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Phenome-wide association study in 25,639 pregnant Chinese women reveals loci associated with maternal comorbidities and child health. 对 25 639 名中国孕妇进行的全表型关联研究揭示了与孕产妇合并症和儿童健康相关的基因位点。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100632
Jintao Guo, Qiwei Guo, Taoling Zhong, Chaoqun Xu, Zhongmin Xia, Hongkun Fang, Qinwei Chen, Ying Zhou, Jieqiong Xie, Dandan Jin, You Yang, Xin Wu, Huanhuan Zhu, Ailing Hour, Xin Jin, Yulin Zhou, Qiyuan Li

Phenome-wide association studies (PheWAS) have been less focused on maternal diseases and maternal-newborn comorbidities, especially in the Chinese population. To enhance our understanding of the genetic basis of these related diseases, we conducted a PheWAS on 25,639 pregnant women and 14,151 newborns in the Chinese Han population using ultra-low-coverage whole-genome sequence (ulcWGS). We identified 2,883 maternal trait-associated SNPs associated with 26 phenotypes, among which 99.5% were near established genome-wide association study (GWAS) loci. Further refinement delineated these SNPs to 442 unique trait-associated loci (TALs) predicated on linkage disequilibrium R2 > 0.8, revealing that 75.6% demonstrated pleiotropy and 50.9% were located in genes implicated in analogous phenotypes. Notably, we discovered 21 maternal SNPs associated with 35 neonatal phenotypes, including two SNPs associated with identical complications in both mothers and children. These findings underscore the importance of integrating ulcWGS data to enrich the discoveries derived from traditional PheWAS approaches.

全表型关联研究(Phenome-wide association studies,PheWAS)较少关注孕产妇疾病和母婴合并症,尤其是在中国人群中。为了进一步了解这些相关疾病的遗传基础,我们利用超低覆盖率全基因组序列(ulcWGS)对中国汉族人群中的 25639 名孕妇和 14151 名新生儿进行了全表型关联研究。我们发现了 2,883 个与 26 种表型相关的母体性状相关 SNPs,其中 99.5% 位于已建立的全基因组关联研究(GWAS)位点附近。进一步细化后,根据连锁不平衡 R2 > 0.8 将这些 SNPs 划分为 442 个独特的性状相关位点(TALs),发现 75.6% 的 SNPs 具有多效性,50.9% 的 SNPs 位于与类似表型有关联的基因中。值得注意的是,我们发现了 21 个与 35 种新生儿表型相关的母体 SNPs,包括两个与母婴相同并发症相关的 SNPs。这些发现强调了整合ulcWGS数据以丰富传统PheWAS方法发现的重要意义。
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引用次数: 0
The loach haplotype-resolved genome and the identification of Mex3a involved in fish air breathing. 泥鳅单倍型基因组和参与鱼类空气呼吸的 Mex3a 的鉴定。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100670
Bing Sun, Qingshan Li, Xinxin Xiao, Jianwei Zhang, Ying Zhou, Yuwei Huang, Jian Gao, Xiaojuan Cao

Fish air breathing is crucial for the transition of vertebrates from water to land. So far, the genes involved in fish air breathing have not been well identified. Here, we performed gene enrichment analysis of positively selected genes (PSGs) in loach (Misgurnus anguillicaudatus, an air-breathing fish) in comparison to Triplophysa tibetana (a non-air-breathing fish), haplotype-resolved genome assembly of the loach, and gene evolutionary analysis of air-breathing and non-air-breathing fishes and found that the PSG mex3a originated from ancient air-breathing fish species. Deletion of Mex3a impaired loach air-breathing capacity by inhibiting angiogenesis through its interaction with T-box transcription factor 20. Mex3a overexpression significantly promoted angiogenesis. Structural analysis and point mutation revealed the critical role of the 201st amino acid in loach Mex3a for angiogenesis. Our findings innovatively indicate that the ancient mex3a is a fish air-breathing gene, which holds significance for understanding fish air breathing and provides a valuable resource for cultivating hypoxia-tolerant fish varieties.

鱼类的空气呼吸对于脊椎动物从水中过渡到陆地至关重要。迄今为止,参与鱼类空气呼吸的基因尚未得到很好的鉴定。在此,我们对泥鳅(Misgurnus anguillicaudatus,一种呼吸空气的鱼类)与非呼吸空气的鱼类西藏鳅(Triplophysa tibetana)进行了正选基因(PSGs)富集分析、泥鳅单倍型解析基因组组装以及呼吸空气和非呼吸空气鱼类的基因进化分析,发现PSG mex3a起源于古代呼吸空气的鱼类物种。缺失Mex3a会通过与T-box转录因子20的相互作用抑制血管生成,从而削弱泥鳅的呼吸空气能力。过表达 Mex3a 则会显著促进血管生成。结构分析和点突变揭示了泥鳅Mex3a中第201个氨基酸对血管生成的关键作用。我们的研究结果创新性地表明,古老的mex3a是一种鱼类呼吸空气的基因,这对理解鱼类呼吸空气具有重要意义,并为培育耐缺氧鱼类品种提供了宝贵的资源。
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引用次数: 0
Utilizing non-invasive prenatal test sequencing data for human genetic investigation. 将无创产前检测测序数据用于人类基因调查。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100669
Siyang Liu, Yanhong Liu, Yuqin Gu, Xingchen Lin, Huanhuan Zhu, Hankui Liu, Zhe Xu, Shiyao Cheng, Xianmei Lan, Linxuan Li, Mingxi Huang, Hao Li, Rasmus Nielsen, Robert W Davies, Anders Albrechtsen, Guo-Bo Chen, Xiu Qiu, Xin Jin, Shujia Huang

Non-invasive prenatal testing (NIPT) employs ultra-low-pass sequencing of maternal plasma cell-free DNA to detect fetal trisomy. Its global adoption has established NIPT as a large human genetic resource for exploring genetic variations and their associations with phenotypes. Here, we present methods for analyzing large-scale, low-depth NIPT data, including customized algorithms and software for genetic variant detection, genotype imputation, family relatedness, population structure inference, and genome-wide association analysis of maternal genomes. Our results demonstrate accurate allele frequency estimation and high genotype imputation accuracy (R2>0.84) for NIPT sequencing depths from 0.1× to 0.3×. We also achieve effective classification of duplicates and first-degree relatives, along with robust principal-component analysis. Additionally, we obtain an R2>0.81 for estimating genetic effect sizes across genotyping and sequencing platforms with adequate sample sizes. These methods offer a robust theoretical and practical foundation for utilizing NIPT data in medical genetic research.

无创产前检测(NIPT)通过对母体血浆无细胞 DNA 进行超低通量测序来检测胎儿三体综合征。无创产前检测在全球范围内的应用使其成为探索遗传变异及其与表型关系的大型人类遗传资源。在此,我们介绍了分析大规模、低深度 NIPT 数据的方法,包括用于遗传变异检测、基因型估算、家族亲缘关系、种群结构推断和母体基因组全基因组关联分析的定制算法和软件。我们的研究结果表明,在 NIPT 测序深度为 0.1× 至 0.3× 的情况下,等位基因频率估算准确,基因型估算准确率高(R2>0.84)。我们还实现了对重复和一级亲属的有效分类,并进行了稳健的主成分分析。此外,我们还获得了 R2>0.81 的结果,可以在样本量充足的情况下估计不同基因分型和测序平台的遗传效应大小。这些方法为在医学遗传研究中利用 NIPT 数据奠定了坚实的理论和实践基础。
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引用次数: 0
Identifying compound-protein interactions with knowledge graph embedding of perturbation transcriptomics. 通过扰动转录组学的知识图嵌入识别化合物与蛋白质之间的相互作用。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 Epub Date: 2024-09-19 DOI: 10.1016/j.xgen.2024.100655
Shengkun Ni, Xiangtai Kong, Yingying Zhang, Zhengyang Chen, Zhaokun Wang, Zunyun Fu, Ruifeng Huo, Xiaochu Tong, Ning Qu, Xiaolong Wu, Kun Wang, Wei Zhang, Runze Zhang, Zimei Zhang, Jiangshan Shi, Yitian Wang, Ruirui Yang, Xutong Li, Sulin Zhang, Mingyue Zheng

The emergence of perturbation transcriptomics provides a new perspective for drug discovery, but existing analysis methods suffer from inadequate performance and limited applicability. In this work, we present PertKGE, a method designed to deconvolute compound-protein interactions from perturbation transcriptomics with knowledge graph embedding. By considering multi-level regulatory events within biological systems that share the same semantic context, PertKGE significantly improves deconvoluting accuracy in two critical "cold-start" settings: inferring targets for new compounds and conducting virtual screening for new targets. We further demonstrate the pivotal role of incorporating multi-level regulatory events in alleviating representational biases. Notably, it enables the identification of ectonucleotide pyrophosphatase/phosphodiesterase-1 as the target responsible for the unique anti-tumor immunotherapy effect of tankyrase inhibitor K-756 and the discovery of five novel hits targeting the emerging cancer therapeutic target aldehyde dehydrogenase 1B1 with a remarkable hit rate of 10.2%. These findings highlight the potential of PertKGE to accelerate drug discovery.

扰动转录组学的出现为药物发现提供了新的视角,但现有的分析方法存在性能不足和适用性有限的问题。在这项工作中,我们提出了 PertKGE,这是一种利用知识图嵌入从扰动转录组学中解构化合物与蛋白质相互作用的方法。通过考虑生物系统中具有相同语义背景的多层次调控事件,PertKGE 显著提高了在两个关键的 "冷启动 "环境中解卷的准确性:推断新化合物的靶点和进行新靶点的虚拟筛选。我们进一步证明了纳入多层次调控事件在减轻表征偏差方面的关键作用。值得注意的是,它使我们确定了外切核苷酸焦磷酸酶/磷酸二酯酶-1 是导致坦克酶抑制剂 K-756 产生独特抗肿瘤免疫治疗效果的靶点,并发现了针对新兴癌症治疗靶点醛脱氢酶 1B1 的五个新靶点,命中率高达 10.2%。这些发现凸显了 PertKGE 在加速药物发现方面的潜力。
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引用次数: 0
CXCR4 orchestrates the TOX-programmed exhausted phenotype of CD8+ T cells via JAK2/STAT3 pathway. CXCR4 通过 JAK2/STAT3 通路协调 CD8+ T 细胞的毒素编程衰竭表型。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 Epub Date: 2024-09-23 DOI: 10.1016/j.xgen.2024.100659
Canhui Cao, Miaochun Xu, Ye Wei, Ting Peng, Shitong Lin, Xiaojie Liu, Yashi Xu, Tian Chu, Shiyi Liu, Ping Wu, Bai Hu, Wencheng Ding, Li Li, Ding Ma, Peng Wu

Evidence from clinical trials suggests that CXCR4 antagonists enhance immunotherapy effectiveness in several cancers. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. Here, we employed single-cell transcriptomic analysis and identified CXCR4 as a marker gene in T cells, with CD8+PD-1high exhausted T (Tex) cells exhibiting high CXCR4 expression. By blocking CXCR4, the Tex phenotype was attenuated in vivo. Mechanistically, CXCR4-blocking T cells mitigated the Tex phenotype by regulating the JAK2-STAT3 pathway. Single-cell RNA/TCR/ATAC-seq confirmed that Cxcr4-deficient CD8+ T cells epigenetically mitigated the transition from functional to exhausted phenotypes. Notably, clinical sample analysis revealed that CXCR4+CD8+ T cells showed higher expression in patients with a non-complete pathological response. Collectively, these findings demonstrate the mechanism by which CXCR4 orchestrates CD8+ Tex cells and provide a rationale for combining CXCR4 antagonists with immunotherapy in clinical trials.

临床试验的证据表明,CXCR4 拮抗剂可提高多种癌症的免疫治疗效果。然而,CXCR4 促进免疫细胞表型的具体机制尚不完全清楚。在这里,我们采用单细胞转录组分析方法,确定了CXCR4是T细胞的标记基因,CD8+PD-1高衰竭T细胞(Tex)表现出高CXCR4表达。通过阻断 CXCR4,Tex 表型在体内得到了减弱。从机制上讲,阻断 CXCR4 的 T 细胞通过调节 JAK2-STAT3 通路减轻了 Tex 表型。单细胞RNA/TCR/ATAC-seq证实,Cxcr4缺陷的CD8+ T细胞从表观遗传学上缓解了从功能性表型向衰竭表型的转变。值得注意的是,临床样本分析显示,在病理反应不完全的患者中,CXCR4+CD8+ T细胞的表达量更高。总之,这些发现证明了 CXCR4 协调 CD8+ Tex 细胞的机制,并为在临床试验中将 CXCR4 拮抗剂与免疫疗法相结合提供了理论依据。
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引用次数: 0
A genome-wide association study of neonatal metabolites. 新生儿代谢物的全基因组关联研究。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100668
Quanze He, Hankui Liu, Lu Lu, Qin Zhang, Qi Wang, Benjing Wang, Xiaojuan Wu, Liping Guan, Jun Mao, Ying Xue, Chunhua Zhang, Xinye Cao, Yuxing He, Xiangwen Peng, Huanhuan Peng, Kangrong Zhao, Hong Li, Xin Jin, Lijian Zhao, Jianguo Zhang, Ting Wang

Genetic factors significantly influence the concentration of metabolites in adults. Nevertheless, the genetic influence on neonatal metabolites remains uncertain. To bridge this gap, we employed genotype imputation techniques on large-scale low-pass genome data obtained from non-invasive prenatal testing. Subsequently, we conducted association studies on a total of 75 metabolic components in neonates. The study identified 19 previously reported associations and 11 novel associations between single-nucleotide polymorphisms and metabolic components. These associations were initially found in the discovery cohort (8,744 participants) and subsequently confirmed in a replication cohort (19,041 participants). The average heritability of metabolic components was estimated to be 76.2%, with a range of 69%-78.8%. These findings offer valuable insights into the genetic architecture of neonatal metabolism.

遗传因素对成人代谢物的浓度有很大影响。然而,遗传因素对新生儿代谢物的影响仍不确定。为了弥补这一差距,我们在无创产前检测获得的大规模低通基因组数据上采用了基因型推算技术。随后,我们对新生儿的 75 种代谢成分进行了关联研究。研究在单核苷酸多态性与代谢成分之间发现了 19 种先前报道过的关联和 11 种新的关联。这些关联最初是在发现队列(8,744 名参与者)中发现的,随后在复制队列(19,041 名参与者)中得到证实。代谢成分的平均遗传率估计为 76.2%,范围在 69%-78.8% 之间。这些发现为新生儿代谢的遗传结构提供了宝贵的见解。
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引用次数: 0
The hidden costs of aneuploidy: New insights from yeast. 非整倍体的隐性成本:来自酵母的新见解
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100673
Yuerong Wang, Xian Fu, Yue Shen

The molecular mechanisms underlying the paradoxical effects1 of aneuploidy are still not completely understood. In this issue, Rojas et al.2 systematically analyzed the associated costs of aneuploidy and the molecular drivers involved, which revealed that aneuploidy stress is primarily driven by the cumulative effects of genes per chromosome. Notably, gene length was predicted as the most significant indicator of aneuploidy toxicity by machine learning.

非整倍体的悖论效应1 的分子机制仍未完全明了。在本期杂志中,Rojas 等人2 系统分析了非整倍体的相关代价和分子驱动因素,发现非整倍体压力主要由每条染色体上基因的累积效应驱动。值得注意的是,通过机器学习,基因长度被预测为非整倍体毒性的最重要指标。
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引用次数: 0
Unlocking the genetic influence on milk variation and its potential implication for infant health. 揭示基因对牛奶变异的影响及其对婴儿健康的潜在影响。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100676
Claudia Nussbaum, Sarah Kim-Hellmuth

Human milk has long been recognized for its critical role in infant and maternal health. In this issue of Cell Genomics, Johnson et al.1 apply a human genetics and genomics approach to shed light on the complex relationship between maternal genetics, milk variation, and the infant gut microbiome.

母乳对婴儿和产妇健康的重要作用早已得到公认。在本期的《细胞基因组学》(Cell Genomics)杂志上,Johnson 等人1运用人类遗传学和基因组学方法,揭示了母体遗传学、牛奶变异和婴儿肠道微生物组之间的复杂关系。
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引用次数: 0
Genome-wide association study of maternal plasma metabolites during pregnancy. 孕期母体血浆代谢物的全基因组关联研究。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100657
Siyang Liu, Jilong Yao, Liang Lin, Xianmei Lan, Linlin Wu, Xuelian He, Nannan Kong, Yan Li, Yuqing Deng, Jiansheng Xie, Huanhuan Zhu, Xiaoxia Wu, Zilong Li, Likuan Xiong, Yuan Wang, Jinghui Ren, Xuemei Qiu, Weihua Zhao, Ya Gao, Yuanqing Chen, Fengxia Su, Yun Zhou, Weiqiao Rao, Jing Zhang, Guixue Hou, Liping Huang, Linxuan Li, Xinhong Liu, Chao Nie, Liqiong Luo, Mei Zhao, Zengyou Liu, Fang Chen, Shengmou Lin, Lijian Zhao, Qingmei Fu, Dan Jiang, Ye Yin, Xun Xu, Jian Wang, Huanming Yang, Rong Wang, Jianmin Niu, Fengxiang Wei, Xin Jin, Siqi Liu

Metabolites are key indicators of health and therapeutic targets, but their genetic underpinnings during pregnancy-a critical period for human reproduction-are largely unexplored. Using genetic data from non-invasive prenatal testing, we performed a genome-wide association study on 84 metabolites, including 37 amino acids, 24 elements, 13 hormones, and 10 vitamins, involving 34,394 pregnant Chinese women, with sample sizes ranging from 6,394 to 13,392 for specific metabolites. We identified 53 metabolite-gene associations, 23 of which are novel. Significant differences in genetic effects between pregnant and non-pregnant women were observed for 16.7%-100% of these associations, indicating gene-environment interactions. Additionally, 50.94% of genetic associations exhibited pleiotropy among metabolites and between six metabolites and eight pregnancy phenotypes. Mendelian randomization revealed potential causal relationships between seven maternal metabolites and 15 human traits and diseases. These findings provide new insights into the genetic basis of maternal plasma metabolites during pregnancy.

代谢物是健康的关键指标和治疗靶点,但它们在孕期--人类生殖的关键时期--的遗传基础在很大程度上尚未被探索。利用无创产前检测的基因数据,我们对包括 37 种氨基酸、24 种元素、13 种激素和 10 种维生素在内的 84 种代谢物进行了全基因组关联研究,涉及 34,394 名中国孕妇,特定代谢物的样本量从 6,394 到 13,392 不等。我们发现了 53 种代谢物与基因的关联,其中 23 种是新发现的。在这些关联中,16.7%-100% 的遗传效应在孕妇和非孕妇之间存在显著差异,这表明基因与环境之间存在相互作用。此外,50.94%的基因关联在代谢物之间以及六种代谢物与八种妊娠表型之间表现出多效性。孟德尔随机化揭示了7种母体代谢物与15种人类特征和疾病之间的潜在因果关系。这些发现为研究孕期母体血浆代谢物的遗传基础提供了新的视角。
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引用次数: 0
FUSE: Improving the estimation and imputation of variant impacts in functional screening. FUSE:改进功能筛选中变异影响的估计和估算。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-10-09 DOI: 10.1016/j.xgen.2024.100667
Tian Yu, James D Fife, Vineel Bhat, Ivan Adzhubey, Richard Sherwood, Christopher A Cassa

Deep mutational scanning enables high-throughput functional assessment of genetic variants. While phenotypic measurements from screening assays generally align with clinical outcomes, experimental noise may affect the accuracy of individual variant estimates. We developed the FUSE (functional substitution estimation) pipeline, which leverages measurements collectively within screening assays to improve the estimation of variant impacts. Drawing data from 115 published functional assays, FUSE assesses the mean functional effect per amino acid position and makes estimates for individual allelic variants. It enhances the correlation of variant functional effects from different assay platforms and increases the classification accuracy of missense variants in ClinVar across 29 genes (area under the receiver operating characteristic [ROC] curve [AUC] from 0.83 to 0.90). In UK Biobank patients with rare missense variants in BRCA1, LDLR, or TP53, FUSE improves the classification accuracy of associated phenotypes. FUSE can also impute variant effects for substitutions not experimentally screened. This approach improves accuracy and broadens the utility of data from functional screening.

深度突变扫描可对基因变异进行高通量功能评估。虽然筛查测定的表型测量结果通常与临床结果一致,但实验噪音可能会影响单个变异估计的准确性。我们开发了 FUSE(功能替代估算)管道,利用筛查测定中的集体测量来改进对变异影响的估算。FUSE 从 115 项已发表的功能测定中提取数据,评估每个氨基酸位置的平均功能效应,并对单个等位基因变异进行估计。它增强了来自不同检测平台的变体功能效应的相关性,并提高了ClinVar中29个基因的错义变体分类准确性(接收器操作特征曲线[ROC]下面积[AUC]从0.83提高到0.90)。在 BRCA1、LDLR 或 TP53 中存在罕见错义变异的英国生物库患者中,FUSE 提高了相关表型的分类准确性。FUSE 还能对未经实验筛选的置换进行变异效应推算。这种方法提高了准确性,扩大了功能筛选数据的用途。
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引用次数: 0
期刊
Cell genomics
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