间细胞组成。研究发现，肿瘤细胞和分泌型磷蛋白1阳性巨噬细胞与胶原XI型α1链阳性癌相关成纤维细胞相互作用，刺激胶原纤维在肿瘤边界沉积和缠结，阻碍T细胞浸润，导致预后不良。研究还揭示了TME中三级淋巴结构（TLS）的不同状态。活化的三级淋巴结构与预后改善有关，而缺氧的微环境似乎会抑制三级淋巴结构的发展，并与预后不良有关。该研究为了解与NSCLC ICB化疗反应性相对应的不同细胞和分子成分提供了新的视角，这将有利于未来的个体化免疫化疗。

9.Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations

深度CRISPR诱变表征了TP53突变的功能多样性

德国菲利普斯大学、歌德大学等机构合作发表

Abstract

The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy.

摘要：

TP53是一种肿瘤抑制因子，在大约一半的癌症中发生突变，其突变情况包括2000多种已知的错义突变。要充分利用TP53的突变状态进行个性化医疗，就必须全面了解这些突变的功能多样性。该研究利用CRISPR介导的同源定向修复饱和基因组编辑技术对癌细胞中的9225个TP53变异进行了深度突变扫描。这种高分辨率方法覆盖了94.5%的癌症相关TP53错义突变，精确地描绘了单个突变对肿瘤细胞健康的影响，在区分良性和致病性变异方面超越了以往的深度突变扫描研究。研究结果甚至揭示了细微的功能缺失表型，并确定了有希望进行药物再激活的突变体。此外，研究还发现了剪接改变和无义介导的信使RNA衰减在突变驱动的TP53功能障碍中的作用。这些发现凸显了饱和基因组编辑在推进临床TP53变异解读，促进遗传咨询和个性化癌症治疗方面的作用。

10.A multilineage screen identifies actionable synthetic lethal interactions in human cancers

多线程筛选确定人类癌症中可操作的合成致死相互作用

美国加州大学圣地亚哥分校

Abstract

Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies.

摘要：

癌症是由不同基因的改变驱动的，从而产生了可作为治疗靶点的依赖性。然而，许多基因依赖关系在不同肿瘤中并不一致。该研究介绍了SCHEMATIC，这是一种识别高穿透性、可操作的基因相互作用核心网络的策略。首先，通过系统性的组合基因敲除，扰乱各肿瘤系的基本细胞过程，识别出1805种合成致死相互作用（95%未报道）。然后通过分层汇集对相互作用进行分析，结果显示，一半的相互作用能通过组织类型或生物标记物状态可靠地分离出来（51%），相当少数的相互作用能跨系渗透（34%）。相互作用集中在49个多基因系统上，包括MAPK信号转导和BAF转录调控复合物，它们在聚合酶被破坏时变得至关重要。66种相互作用可转化为药物敏感性的可靠生物标志物，包括KDM5C/6A组蛋白去甲基化酶的频繁基因改变，这种改变对TIPARP (PARP7)的抑制作用敏感。SCHEMATIC提供了一种情境感知、数据驱动的方法，将基因改变与靶向疗法相匹配。

11.Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A–menin to bivalent promoters

Kmt2c或Kmt2d的缺失会使尿路上皮细胞形成肿瘤，并将KMT2A-menin重新分配到二价启动子上

美国纪念斯隆凯特琳癌症中心、国立卫生研究院、康奈尔大学

Abstract

Members of the KMT2C/D–KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation. Kmt2c/d knockout further led to KMT2A–menin redistribution from KMT2D localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes. Therapeutically, Kmt2c/d knockout upregulated epidermal growth factor receptor signaling and conferred vulnerability to epidermal growth factor receptor inhibitors. Together, our data posit that functional loss of Kmt2c/d licenses a molecular ‘field effect’ priming histologically normal urothelium for oncogenic transformation and presents therapeutic vulnerabilities.

摘要：

KMT2C/D-KDM6A复合物成员在尿路上皮癌和组织学正常的尿路上皮中反复发生突变。该研究利用基因工程小鼠模型证明，Kmt2c/d基因敲除会导致尿路细胞分化受损、对生长和炎症刺激的反应增强以及对致癌物质和致癌物质的致癌转化敏感。从机理上讲，KMT2D定位于活性增强子和CpG贫乏的启动子，它们优先调控尿路细胞系程序，Kmt2c/d基因敲除导致这些位点的H3K4me1、H3K27ac和新生RNA转录减少，从而导致分化受损。Kmt2c/d基因敲除进一步导致KMT2A-menin从KMT2D定位的增强子重新分布到CpG-高和二价启动子，从而导致信号诱导的即刻早期基因受到抑制。从治疗角度看，Kmt2c/d基因敲除会上调表皮生长因子受体信号转导，并使患者易受表皮生长因子受体抑制剂的影响。综上所述，该研究数据推测，Kmt2c/d的功能性缺失会产生分子“场效应”，使组织学上正常的尿路上皮细胞发生致癌转化，并带来治疗上的脆弱性。

12.Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits

脂肪组织eQTL meta分析凸显等位基因异质性对基因表达调控和心脏代谢特征的贡献

美国北卡罗来纳大学、密歇根大学、英国伦敦国王学院等机构合作发表

Abstract

Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared with primary eQTL signals, nonprimary eQTL signals had lower effect sizes, lower minor allele frequencies and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTLs with genome-wide association study (GWAS) signals for 28 cardiometabolic traits identified 1,835 genes. Inclusion of nonprimary eQTL signals increased discovery of colocalized GWAS–eQTL signals by 46%. Furthermore, 21 genes with ≥2 colocalized GWAS–eQTL signals showed a mediating gene dosage effect on the GWAS trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

摘要：

要阐明组织生物学和复杂性状的病因学，就需要完整描述基因表达的遗传效应。该研究分析了2,344份皮下脂肪组织样本，在18,476个基因上确定了34,774个条件不同的表达定量性状位点（eQTL）信号。一半以上的eQTL基因至少有两个eQTL信号。与一级eQTL信号相比，非一级eQTL信号的效应大小较低、小等位基因频率较低、启动子富集程度较低；它们对应于遗传率较高和对功能缺失耐受性较高的基因。针对28个心脏代谢特征的eQTL与全基因组关联研究（GWAS）信号的共定位发现了1,835个基因。纳入非主要eQTL信号后，共定位GWAS-eQTL信号的发现率提高了46%。此外，有21个基因的共定位GWAS-eQTL信号≥2个，显示出基因剂量对GWAS性状的中介效应。因此，扩大的eQTL鉴定揭示了更多复杂性状的内在机制，并增进了对基因表达调控复杂性的了解。

13.Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits

联合代谢组学与外显子组测序揭示了罕见损伤性杂合变异对基因功能和人类性状的分级影响

德国弗莱堡大学、格赖夫斯瓦尔德大学、美国约翰霍普金斯大学等机构合作发表

Abstract

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene–metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height and pinpointed alleles associated with increased odds of diverse musculoskeletal traits and diseases in the population. This integrative approach can identify new players in incompletely characterized human metabolic reactions and reveal metabolic readouts informative of human traits and diseases.

摘要：

代谢组的基因研究可以揭示影响人体代谢的酶和转运过程。利用基于全外显子组测序数据的罕见变异聚合测试，检测与1,294种血浆和1,396种尿液代谢物水平相关的基因，发现了235种基因与代谢物的关联，其中许多以前从未报道过。互补方法（遗传、计算（在人体代谢全身模型中进行基因敲除）和一个实验性原理证明）提供了正交的证据，证明对杂合状态下罕见的破坏性变异的研究可以得出与先天性代谢错误的研究一致的推论。负责跨细胞硫酸盐重吸收的转运体（SLC13A1、SLC26A1）的功能变体等位基因系列对血浆硫酸盐和人的身高有不同程度的影响，并确定了与人群中各种肌肉骨骼特征和疾病发生几率增加有关的等位基因。这种综合方法可以在特征不完全的人类代谢反应中发现新的参与者，并揭示出与人类特征和疾病相关的代谢读数。

14.Gene regulation by convergent promoters

收敛启动子的基因调控

德国莱布尼茨老龄化研究所、达姆施塔特工业大学、美国纽约州立大学

Abstract

Convergent transcription, that is, the collision of sense and antisense transcription, is ubiquitous in mammalian genomes and believed to diminish RNA expression. Recently, antisense transcription downstream of promoters was found to be surprisingly prevalent. However, functional characteristics of affected promoters are poorly investigated. Here we show that convergent transcription marks an unexpected positively co-regulated promoter constellation. By assessing transcriptional dynamic systems, we identified co-regulated constituent promoters connected through a distinct chromatin structure. Within these cis-regulatory domains, transcription factors can regulate both constituting promoters by binding to only one of them. Convergent promoters comprise about a quarter of all active transcript start sites and initiate 5′-overlapping antisense RNAs—an RNA class believed previously to be rare. Visualization of nascent RNA molecules reveals convergent cotranscription at these loci. Together, our results demonstrate that co-regulated convergent promoters substantially expand the cis-regulatory repertoire, reveal limitations of the transcription interference model and call for adjusting the promoter concept.

摘要：

收敛转录，即有义和反义转录的碰撞，在哺乳动物基因组中无处不在，被认为会降低RNA的表达。最近，人们发现启动子下游的反义转录惊人地普遍。然而，对受影响的启动子的功能特征研究甚少。该研究发现，收敛转录标志着一个意想不到的正向共调启动子群。通过评估转录动态系统，确定了通过不同染色质结构连接的共调成分启动子。在这些顺式调控域中，转录因子只需与其中一个结合，就能调控两个组成启动子。收敛启动子约占所有活性转录本起始位点的四分之一，并能启动5’重叠的反义RNA--一种以前认为罕见的RNA类别。新生RNA分子的可视化显示了这些位点上的相向共转录。研究结果表明，共调收敛启动子大大扩展了顺式调节的范围，揭示了转录干扰模型的局限性，并呼吁调整启动子的概念。

Volume 57 Issue 2, February 2025

在2025年2月，Nature Genetics共发表28篇文章，其中包括1篇Comment，4篇Research Highlights，2篇News & Views，1篇Research Briefings，1篇Perspectives，1篇Review Articles，1篇Brief Communications，1篇Letters，11篇Articles，3篇Technical Reports，2篇Amendments & Corrections。

1.Prioritizing effector genes at trait-associated loci using multimodal evidence

利用多模态证据确定性状相关位点效应基因的优先顺序

荷兰阿姆斯特丹神经科学大学、阿姆斯特丹自由大学、英国卡迪夫大学

Abstract

Genome-wide association studies (GWAS) yield large numbers of genetic loci associated with traits and diseases. Predicting the effector genes that mediate these locus-trait associations remains challenging. Here we present the FLAMES (fine-mapped locus assessment model of effector genes) framework, which predicts the most likely effector gene in a locus. FLAMES creates machine learning predictions from biological data linking single-nucleotide polymorphisms to genes, and then evaluates these scores together with gene-centric evidence of convergence of the GWAS signal in functional networks. We benchmark FLAMES on gene-locus pairs derived by expert curation, rare variant implication and domain knowledge of molecular traits. We demonstrate that combining single-nucleotide-polymorphism-based and convergence-based modalities outperforms prioritization strategies using a single line of evidence. Applying FLAMES, we resolve the FSHB locus in the GWAS for dizygotic twinning and further leverage this framework to find schizophrenia risk genes that converge with rare coding evidence and are relevant in different stages of life.

摘要：

全基因组关联研究（GWAS）发现了大量与性状和疾病相关的基因位点。预测介导这些位点-性状关联的效应基因仍然具有挑战性。该研究介绍了FLAMES（效应基因精细映射位点评估模型）框架，它可以预测一个位点中最可能的效应基因。FLAMES从连接单核苷酸多态性与基因的生物数据中创建机器学习预测，然后将这些分数与功能网络中以基因为中心的GWAS信号收敛证据一起进行评估。通过专家策划、罕见变异影响和分子性状领域知识得出基因-病灶对，以此对FLAMES进行了基准测试。结果证明，将基于单核苷酸多态性的模式和基于趋同性的模式相结合，其效果优于使用单一证据的优先排序策略。应用FLAMES，解决了双卵孪生子GWAS中的FSHB基因座问题，并进一步利用这一框架找到了与罕见编码证据趋同且与人生不同阶段相关的精神分裂症风险基因。

2.Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups

对392,522名男性进行的前列腺特异性抗原水平全基因组关联研究确定了新的基因位点，并提高了对不同血统群体的预测能力

美国加州大学、斯坦福大学、南加州大学等机构合作发表

Abstract

We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10−8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.

摘要：

该研究对96,754名男性（211,342人具有欧洲血统，58,236人具有非洲血统，23,546人具有西班牙/拉丁美洲血统，3,630人具有亚洲血统；96.5%的参与者来自“百万退伍军人计划”）的前列腺特异性抗原(PSA)水平进行了多种族全基因组关联研究。发现了318个独立的全基因组显著变异（P≤5×10-8），其中184个是新变异。大多数变异在独立队列（n = 95,768）中都有复制证据。对发现和复制（n = 392,522个）进行meta分析后发现了447个变异体，其中111个为新型变异体。全基因组多基因风险评分所解释的PSA样本外变异率为：欧洲血统11.6%至16.6%，非洲血统5.5%至9.5%，西班牙/拉丁美洲血统13.5%至18.2%，亚洲血统8.6%至15.3%，且预测效能随年龄增长而降低。与未经调整的PSA水平相比，中年期经基因调整的PSA水平与总体前列腺癌和侵袭性前列腺癌的相关性更强。该研究强调了如何通过按比例增加来自代表性不足人群的参与者来改善PSA水平的遗传预测，从而为个性化前列腺癌筛查提供可能。

3.Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease

综合蛋白质基因组分析确定 COL6A3 衍生的内营养素是肥胖对冠状动脉疾病影响的介质

加拿大麦吉尔大学、多伦多大学、威斯康星大学等机构合作发表

Abstract

Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity strongly influences circulating protein levels, we investigated proteins mediating the effects of obesity on coronary artery disease, stroke and type 2 diabetes. By integrating two-step proteome-wide Mendelian randomization, colocalization, epigenomics and single-cell RNA sequencing, we identified five mediators and prioritized collagen type VI α3 (COL6A3). COL6A3 levels were strongly increased by body mass index and increased coronary artery disease risk. Notably, the carboxyl terminus product of COL6A3, endotrophin, drove this effect. COL6A3 was highly expressed in disease-relevant cell types and tissues. Finally, we found that body fat reduction could reduce plasma levels of COL6A3-derived endotrophin, indicating a tractable way to modify endotrophin levels. In summary, we provide actionable insights into how circulating proteins mediate the effects of obesity on cardiometabolic diseases and prioritize endotrophin as a potential therapeutic target.

摘要：

肥胖会大大增加罹患心血管代谢疾病的风险，但这种关系的潜在介导因素尚未完全明了。鉴于肥胖会强烈影响循环蛋白质水平，该研究探索了介导肥胖对冠心病、中风和2型糖尿病影响的蛋白质。通过整合两步全蛋白质组孟德尔随机化、共定位、表观基因组学和单细胞RNA测序，确定了五个介导因子，并优先选择了VI型胶原蛋白α3（COL6A3）。体重指数和冠状动脉疾病风险的增加都会显著提高COL6A3的水平。值得注意的是，COL6A3的羧基末端产物--内营养素--也会产生这种效应。COL6A3在与疾病相关的细胞类型和组织中高度表达。最后，研究发现减少体内脂肪可以降低血浆中COL6A3衍生的内营养素水平，这表明改变内营养素水平的方法是可行的。总之，该研究就循环蛋白如何介导肥胖对心脏代谢疾病的影响提供了可行的见解，并将内营养素列为潜在的治疗靶点。

4.Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes

人脑表型的细胞状态依赖性等位基因效应和上下文孟德尔随机分析

英国帝国理工学院、牛津大学、伦敦大学等机构合作发表

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.

摘要：

基因表达量性状位点被广泛用于推断基因与中枢神经系统（CNS）表型之间的关系；然而，脑部疾病对这些推断的影响尚不清楚。利用来自391个疾病病例和对照组大脑的2,348,438个单核图谱，该研究报告了13,939个基因的表达与遗传变异相关，其中16.7%-40.8%（取决于细胞类型）显示出疾病依赖性等位基因效应。在30个中枢神经系统性状的501个共轭基因中，有23.6%的基因具有疾病依赖性，即使在调整了疾病状态之后也是如此。为了估算基因对结果的无约束效应，使用未患病大脑（n = 183）重复进行了分析，并报告了在更大的疾病和对照混合数据集中不存在的另外91个共定位，这表明对疾病相关变异的解释得到了加强。在仅有对照的大脑中原则性地实施单细胞孟德尔随机化，发现了140个潜在因果关系的基因-性状关联，其中11个在英国生物库中得到了验证，优先选择了可预测中枢神经系统结果的候选外周生物标记物。

5.Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain

多组学定量性状位点将串联重复大小变异与人脑基因调控联系起来

美国加州大学、加利福尼亚大学、德国乌尔姆大学

Abstract

Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease.

摘要：

串联重复（TR）大小变异与约50种神经系统疾病有关，但它对人脑基因调控的影响在很大程度上仍不为人所知。该研究基于来自1,597名供体的4,412份多组学样本（包括1,586份新测序样本），量化了TR大小变异对不同分子表型的大脑基因调控的影响。确定了约220万个TR分子定量性状位点（TR-xQTLs），将约13.9万个独特的TR与附近的分子表型联系起来，包括许多已知的疾病风险TR，如与肌萎缩侧索硬化症相关的C9orf72中的G2C4扩增。精细定位显示，约有18,700个TR是潜在的致病变异。体外实验进一步证实了三个TRs的因果关系和独立调控效应。额外的共定位分析表明了TR变异在大脑相关表型中的潜在因果作用，NUDT14中的3ʹ-UTR TR与大脑皮层表面积有关，PLEKHA1中的TG重复与阿尔茨海默病有关。

6.Fine-scale population structure and widespread conservation of genetic effect sizes between human groups across traits

人类群体之间的精细种群结构和广泛保守的遗传效应大小在不同特征之间保持一致

英国牛津大学、伦敦大学、布里斯托大学

Abstract

Understanding genetic differences between populations is essential for avoiding confounding in genome-wide association studies and improving polygenic score (PGS) portability. We developed a statistical pipeline to infer fine-scale Ancestry Components and applied it to UK Biobank data. Ancestry Components identify population structure not captured by widely used principal components, improving stratification correction for geographically correlated traits. To estimate the similarity of genetic effect sizes between groups, we developed ANCHOR, which estimates changes in the predictive power of an existing PGS in distinct local ancestry segments. ANCHOR infers highly similar (estimated correlation 0.98 ± 0.07) effect sizes between UK Biobank participants of African and European ancestry for 47 of 53 quantitative phenotypes, suggesting that gene–environment and gene–gene interactions do not play major roles in poor cross-ancestry PGS transferability for these traits in the United Kingdom, and providing optimism that shared causal mutations operate similarly in different populations.

摘要：

了解不同人群之间的遗传差异对于避免全基因组关联研究中的混杂和提高多基因评分（PGS）的可移植性至关重要。该研究开发了一个统计流程来推断精细尺度的祖先成分，并将其应用于英国生物库数据。祖先成分能识别广泛使用的主成分无法捕捉的种群结构，从而改善地理相关性状的分层校正。为了估算群体间遗传效应大小的相似性，研究开发了ANCHOR，用于估算不同地方祖先区段中现有PGS预测能力的变化。ANCHOR推断出英国生物库中非洲裔和欧洲裔参与者在53个定量表型中的47个表型上的效应大小高度相似（估计相关性为0.98±0.07），这表明在英国，基因-环境和基因-基因相互作用并没有在这些性状的跨祖先PGS可转移性差中发挥主要作用，并为共享的因果突变在不同人群中的相似运作提供了乐观的预期。

7.Structural polymorphism and diversity of human segmental duplications

人类片段重复的结构多态性和多样性

美国华盛顿大学、杰克逊基因组医学实验室、堪萨斯城儿童慈善医院和密苏里大学

Abstract

Segmental duplications (SDs) contribute significantly to human disease, evolution and diversity but have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies (from 85 samples representing 38 Africans and 47 non-Africans) in which the majority of autosomal SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms and sex chromosomes, we identify 173.2 Mb of duplicated sequence (47.4 Mb not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable, with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy numbers than non-African samples. Comparison to a resource of 563 million full-length isoform sequencing reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs.

摘要：

片段重复（SD）对人类疾病、进化和多样性有重要影响，但却很难在序列水平上解决。该研究通过分析170个人类基因组组装（来自代表38个非洲人和47个非非洲人的85个样本），对SDs进行了群体遗传学调查。除去同心短臂和性染色体，发现了173.2 Mb的重复序列（47.4 Mb的重复序列不存在于端粒到端粒的参考序列中），这些重复序列区分了固定多态和结构多态事件。研究发现，染色体内SD是最多变的，罕见事件映射在其祖先序列附近。与非洲以外的样本相比，非洲基因组中染色体内SD明显较多，而且更有可能出现拷贝数较高的新近重复的基因家族。通过与5.63亿个全长同工酶测序读数资源进行比较，发现了与这些拷贝数多态性SD相对应的201个可能编码蛋白质的新基因。

8.Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

癌胎重编程驱动WNT依赖性结直肠癌的表型可塑性

美国西奈山伊坎医学院、德国马克斯·德尔布吕克分子医学中心、新加坡科学技术研究局等机构合作发表

Abstract

Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5+ CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF ‘memory’ sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5+ states in isolation is constrained by their functional redundancy. Although the canonical LGR5+ state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment.

摘要：

靶向癌症干细胞（CSCs）是有效治疗癌症的关键，然而在WNT驱动的结直肠癌（CRC）中，LGR5+ CSC耗竭的抗性机制仍然难以捉摸。该研究发现突变的肠干细胞（SCs）偏离了其典型特征，呈现动态表型谱转变。这种增强的可塑性是由YAP和AP-1驱动的癌胎（OnF）重编程启动的，随后的AP-1超活化促进了谱系不忠。视黄醇X受体是OnF重编程的看门人，在腺瘤性息肉病大肠杆菌（APC）功能丧失后，视黄醇X受体的失调建立了由YAP和AP-1维持的OnF “记忆”。值得注意的是，OnF和LGR5+状态的临床意义因其功能冗余而受到限制。虽然典型的LGR5+状态对FOLFIRI方案敏感，但活跃的OnF程序与耐药性相关，支持其在驱动耐药状态中的作用。将这一程序与目前的标准疗法相结合是实现有效、持久的CRC治疗的关键。

9.Human subcutaneous and visceral adipocyte atlases uncover classical and nonclassical adipocytes and depot-specific patterns

人类皮下和内脏脂肪细胞图谱揭示了经典和非经典脂肪细胞以及脂肪库特异性模式

以色列内盖夫本古里安大学、马卡比医疗保健服务公司等机构合作发表

Abstract

Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA sequencing (snRNA-seq) analyses largely uncovered overlapping or similar cell-type landscapes. We hypothesized that adipocyte subtypes, differentiation trajectories and/or intercellular communication patterns could illuminate this depot similarity–difference gap. For this, we performed snRNA-seq of human subcutaneous or visceral adipose tissues (five or ten samples, respectively). Of 27,665 adipocyte nuclei in both depots, most were ‘classical’, namely enriched in lipid metabolism pathways. However, we also observed ‘nonclassical’ adipocyte subtypes, enriched in immune-related, extracellular matrix deposition (fibrosis), vascularization or angiogenesis or ribosomal and mitochondrial processes. Pseudo-temporal analysis showed a developmental trajectory from adipose progenitor cells to classical adipocytes via nonclassical adipocytes, suggesting that the classical state stems from loss, rather than gain, of specialized functions. Last, intercellular communication routes were consistent with the different inflammatory tone of the two depots. Jointly, these findings provide a high-resolution view into the contribution of cellular composition, differentiation and intercellular communication patterns to human fat depot differences.

摘要：

人类脂肪库在功能上各不相同。然而，最近的单核RNA测序（snRNA-seq）分析在很大程度上发现了重叠或相似的细胞类型现象。该研究假设，脂肪细胞亚型、分化轨迹和/或细胞间通信模式可能会揭示脂肪库相似性与差异性之间的差距。为此，该研究对人体皮下或内脏脂肪组织（分别为五个或十个样本）进行了snRNA-seq分析。在这两个组织中的27,665个脂肪细胞核中，大多数是“经典”的，即富含脂质代谢途径。不过，也观察到了“非典型”脂肪细胞亚型，它们富集于免疫相关、细胞外基质沉积（纤维化）、血管形成或血管生成或核糖体和线粒体过程。拟时序分析显示了从脂肪祖细胞到经典脂肪细胞再到非经典脂肪细胞的发育轨迹，表明经典状态源于特化功能的丧失而非获得。最后，细胞间的通讯途径与两个脂肪库不同的炎症基调相一致。这些发现共同提供了一个高分辨率的视角，有助于了解细胞组成、分化和细胞间通讯模式对人体脂肪库差异的贡献。

Volume 57 Issue 3, March 2025

在2025年3月，Nature Genetics共发表38篇文章，其中包括1篇Comment，4篇Research Highlights，2篇News & Views，3篇Research Briefings，2篇Perspectives，4篇Letters，19篇Articles，3篇Amendments & Corrections。

1.Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

对50,000多例病例进行测序，确定了心房颤动风险的编码和结构变异基础

美国麻省理工学院、哈佛大学、波士顿大学等机构合作发表

Abstract

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

摘要：

心房颤动（房颤）是一种常见的心律失常，发病率高，与遗传因素密切相关。该研究对来自36项研究的基因组和外显子组测序数据进行了meta分析，这些研究包括52,416例房颤病例和277,762例对照。在罕见编码变异的负荷测试中，发现房颤与MYBPC3、LMNA、PKP2、FAM189A2和KDM5B基因之间存在新的关联。研究进一步确定了房颤与CTNNA3基因缺失和GATA4基因重复导致的罕见结构变异之间的关联。在来自MyCode、deCODE和英国生物库的独立样本中广泛验证了该发现。最后，研究发现在干细胞衍生的心房心肌细胞中CRISPR敲除KDM5B会导致动作电位持续时间缩短以及心房稳态和传导相关基因的广泛转录组失调。该研究结果突显了罕见编码和结构变异对房颤的贡献，包括房颤和心肌病之间的遗传联系，并拓展了对这种常见心律失常的罕见变异结构的理解。

2.Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings

评估普通人群和不同临床环境中肥厚型心肌病的多基因评分

英国帝国理工学院、皇家布朗普顿和哈尔菲尔德医院、荷兰阿姆斯特丹大学等机构合作发表

Abstract

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.

摘要：

肥厚型心肌病（HCM）是发病和死亡的重要原因，约有三分之一的病例存在致病变异。大规模的全基因组关联研究（GWAS）表明，常见的遗传变异会导致 HCM 风险。该研究从HCM GWAS和遗传相关性状中得出了多基因评分（PGS），并在英国生物库、10万基因组计划和临床队列中对其性能进行了测试。研究表明，较高的PGS会显著增加普通人群罹患HCM的风险，尤其是在致病变异携带者中，PGS最高和最低五分位数的HCM穿透性相差10 倍。在HCM疑似者的亲属中，PGS可将患HCM和不良后果的风险分层。最后，在HCM病例中，PGS可有力预测不良后果和死亡风险。这些发现支持了PGS在临床环境中的广泛用途，使其能够进行有针对性的筛查和监测，并对不良后果的风险进行分层。

3.Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis

墨西哥城前瞻性研究与英国生物库的比较分析确定了祖先对克隆造血的特异性影响

阿斯利康公司、剑桥大学、牛津大学等机构合作发表

Abstract

The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10−185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10−19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.

摘要：

遗传血统对克隆造血（CH）发展的影响在很大程度上仍未得到探讨。该研究比较了墨西哥城前瞻性研究（MCPS）136401名参与者和英国生物库（UKB）416118名参与者的克隆性造血（CH）情况，结果发现，与英国生物库相比，墨西哥城前瞻性研究参与者的克隆性造血（CH）发生率明显较低（调整后的比值比= 0.59，95% 置信区间 (CI) = [0.57, 0.61]，P = 7.31×10-185）。在MCPS参与者中，CH频率与欧洲血统的百分比呈正相关（调整后的β值= 0.84，95% CI = [0.66，1.03]，P = 7.35×10-19）。对MCPS进行的全基因组和全外显子组关联分析发现，TCL1B位点上的祖先特异性变异对DNMT3A-CH和非DNMT3A-CH的影响截然相反。对MCPS和UKB的meta分析发现了五个与CH相关的新基因位点，包括PARP11/CCND2、MEIS1和MYCN的多态性。该CH研究是迄今为止在非欧洲人群中开展的规模最大的研究，它证明了跨种属比较在深入了解CH发病机制方面的作用。

4.Comparison of the multivariate genetic architecture of eight major psychiatric disorders across sex

八种主要精神疾病的多变量遗传结构的性别比较

美国密歇根州立大学、麻省总医院和哈佛医学院等机构合作发表

Abstract

Differences in the patterning of genetic sharing between groups of individuals may arise from biological pathways, social mechanisms, phenotyping and ascertainment. We expand genomic structural equation modeling to allow for testing genomic structural invariance (GSI), that is, the formal comparison of multivariate genetic architecture across groups. We apply GSI to compare the autosomal multivariate genetic architecture of eight psychiatric disorders spanning three factors (psychotic, neurodevelopmental and internalizing) between cisgender males and females. We find that the genetic factor structure is largely similar across sex, permitting meaningful comparisons of associations at the level of the factors. However, in females, problematic alcohol use and posttraumatic stress disorder loaded more strongly on the internalizing factor, while the neurodevelopmental disorder factor exhibited weaker genetic correlations with the other factors. Four phenotypes (educational attainment, insomnia, smoking and deprivation) showed significant, albeit small, sex-differentiated associations with the psychotic factor. As genome-wide association study samples grow and diversify, GSI will become increasingly valuable for comparing multivariate genetic architecture across groups.

摘要：

个体群体间遗传共享模式的差异可能来自生物途径、社会机制、表型和确定。该研究扩展了基因组结构方程模型，以便测试基因组结构不变性（GSI），即对不同群体的多变量遗传结构进行正式比较。研究应用GSI比较了顺性别男性和女性之间在三个因子下（精神病、神经发育和内化）的八种精神疾病的常染色体多变量遗传结构。结果发现，不同性别的遗传因子结构基本相似，因此可以在因子水平上对相关性进行有意义的比较。然而，在女性中，酗酒问题和创伤后应激障碍对内化因子的影响更大，而神经发育障碍因子与其他因子的遗传相关性较弱。四种表型（受教育程度、失眠、吸烟和贫困）与精神病因子有显著的性别差异关联，尽管这种关联很小。随着全基因组关联研究样本的增加和多样化，GSI在比较不同群体的多变量遗传结构方面将变得越来越有价值。

5.Multiomic single-cell profiling identifies critical regulators of postnatal brain

多组学单细胞图谱确定出生后大脑的关键调控因子

美国西奈山伊坎医学院

Abstract

Human brain development spans from embryogenesis to adulthood, with dynamic gene expression controlled by cell-type-specific cis-regulatory element activity and three-dimensional genome organization. To advance our understanding of postnatal brain development, we simultaneously profiled gene expression and chromatin accessibility in 101,924 single nuclei from four brain regions across ten donors, covering five key postnatal stages from infancy to late adulthood. Using this dataset and chromosome conformation capture data, we constructed enhancer-based gene regulatory networks to identify cell-type-specific regulators of brain development and interpret genome-wide association study loci for ten main brain disorders. Our analysis connected 2,318 cell-specific loci to 1,149 unique genes, representing 41% of loci linked to the investigated traits, and highlighted 55 genes influencing several disease phenotypes. Pseudotime analysis revealed distinct stages of postnatal oligodendrogenesis and their regulatory programs. These findings provide a comprehensive dataset of cell-type-specific gene regulation at critical timepoints in postnatal brain development.

摘要：

人类大脑的发育跨越了胚胎发生到成年期，其动态基因表达受细胞类型特异性顺式调控元件活性和三维基因组组织的控制。为了加深对出生后大脑发育的了解，该研究同时分析了来自十个供体四个脑区的101,924个单个细胞核的基因表达和染色质可及性，涵盖了从婴儿到成年晚期的五个关键出生后阶段。利用该数据集和染色体构象捕获数据，构建了基于增强子的基因调控网络，以确定大脑发育的细胞类型特异性调控因子，并解释十种主要脑部疾病的全基因组关联研究位点。该研究分析将2,318个细胞特异性基因座与1,149个独特基因连接起来，占与所研究性状相关基因座的41%，并突出显示了影响多种疾病表型的55个基因。拟时序分析揭示了出生后少突发生的不同阶段及其调控程序。这些发现提供了一个全面的数据集，说明在出生后大脑发育的关键时间点上细胞类型特异性基因的调控情况。

6.Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing

人类小胶质细胞同工酶的长读长RNA测序图谱阐明了与疾病相关的剪接基因调控

美国西奈山伊坎医学院、西班牙康普顿斯大学等机构合作发表

Abstract

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. Mapping the genetics of gene expression in human microglia has identified several loci associated with disease-associated genetic variants in microglia-specific regulatory elements. However, identifying genetic effects on splicing is challenging because of the use of short sequencing reads. Here, we present the isoform-centric microglia genomic atlas (isoMiGA), which leverages long-read RNA sequencing to identify 35,879 novel microglia isoforms. We show that these isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ancestry meta-analysis of 555 human microglia short-read RNA sequencing samples from 391 donors, and found associations with genetic risk loci in Alzheimer’s and Parkinson’s disease. We nominate several loci that may act through complex changes in isoform and splice-site usage.

摘要：

小胶质细胞是中枢神经系统的先天性免疫细胞，其基因与多种神经退行性疾病有关。绘制人类小胶质细胞基因表达的遗传学图谱已经确定了几个与小胶质细胞特异性调控元件中疾病相关遗传变异有关的位点。然而，由于使用短读长测序技术的局限性，确定基因对剪接的影响具有挑战性。该研究展示了以转录本异构体为中心的小胶质细胞基因组图谱（isoMiGA），该图谱利用长读长RNA测序鉴定出35879种新型小胶质细胞转录本异构体。研究发现这些异构体参与刺激反应和脑区特异性。然后对来自391名供体的555份人类小胶质细胞短读长RNA测序样本进行了多巢荟萃分析，量化了已知和新型异构体的表达，发现它们与阿尔茨海默氏症和帕金森氏症的遗传风险位点有关。该研究提名了几个可能通过转录本异构体和剪接位点使用的复杂变化发挥作用的位点。

7.The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes

血液基因表达和剪接的遗传决定因素对分子表型和健康结果的贡献

英国维康桑格研究所、剑桥大学等机构合作发表

Abstract

The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans (https://IntervalRNA.org.uk).

摘要：

大多数非蛋白编码基因变异影响疾病风险的生物学机制尚不清楚。为了研究基因调控机制，该研究通过对4,732名参与者的批量RNA测序绘制了血液基因表达和剪接定量性状位点（QTL）图，并整合了来自相同个体的蛋白质、代谢物和脂质数据。研究确定了17,233个基因表达的顺式QTL和29,514个剪接事件（涉及6,853个基因）。共定位分析揭示了3430个蛋白质组和代谢组特征与基因表达或剪接具有共同的关联信号。对具有共同病因的基因位点的遗传效应的相对贡献进行了量化，观察到有222种分子表型由基因表达或剪接显著介导。研究发现了具有治疗意义的疾病基因位点的基因调控机制，如高血压中的WARS1、皮炎中的IL7R和COVID-19中的IFNAR2。该研究为人类转录表型、分子性状和健康结果的共同遗传病因学提供了一个开放获取的资源 (https://IntervalRNA.org.uk)。

8.Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels

全基因组测序分析确定了与循环蛋白水平相关的罕见大效应非编码变异和调控区域

英国埃克塞特大学、瑞士卡内基梅隆大学

Abstract

The contribution of rare noncoding genetic variation to common phenotypes is largely unknown, as a result of a historical lack of population-scale whole-genome sequencing data and the difficulty of categorizing noncoding variants into functionally similar groups. To begin addressing these challenges, we performed a cis association analysis using whole-genome sequencing data, consisting of 1.1 billion variants, 123 million noncoding aggregate-based tests and 2,907 circulating protein levels in ~50,000 UK Biobank participants. We identified 604 independent rare noncoding single-variant associations with circulating protein levels. Unlike protein-coding variation, rare noncoding genetic variation was almost as likely to increase or decrease protein levels. Rare noncoding aggregate testing identified 357 conditionally independent associated regions. Of these, 74 (21%) were not detectable by single-variant testing alone. Our findings have important implications for the identification, and role, of rare noncoding genetic variation associated with common human phenotypes, including the importance of testing aggregates of noncoding variants.

摘要：

由于历来缺乏人群规模的全基因组测序数据，而且很难将非编码变异归类到功能相似的群体中，因此罕见的非编码基因变异对常见表型的贡献在很大程度上是未知的。为了着手解决这些难题，该研究利用全基因组测序数据进行了顺式关联分析，这些数据包括约5万名英国生物库参与者的11亿个变异、1.23亿个基于聚合体的非编码检测和2907个循环蛋白水平。发现了604个独立的罕见非编码单变异与循环蛋白水平的关联。与蛋白质编码变异不同，罕见非编码基因变异增加或减少蛋白质水平的概率几乎相等。稀有非编码集合测试确定了357个条件独立的相关区域。其中有74个（21%）是单个变异检测无法检测到的。该研究结果对识别与人类常见表型相关的罕见非编码基因变异及其作用具有重要意义，包括检测非编码变异聚合体的重要性。

9.Plasma proteome variation and its genetic determinants in children and adolescents

儿童和青少年血浆蛋白质组变异及其遗传决定因素

丹麦哥本哈根大学、德国马克斯普朗克生物化学研究所等机构合作发表

Abstract

Our current understanding of the determinants of plasma proteome variation during pediatric development remains incomplete. Here, we show that genetic variants, age, sex and body mass index significantly influence this variation. Using a streamlined and highly quantitative mass spectrometry-based proteomics workflow, we analyzed plasma from 2,147 children and adolescents, identifying 1,216 proteins after quality control. Notably, the levels of 70% of these were associated with at least one of the aforementioned factors, with protein levels also being predictive. Quantitative trait loci (QTLs) regulated at least one-third of the proteins; between a few percent and up to 30-fold. Together with excellent replication in an additional 1,000 children and 558 adults, this reveals substantial genetic effects on plasma protein levels, persisting from childhood into adulthood. Through Mendelian randomization and colocalization analyses, we identified 41 causal genes for 33 cardiometabolic traits, emphasizing the value of protein QTLs in drug target identification and disease understanding.

摘要：

目前对儿科发育过程中血浆蛋白质组变异的决定因素的了解仍不全面。该研究发现基因变异、年龄、性别和体重指数对这种变异有显著影响。使用基于质谱的简化和高度定量的蛋白质组学工作流程，分析了2,147名儿童和青少年的血浆，经过质量控制后鉴定出1,216种蛋白质。值得注意的是，其中70%蛋白质的水平至少与上述一种因素相关，蛋白质水平还具有预测性。定量性状位点（QTL）调节了至少三分之一的蛋白质；调节幅度从百分之几到高达30倍不等。结合在另外1000名儿童和558名成人中进行的出色验证，这揭示了遗传对血浆蛋白水平的巨大影响，这种影响从儿童期一直持续到成年期。通过孟德尔随机化和共定位分析，确定了33种心脏代谢特征的41个因果基因，强调了蛋白质QTL在药物靶标鉴定和疾病认识方面的价值。

10.Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

空间转录组学发现与肺纤维化远端肺重塑相关的分子生态位失调

美国凤凰城转化基因组学研究所、澳大利亚墨尔本大学等机构合作发表

Abstract

Large-scale changes in the structure and cellular makeup of the distal lung are a hallmark of pulmonary fibrosis (PF), but the spatial contexts that contribute to disease pathogenesis have remained uncertain. Using image-based spatial transcriptomics, we analyzed the gene expression of 1.6 million cells from 35 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell types, established the cellular and molecular basis of classical PF histopathologic features and identified a diversity of distinct molecularly defined spatial niches in control and PF lungs. Using machine learning and trajectory analysis to segment and rank airspaces on a gradient of remodeling severity, we identified compositional and molecular changes associated with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially resolved view of PF and establish methods that could be applied to other spatial transcriptomic studies.

摘要：

远端肺部结构和细胞组成的大规模变化是肺纤维化（PF）的标志，但导致疾病发病的空间环境仍不确定。利用基于图像的空间转录组学，该研究分析了来自35个独特肺部的160万个细胞的基因表达。通过基于细胞的互补分析和创新的细胞非依赖性分析，确定了PF发病细胞类型的定位特征，建立了经典PF组织病理学特征的细胞和分子基础，并在对照肺和PF肺中发现了多种不同的分子定义的空间壁龛。利用机器学习和轨迹分析沿重构严重程度梯度对气道进行分级，确定了与渐进性远端肺病理学相关的组成和分子变化，这些变化从肺泡上皮失调开始，以巨噬细胞极化的变化达到顶峰。总之，这些结果提供了一个独特的、空间分辨的PF视图，并建立了可应用于其他空间转录组研究的方法。

11.Analysis of multi-condition single-cell data with latent embedding multivariate regression

利用潜在嵌入多元回归分析多条件单细胞数据

德国欧洲分子生物学实验室 （EMBL）、海德堡大学

Abstract

Identifying gene expression differences in heterogeneous tissues across conditions is a fundamental biological task, enabled by multi-condition single-cell RNA sequencing (RNA-seq). Current data analysis approaches divide the constituent cells into clusters meant to represent cell types, but such discrete categorization tends to be an unsatisfactory model of the underlying biology. Here, we introduce latent embedding multivariate regression (LEMUR), a model that operates without, or before, commitment to discrete categorization. LEMUR (1) integrates data from different conditions, (2) predicts each cell’s gene expression changes as a function of the conditions and its position in latent space and (3) for each gene, identifies a compact neighborhood of cells with consistent differential expression. We apply LEMUR to cancer, zebrafish development and spatial gradients in Alzheimer’s disease, demonstrating its broad applicability.

摘要：

通过多条件单细胞RNA测序（RNA-seq）来识别不同条件下异质组织的基因表达差异是一项基本的生物学任务。目前的数据分析方法将组成细胞划分为代表细胞类型的群组，但这种离散分类往往不能充分反映潜在的生物学模型。该研究引入了潜在嵌入多元回归（LEMUR），这是一种无需或先于离散分类而运行的模型。LEMUR (1) 整合来自不同条件的数据，(2) 通过细胞在潜在空间的位置坐标和所处条件， 预测每个细胞的基因表达变化，(3) 为每个基因确定具有一致差异表达的紧凑细胞邻域。该研究将LEMUR应用于癌症、斑马鱼发育和阿尔茨海默病的空间梯度，证明了它的广泛适用性。

12.Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis

PROX1对细胞命运可塑性的主动抑制可保护肝细胞特性并防止肝脏肿瘤发生

德国癌症研究中心、德国曼海姆大学、海德堡大学等机构合作发表

Abstract

Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.

摘要：

细胞命运的可塑性是发育的基础，然而失控的可塑性是癌症的标志。虽然转录主调控因子能诱导细胞系特异性基因来限制可塑性，但细胞系特异性抑制因子是否会主动抑制可塑性仍不清楚。该研究通过计算预测了18种细胞类型的所谓保障抑制因子，这些抑制因子会阻碍表型可塑性的终身发展。利用重编程验证了肝细胞特异性候选者，发现prospero homeobox蛋白1（PROX1）通过直接抑制替代命运主调节因子增强了肝细胞的特性。在小鼠体内，Prox1是损伤后肝细胞有效再生的必要条件，并且足以防止肝脏肿瘤发生。与患者数据一致的是，Prox1缺失会导致体内肝细胞命运丧失，并使肝细胞癌转变为胆管癌。相反，过表达会促进胆管癌向肝细胞癌的转分化。该研究结果为PROX1作为肝细胞特异性保护因子提供了证据，并支持细胞类型特异性抑制因子在整个生命过程中积极抑制可塑性以保护谱系特性从而预防疾病的模型。

13.Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma

PD-L1琥珀酰化的变化影响黑色素瘤的抗肿瘤免疫反应

湘雅医院、中南大学、英国伦敦大学等机构合作发表

Abstract

Tumors undergo metabolic reprogramming to meet the energetic, synthetic and redox demands essential for malignancy, often characterized by increased glycolysis and lactate production. However, the role of mitochondrial metabolism in tumor immunity remains unclear. The present study integrates spatial transcriptomics, bulk transcriptomics and proteomics, revealing a strong link between the metabolite succinyl-CoA and tumor immunity as well as the efficacy of anti-programmed cell death protein-1 (PD-1) therapy in patients with melanoma. Elevated succinyl-CoA levels, through α-ketoglutarate or succinate supplementation, enhanced T cell-mediated tumor elimination, both in vitro and in vivo. Mechanistically, succinylation of the ligand of PD-1 (PD-L1) at lysine 129 led to its degradation. Increased carnitine palmitoyltransferase 1A (CPT1A), identified as a succinyltransferase for PD-L1, boosted anti-tumor activity. Preclinically, bezafibrate, a hyperlipidemia drug, upregulated CPT1A and synergized with CTLA-4 monoclonal antibody to inhibit tumor growth. Clinically, higher PD-L1 and lower CPT1A levels in tumors correlated with better anti-PD-1 therapy responses, suggesting potential biomarkers for prediction of treatment efficacy.

摘要：

肿瘤会进行新陈代谢重编程，以满足恶性肿瘤所必需的能量、合成和氧化还原需求，其特点通常是糖酵解和乳酸生成增加。然而，线粒体代谢在肿瘤免疫中的作用仍不清楚。该研究整合了空间转录组学、批量转录组学和蛋白质组学，揭示了代谢物琥珀酰-CoA与肿瘤免疫以及黑色素瘤患者抗程序性细胞死亡蛋白-1（PD-1）疗法疗效之间的密切联系。通过补充α-酮戊二酸或琥珀酸来提高琥珀酰-CoA的水平，可以增强体外和体内T细胞介导的肿瘤消除作用。从机理上讲，PD-1配体（PD-L1）赖氨酸129处的琥珀酰化会导致其降解。肉碱棕榈酰基转移酶1A（CPT1A）被认为是PD-L1的琥珀酰基转移酶，它的增加增强了抗肿瘤活性。临床前研究发现，降脂药物贝扎贝特能上调CPT1A，并与CTLA-4单克隆抗体协同抑制肿瘤生长。在临床上，肿瘤中较高的PD-L1水平和较低的CPT1A水平与较好的抗PD-1治疗反应相关，这提示了预测疗效的潜在生物标记物。

14.ImmuneLENS characterizes systemic immune dysregulation in aging and cancer

ImmuneLENS表征衰老和癌症中的全身免疫失调

英国伦敦大学癌症研究所、美国斯坦福大学等机构合作发表

Abstract

Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.

摘要：

病原体和癌细胞的识别和清除依赖于适应性免疫系统。因此，准确量化免疫亚群对精准医疗至关重要。该研究介绍了基于核苷酸测序的免疫淋巴细胞估算（ImmuneLENS），它能从深度低至5倍覆盖率的全基因组测序数据中估算出T细胞和B细胞的比例、类别转换和克隆型多样性。通过将ImmuneLENS应用于10万基因组计划，发现了T细胞丰富的肿瘤中富含体细胞突变的基因、循环T细胞比例的显著性别差异，并证明癌症患者的循环T细胞比例明显低于健康人。循环B细胞比例低与癌症发病率增加有关。最后，循环T细胞丰度比浸润T细胞更能预示癌症患者的5年生存率。

15.Quantifying cell divisions along evolutionary lineages in cancer

量化癌症进化过程中的细胞分裂

美国哈佛医学院、麻省总医院、德国夏里特医学院、海德堡大学等机构合作发表

Abstract

Cell division drives somatic evolution but is challenging to quantify. We developed a framework to count cell divisions with DNA replication-related mutations in polyguanine homopolymers. Analyzing 505 samples from 37 patients, we studied the milestones of colorectal cancer evolution. Primary tumors diversify at ~250 divisions from the founder cell, while distant metastasis divergence occurs significantly later, at ~500 divisions. Notably, distant but not lymph node metastases originate from primary tumor regions that have undergone surplus divisions, tying subclonal expansion to metastatic capacity. Then, we analyzed a cohort of 73 multifocal lung cancers and showed that the cell division burden of the tumors’ common ancestor distinguishes independent primary tumors from intrapulmonary metastases and correlates with patient survival. In lung cancer too, metastatic capacity is tied to more extensive proliferation. The cell division history of human cancers is easily accessible using our simple framework and contains valuable biological and clinical information.

摘要：

细胞分裂推动着体细胞的进化，但量化细胞分裂却具有挑战性。该研究开发了一个框架，用于计算多聚鸟嘌呤均聚物中发生DNA复制相关突变的细胞分裂。分析了来自37名患者的505份样本，研究了结直肠癌进化的里程碑。原发性肿瘤从创始细胞开始约250次分裂就出现了分化，而远处转移的分化则要晚很多（约500次分裂）。值得注意的是，远处转移灶（而非淋巴结转移灶）起源于经历过剩分裂的原发肿瘤区域，这将亚克隆扩增与转移能力联系在了一起。随后，研究分析了一组73例多灶肺癌，结果表明，肿瘤共同祖先的细胞分裂负荷可将独立的原发肿瘤与肺内转移瘤区分开来，并与患者的存活率相关。在肺癌中，转移能力也与更广泛的增殖有关。利用该研究的简单框架，可以轻松获得人类癌症的细胞分裂史，其中包含宝贵的生物和临床信息。

16.Functional analysis of cancer-associated germline risk variants

癌症相关种系风险变异的功能分析

美国哈佛医学院、麻省总医院、德国夏里特医学院、海德堡大学等机构合作发表

Abstract

Single-nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays of 4,041 SNVs linked to 13 neoplasms comprising >90% of human malignancies were performed in pertinent primary human cell types and then integrated with matching chromatin accessibility, DNA looping and expression quantitative trait loci data to nominate 380 potentially regulatory SNVs and their putative target genes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, DNA damage repair and Rho GTPase activity. A CRISPR knockout screen demonstrated that a subset of germline putative risk genes also enables the growth of established cancers. Editing one SNV, rs10411210, showed that its risk allele increases rhophilin RHPN2 expression and stimulus-responsive RhoA activation, indicating that individual SNVs may upregulate cancer-linked pathways. These functional data are a resource for variant prioritization efforts and further interrogation of the mechanisms underlying inherited risk for cancer.

摘要：

调控DNA中的单核苷酸变异（SNV）与遗传性癌症风险有关。在相关的原代人类细胞类型中，对与13种肿瘤（占人类恶性肿瘤的90%以上）相关的4,041个SNV进行了大规模平行报告检测，然后与匹配的染色质可及性、DNA循环和表达定量性状位点数据整合，筛选出380个潜在的调控SNV及其推测的靶基因。这些靶基因强调了与终生癌症风险有关的特定蛋白质网络，包括线粒体翻译、DNA损伤修复和Rho GTPase活性。CRISPR基因敲除筛选表明，一部分种系潜在风险基因也能促进已确诊癌症的生长。编辑一个SNV（rs10411210）后发现，其风险等位基因会增加rhophilin RHPN2的表达和刺激反应性RhoA的激活，这表明单个SNV可能会上调与癌症相关的通路。这些功能数据是确定变异优先次序和进一步研究癌症遗传风险机制的资源。

汇报人：张宇阳

导师：赵宇

审核：肖瑶、任建君