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SpRY-mediated screens facilitate functional dissection of non-coding sequences at single-base resolution. SpRY 介导的筛选有助于以单碱基分辨率对非编码序列进行功能分析。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 Epub Date: 2024-06-17 DOI: 10.1016/j.xgen.2024.100583
Yao Yao, Zhiwei Zhou, Xiaoling Wang, Zhirui Liu, Yixin Zhai, Xiaolin Chi, Jingyi Du, Liheng Luo, Zhigang Zhao, Xiaoyue Wang, Chaoyou Xue, Shuquan Rao

CRISPR mutagenesis screens conducted with SpCas9 and other nucleases have identified certain cis-regulatory elements and genetic variants but at a limited resolution due to the absence of protospacer adjacent motif (PAM) sequences. Here, leveraging the broad targeting scope of the near-PAMless SpRY variant, we have demonstrated that saturated SpRY mutagenesis and base editing screens can faithfully identify functional regulatory elements and essential genetic variants for target gene expression at single-base resolution. We further extended this methodology to investigate a genome-wide association study (GWAS) locus at 10q22.1 associated with a red blood cell trait, where we identified potential enhancers regulating HK1 gene expression, despite not all of these enhancers exhibiting typical chromatin signatures. More importantly, our saturated base editing screens pinpoint multiple causal variants within this locus that would otherwise be missed by Bayesian statistical fine-mapping. Our approach is generally applicable to functional interrogation of all non-coding genomic elements while complementing other high-coverage CRISPR screens.

使用 SpCas9 和其他核酸酶进行的 CRISPR 诱变筛选已经鉴定出了某些顺式调控元件和遗传变异,但由于缺乏原间隔邻接基序(PAM),分辨率有限。在这里,我们利用近乎无 PAM 的 SpRY 变体的广泛靶向范围,证明了饱和 SpRY 诱变和碱基编辑筛选能以单碱基分辨率忠实地鉴定功能调控元件和靶基因表达的基本遗传变异。我们进一步扩展了这一方法,研究了与红细胞性状相关的 10q22.1 全基因组关联研究(GWAS)位点,发现了调控 HK1 基因表达的潜在增强子,尽管这些增强子并非都表现出典型的染色质特征。更重要的是,我们的饱和碱基编辑筛选确定了该基因座中的多个因果变异,否则贝叶斯统计精细作图就会漏掉这些变异。我们的方法普遍适用于所有非编码基因组元件的功能检测,同时也是对其他高覆盖率 CRISPR 筛选的补充。
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引用次数: 0
eQTLs identify regulatory networks and drivers of variation in the individual response to sepsis. eQTLs 确定了个体对败血症反应的调控网络和变异驱动因素。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 Epub Date: 2024-06-18 DOI: 10.1016/j.xgen.2024.100587
Katie L Burnham, Nikhil Milind, Wanseon Lee, Andrew J Kwok, Kiki Cano-Gamez, Yuxin Mi, Cyndi G Geoghegan, Ping Zhang, Stuart McKechnie, Nicole Soranzo, Charles J Hinds, Julian C Knight, Emma E Davenport

Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection, for which disease heterogeneity is a major obstacle to developing targeted treatments. We have previously identified gene-expression-based patient subgroups (sepsis response signatures [SRS]) informative for outcome and underlying pathophysiology. Here, we aimed to investigate the role of genetic variation in determining the host transcriptomic response and to delineate regulatory networks underlying SRS. Using genotyping and RNA-sequencing data on 638 adult sepsis patients, we report 16,049 independent expression (eQTLs) and 32 co-expression module (modQTLs) quantitative trait loci in this disease context. We identified significant interactions between SRS and genotype for 1,578 SNP-gene pairs and combined transcription factor (TF) binding site information (SNP2TFBS) and predicted regulon activity (DoRothEA) to identify candidate upstream regulators. Overall, these approaches identified putative mechanistic links between host genetic variation, cell subtypes, and the individual transcriptomic response to infection.

败血症是一种由感染反应失调引起的危及生命的器官功能障碍临床综合征,其疾病异质性是开发靶向治疗的主要障碍。我们之前已经确定了基于基因表达的患者亚群(脓毒症反应特征 [SRS]),这些亚群对预后和潜在的病理生理学具有参考价值。在此,我们旨在研究基因变异在决定宿主转录组反应中的作用,并勾勒出 SRS 的基础调控网络。利用对 638 名成年败血症患者的基因分型和 RNA 测序数据,我们报告了这种疾病背景下的 16,049 个独立表达(eQTLs)和 32 个共表达模块(modQTLs)定量性状位点。我们确定了 1,578 个 SNP 基因对的 SRS 与基因型之间的显着交互作用,并结合转录因子 (TF) 结合位点信息(SNP2TFBS)和预测调控子活性(DoRothEA)确定了候选上游调控因子。总之,这些方法确定了宿主遗传变异、细胞亚型和个体转录组对感染的反应之间的潜在机理联系。
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引用次数: 0
Lineage-specific splicing regulation of MAPT gene in the primate brain. 灵长类动物大脑中 MAPT 基因的特异性剪接调控。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-06-12 Epub Date: 2024-05-20 DOI: 10.1016/j.xgen.2024.100563
Yocelyn Recinos, Suying Bao, Xiaojian Wang, Brittany L Phillips, Yow-Tyng Yeh, Sebastien M Weyn-Vanhentenryck, Maurice S Swanson, Chaolin Zhang

Divergence of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is widespread in mammals, including primates, but the underlying mechanisms and functional impact are poorly understood. Here, we modeled cassette exon inclusion in primate brains as a quantitative trait and identified 1,170 (∼3%) exons with lineage-specific splicing shifts under stabilizing selection. Among them, microtubule-associated protein tau (MAPT) exons 2 and 10 underwent anticorrelated, two-step evolutionary shifts in the catarrhine and hominoid lineages, leading to their present inclusion levels in humans. The developmental-stage-specific divergence of exon 10 splicing, whose dysregulation can cause frontotemporal lobar degeneration (FTLD), is mediated by divergent distal intronic MBNL-binding sites. Competitive binding of these sites by CRISPR-dCas13d/gRNAs effectively reduces exon 10 inclusion, potentially providing a therapeutically compatible approach to modulate tau isoform expression. Our data suggest adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain.

前体信使 RNA(pre-mRNA)替代剪接(AS)的分化在哺乳动物(包括灵长类动物)中很普遍,但对其潜在机制和功能影响却知之甚少。在这里,我们将灵长类动物大脑中的盒式外显子包含作为一种数量性状建模,并鉴定出1170个(∼3%)外显子在稳定选择下具有品系特异性剪接转变。其中,微管相关蛋白 tau(MAPT)外显子 2 和 10 在猫科动物和同系动物中经历了反相关的两步进化转变,导致了它们在人类中目前的内含水平。第 10 号外显子剪接的发育阶段特异性分化(其失调可导致额颞叶变性(FTLD))是由不同的远端内含子 MBNL 结合位点介导的。CRISPR-dCas13d/gRNA 与这些位点的竞争性结合可有效减少第 10 号外显子的包含,从而为调节 tau 异构体的表达提供了一种潜在的治疗方法。我们的数据表明了 MAPT 功能的适应性,更广泛地说,AS 在灵长类动物大脑的进化扩张中扮演着重要角色。
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引用次数: 0
Gut microbial genomes with paired isolates from China illustrate probiotic and cardiometabolic effects. 中国成对分离的肠道微生物基因组说明益生菌和心脏代谢的影响。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-06-12 Epub Date: 2024-05-12 DOI: 10.1016/j.xgen.2024.100559
Pan Huang, Quanbin Dong, Yifeng Wang, Yunfan Tian, Shunhe Wang, Chengcheng Zhang, Leilei Yu, Fengwei Tian, Xiaoxiang Gao, Hang Guo, Shanrong Yi, Mingyang Li, Yang Liu, Qingsong Zhang, Wenwei Lu, Gang Wang, Bo Yang, Shumao Cui, Dongxu Hua, Xiuchao Wang, Yuwen Jiao, Lu Liu, Qiufeng Deng, Beining Ma, Tingting Wu, Huayiyang Zou, Jing Shi, Haifeng Zhang, Daming Fan, Yanhui Sheng, Jianxin Zhao, Liming Tang, Hao Zhang, Wei Sun, Wei Chen, Xiangqing Kong, Lianmin Chen, Qixiao Zhai

The gut microbiome displays genetic differences among populations, and characterization of the genomic landscape of the gut microbiome in China remains limited. Here, we present the Chinese Gut Microbial Reference (CGMR) set, comprising 101,060 high-quality metagenomic assembled genomes (MAGs) of 3,707 nonredundant species from 3,234 fecal samples across primarily rural Chinese locations, 1,376 live isolates mainly from lactic acid bacteria, and 987 novel species relative to worldwide databases. We observed region-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. Preliminary mouse experiments suggest a probiotic effect of two Faecalibacillus intestinalis isolates in alleviating constipation, cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and isolates from the genera Parabacteroides and Lactobacillus in host lipid metabolism. Our study expands the current microbial genomes with paired isolates and demonstrates potential host effects, contributing to the mechanistic understanding of host-microbe interactions.

肠道微生物组在不同人群中存在遗传差异,而中国肠道微生物组的基因组特征描述仍然有限。在这里,我们展示了中国肠道微生物参考文献集(CGMR),其中包括来自中国主要农村地区 3,234 份粪便样本的 101,060 个高质量元基因组组装基因组(MAGs),包含 3,707 个非冗余物种,1,376 个主要来自乳酸菌的活体分离物,以及相对于全球数据库的 987 个新物种。我们观察到了特定区域共存的 MAGs 以及具有益生菌和心脏代谢功能的 MAGs。初步的小鼠实验表明,两种肠道粪杆菌分离物具有缓解便秘的益生作用,三种脆弱乳杆菌分离物对肥胖症具有心脏代谢影响,副乳杆菌属和乳酸杆菌属分离物对宿主的脂质代谢具有影响。我们的研究扩大了目前微生物基因组中成对分离物的范围,并展示了对宿主的潜在影响,有助于从机理上理解宿主与微生物之间的相互作用。
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引用次数: 0
Complete spatially resolved gene expression is not necessary for identifying spatial domains. 完整的空间解析基因表达并不是识别空间域的必要条件。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-06-12 Epub Date: 2024-05-22 DOI: 10.1016/j.xgen.2024.100565
Senlin Lin, Yan Cui, Fangyuan Zhao, Zhidong Yang, Jiangning Song, Jianhua Yao, Yu Zhao, Bin-Zhi Qian, Yi Zhao, Zhiyuan Yuan

Spatially resolved transcriptomics (SRT) technologies have revolutionized the study of tissue organization. We introduce a graph convolutional network with an attention and positive emphasis mechanism, termed BINARY, relying exclusively on binarized SRT data to accurately delineate spatial domains. BINARY outperforms existing methods across various SRT data types while using significantly less input information. Our study suggests that precise gene expression quantification may not always be essential, inspiring further exploration of the broader applications of spatially resolved binarized gene expression data.

空间分辨转录组学(SRT)技术彻底改变了对组织结构的研究。我们介绍了一种具有注意力和正向强调机制的图卷积网络,称为 "BINARY",它完全依靠二值化的 SRT 数据来精确划分空间域。在各种 SRT 数据类型中,BINARY 的表现优于现有的方法,同时使用的输入信息也少得多。我们的研究表明,精确的基因表达量化并不总是必要的,这激励我们进一步探索空间分辨二值化基因表达数据的更广泛应用。
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引用次数: 0
A gene with a thousand alleles: The hyper-variable effectors of plant-parasitic nematodes. 千变万化的基因:植物寄生线虫的超变异效应因子。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-06-12 Epub Date: 2024-05-29 DOI: 10.1016/j.xgen.2024.100580
Unnati Sonawala, Helen Beasley, Peter Thorpe, Kyriakos Varypatakis, Beatrice Senatori, John T Jones, Lida Derevnina, Sebastian Eves-van den Akker

Pathogens are engaged in a fierce evolutionary arms race with their host. The genes at the forefront of the engagement between kingdoms are often part of diverse and highly mutable gene families. Even in this context, we discovered unprecedented variation in the hyper-variable (HYP) effectors of plant-parasitic nematodes. HYP effectors are single-gene loci that potentially harbor thousands of alleles. Alleles vary in the organization, as well as the number, of motifs within a central hyper-variable domain (HVD). We dramatically expand the HYP repertoire of two plant-parasitic nematodes and define distinct species-specific "rules" underlying the apparently flawless genetic rearrangements. Finally, by analyzing the HYPs in 68 individual nematodes, we unexpectedly found that despite the huge number of alleles, most individuals are germline homozygous. These data support a mechanism of programmed genetic variation, termed HVD editing, where alterations are locus specific, strictly governed by rules, and theoretically produce thousands of variants without errors.

病原体与其宿主进行着激烈的进化军备竞赛。处于王国间交战最前沿的基因往往是多样化和高度变异基因家族的一部分。即使在这种情况下,我们也在植物寄生线虫的超变异(HYP)效应因子中发现了前所未有的变异。HYP 效应子是单基因位点,可能包含数千个等位基因。等位基因在中心超变异结构域(HVD)内的基序组织和数量上各不相同。我们极大地扩展了两种植物寄生线虫的 HYP 基因库,并确定了表面上完美无瑕的基因重排所依据的不同物种特异性 "规则"。最后,通过分析 68 条线虫个体的 HYPs,我们意外地发现,尽管等位基因数量巨大,但大多数个体都是种系同源的。这些数据支持一种被称为 HVD 编辑的程序化基因变异机制,在这种机制下,基因改变是特定位点的,严格受规则约束,理论上可以无差错地产生成千上万个变体。
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引用次数: 0
SIMS: A deep-learning label transfer tool for single-cell RNA sequencing analysis. SIMS:用于单细胞 RNA 测序分析的深度学习标签转移工具。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-06-12 Epub Date: 2024-05-31 DOI: 10.1016/j.xgen.2024.100581
Jesus Gonzalez-Ferrer, Julian Lehrer, Ash O'Farrell, Benedict Paten, Mircea Teodorescu, David Haussler, Vanessa D Jonsson, Mohammed A Mostajo-Radji

Cell atlases serve as vital references for automating cell labeling in new samples, yet existing classification algorithms struggle with accuracy. Here we introduce SIMS (scalable, interpretable machine learning for single cell), a low-code data-efficient pipeline for single-cell RNA classification. We benchmark SIMS against datasets from different tissues and species. We demonstrate SIMS's efficacy in classifying cells in the brain, achieving high accuracy even with small training sets (<3,500 cells) and across different samples. SIMS accurately predicts neuronal subtypes in the developing brain, shedding light on genetic changes during neuronal differentiation and postmitotic fate refinement. Finally, we apply SIMS to single-cell RNA datasets of cortical organoids to predict cell identities and uncover genetic variations between cell lines. SIMS identifies cell-line differences and misannotated cell lineages in human cortical organoids derived from different pluripotent stem cell lines. Altogether, we show that SIMS is a versatile and robust tool for cell-type classification from single-cell datasets.

细胞图谱是对新样本进行自动细胞标记的重要参考,但现有的分类算法在准确性方面却举步维艰。在此,我们介绍 SIMS(用于单细胞的可扩展、可解释的机器学习),这是一种用于单细胞 RNA 分类的低代码数据高效管道。我们针对不同组织和物种的数据集对 SIMS 进行了基准测试。我们证明了 SIMS 在大脑细胞分类中的功效,即使使用较小的训练集也能达到很高的准确率(见图 1)。
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引用次数: 0
Identification of biomarkers and potential therapeutic targets for pancreatic cancer by proteomic analysis in two prospective cohorts. 通过对两个前瞻性队列进行蛋白质组分析,确定胰腺癌的生物标志物和潜在治疗靶点。
Pub Date : 2024-06-12 Epub Date: 2024-05-15 DOI: 10.1016/j.xgen.2024.100561
Jingjing Lyu, Minghui Jiang, Ziwei Zhu, Hongji Wu, Haonan Kang, Xingjie Hao, Shanshan Cheng, Huan Guo, Xia Shen, Tangchun Wu, Jiang Chang, Chaolong Wang

Pancreatic cancer (PC) is the deadliest malignancy due to late diagnosis. Aberrant alterations in the blood proteome might serve as biomarkers to facilitate early detection of PC. We designed a nested case-control study of incident PC based on a prospective cohort of 38,295 elderly Chinese participants with ∼5.7 years' follow-up. Forty matched case-control pairs passed the quality controls for the proximity extension assay of 1,463 serum proteins. With a lenient threshold of p < 0.005, we discovered regenerating family member 1A (REG1A), REG1B, tumor necrosis factor (TNF), and phospholipase A2 group IB (PLA2G1B) in association with incident PC, among which the two REG1 proteins were replicated using the UK Biobank Pharma Proteomics Project, with effect sizes increasing steadily as diagnosis time approaches the baseline. Mendelian randomization analysis further supported the potential causal effects of REG1 proteins on PC. Taken together, circulating REG1A and REG1B are promising biomarkers and potential therapeutic targets for the early detection and prevention of PC.

胰腺癌(PC)因诊断较晚而成为最致命的恶性肿瘤。血液蛋白质组的异常改变可作为生物标志物,有助于早期发现胰腺癌。我们设计了一项巢式病例对照研究,研究对象是38 295名随访时间在5.7年以上的中国老年人。40对匹配的病例对照通过了1463种血清蛋白的近似延伸检测质量控制。以 p
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引用次数: 0
Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations. 常见视网膜疾病视网膜外膜的全基因组关联研究:三个美国人群中的重要风险位点。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-06-12 DOI: 10.1016/j.xgen.2024.100582
Joel Gelernter, Daniel F Levey, Marco Galimberti, Kelly Harrington, Hang Zhou, Keyrun Adhikari, Priya Gupta, J Michael Gaziano, Dean Eliott, Murray B Stein

Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis-a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM.

视网膜外膜(ERM)是一种常见的视网膜病变,其特征是视网膜表面存在纤维细胞组织,通常伴有视物变形和视力下降。我们对 "百万退伍军人计划"(MVP)中的欧洲裔美国人(EUR)、非洲裔美国人(AFR)和拉丁裔美国人(AMR)ERM 参与者进行了全基因组关联分析--共有 38,232 例病例和 557,988 例对照。我们在每个人群中分别完成了全基因组关联研究(GWAS),然后对结果进行了荟萃分析。在所研究的所有三个人群中都观察到了全基因组显性(GWS)关联:在欧洲受试者中有 31 个风险位点,在非洲裔受试者中有 3 个,在亚洲裔受试者中有 2 个,在跨种群荟萃分析中有 48 个。许多结果在芬兰基因样本中得到了重复。一些 GWS 变异与黄斑中基因表达的改变有关。ERM与多种性状有明显的遗传相关性。途径富集分析涉及胶原蛋白和胶原蛋白相关机制等。这项强大的 ERM GWAS 发现了新的遗传关联,指出了 ERM 的生物学机制。
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引用次数: 0
Ribosomal DNA copy number variation associates with hematological profiles and renal function in the UK Biobank. 英国生物库中核糖体 DNA 拷贝数变异与血液学特征和肾功能的关系。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-06-12 Epub Date: 2024-05-14 DOI: 10.1016/j.xgen.2024.100562
Francisco Rodriguez-Algarra, David M Evans, Vardhman K Rakyan

The phenotypic impact of genetic variation of repetitive features in the human genome is currently understudied. One such feature is the multi-copy 47S ribosomal DNA (rDNA) that codes for rRNA components of the ribosome. Here, we present an analysis of rDNA copy number (CN) variation in the UK Biobank (UKB). From the first release of UKB whole-genome sequencing (WGS) data, a discovery analysis in White British individuals reveals that rDNA CN associates with altered counts of specific blood cell subtypes, such as neutrophils, and with the estimated glomerular filtration rate, a marker of kidney function. Similar trends are observed in other ancestries. A range of analyses argue against reverse causality or common confounder effects, and all core results replicate in the second UKB WGS release. Our work demonstrates that rDNA CN is a genetic influence on trait variance in humans.

目前对人类基因组中重复特征的遗传变异对表型的影响研究不足。多拷贝 47S 核糖体 DNA(rDNA)就是这样一种特征,它编码核糖体的 rRNA 成分。在此,我们对英国生物库(UKB)中的 rDNA 拷贝数(CN)变异进行了分析。从首次发布的英国生物库全基因组测序(WGS)数据中,对英国白人的发现分析表明,rDNA拷贝数与特定血细胞亚型(如中性粒细胞)数量的改变以及肾功能标志物--肾小球滤过率的估计值有关。在其他血统中也观察到类似的趋势。一系列分析表明,反向因果关系或共同混杂物效应并不存在,而且所有核心结果都在第二次发布的 UKB WGS 中得到了重复。我们的工作证明了 rDNA CN 对人类性状变异的遗传影响。
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引用次数: 0
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Cell genomics
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