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Identifying genetic variants that influence the abundance of cell states in single-cell data 识别影响单细胞数据中细胞状态丰度的基因变异
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01909-1
Laurie Rumker, Saori Sakaue, Yakir Reshef, Joyce B. Kang, Seyhan Yazar, Jose Alquicira-Hernandez, Cristian Valencia, Kaitlyn A. Lagattuta, Annelise Mah-Som, Aparna Nathan, Joseph E. Powell, Po-Ru Loh, Soumya Raychaudhuri
Disease risk alleles influence the composition of cells present in the body, but modeling genetic effects on the cell states revealed by single-cell profiling is difficult because variant-associated states may reflect diverse combinations of the profiled cell features that are challenging to predefine. We introduce Genotype–Neighborhood Associations (GeNA), a statistical tool to identify cell-state abundance quantitative trait loci (csaQTLs) in high-dimensional single-cell datasets. Instead of testing associations to predefined cell states, GeNA flexibly identifies the cell states whose abundance is most associated with genetic variants. In a genome-wide survey of single-cell RNA sequencing peripheral blood profiling from 969 individuals, GeNA identifies five independent loci associated with shifts in the relative abundance of immune cell states. For example, rs3003-T (P = 1.96 × 10−11) associates with increased abundance of natural killer cells expressing tumor necrosis factor response programs. This csaQTL colocalizes with increased risk for psoriasis, an autoimmune disease that responds to anti-tumor necrosis factor treatments. Flexibly characterizing csaQTLs for granular cell states may help illuminate how genetic background alters cellular composition to confer disease risk. GeNA identifies cell-state abundance quantitative trait loci (csaQTLs) in single-cell RNA sequencing data. Applied to OneK1K, GeNA identifies natural killer cell and myeloid csaQTLs and implicates interferon-α-related cell states using a polygenic risk score for systemic lupus erythematosus.
疾病风险等位基因会影响体内细胞的组成,但对单细胞图谱揭示的细胞状态的遗传效应建模却很困难,因为变异相关状态可能反映了图谱细胞特征的不同组合,而这些组合很难预先确定。我们介绍了基因型-邻近关联(GeNA),这是一种在高维单细胞数据集中识别细胞状态丰度定量性状位点(csaQTLs)的统计工具。GeNA 不测试与预定义细胞状态的关联,而是灵活地确定其丰度与遗传变异关联最大的细胞状态。在对 969 人的外周血单细胞 RNA 测序分析进行的全基因组调查中,GeNA 发现了五个与免疫细胞状态相对丰度变化相关的独立位点。例如,rs3003-T(P = 1.96 × 10-11)与表达肿瘤坏死因子反应程序的自然杀伤细胞数量增加有关。这种 csaQTL 与银屑病风险的增加有关,银屑病是一种自身免疫性疾病,对抗肿瘤坏死因子治疗有反应。灵活表征颗粒细胞状态的 csaQTL 可能有助于阐明遗传背景如何改变细胞组成,从而导致疾病风险。
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引用次数: 0
Enhancing the Polygenic Score Catalog with tools for score calculation and ancestry normalization 利用分数计算和祖先归一化工具增强多基因分数目录
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01937-x
Samuel A. Lambert, Benjamin Wingfield, Joel T. Gibson, Laurent Gil, Santhi Ramachandran, Florent Yvon, Shirin Saverimuttu, Emily Tinsley, Elizabeth Lewis, Scott C. Ritchie, Jingqin Wu, Rodrigo Cánovas, Aoife McMahon, Laura W. Harris, Helen Parkinson, Michael Inouye
Polygenic scores (PGSs) have transformed human genetic research and have numerous potential clinical applications. Here we present a series of recent enhancements to the PGS Catalog and highlight the PGS Catalog Calculator, an open-source, scalable and portable pipeline for reproducibly calculating PGSs that democratizes equitable PGS applications.
多基因评分(PGS)改变了人类基因研究,并具有众多潜在的临床应用价值。在此,我们介绍了 PGS 目录的一系列最新改进,并重点介绍了 PGS 目录计算器,这是一个开源、可扩展、可移植的管道,用于重复计算 PGS,使公平的 PGS 应用民主化。
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引用次数: 0
Spatial mapping of primary and metastatic pancreatic tumor ecosystems 原发性和转移性胰腺肿瘤生态系统的空间分布图
IF 30.8 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01915-3
This study presents a spatial transcriptomic analysis of matched primary tumors, liver metastases and lymph node metastases from patients with pancreatic ductal adenocarcinoma. Using a tumor ecosystem approach, we uncovered notable tumor microenvironmental heterogeneity and marked differences between primary and metastatic samples, providing key insights into metastatic pancreatic cancer.
本研究对胰腺导管腺癌患者的匹配原发肿瘤、肝转移灶和淋巴结转移灶进行了空间转录组学分析。利用肿瘤生态系统方法,我们发现了原发样本和转移样本之间显著的肿瘤微环境异质性和明显差异,为我们深入了解转移性胰腺癌提供了关键信息。
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引用次数: 0
Host physiology shapes the mutational landscape of normal and carcinogenic tissue 宿主生理决定正常组织和致癌组织的突变情况
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-26 DOI: 10.1038/s41588-024-01922-4
Nadia Nasreddin, Owen J. Sansom
Somatic mutations accrue with age as patches of mutant clones arise in otherwise histologically normal tissue. The clones’ persistence, expansion and roles in physiology and tumorigenesis are unclear. New work on the behavior of Pik3caH1047R mutant esophageal clones shows that host-dependent metabolic features underpin their expansion.
随着年龄的增长,组织学上正常的组织中会出现成片的突变克隆,从而导致体细胞突变。这些克隆的持续性、扩展性以及在生理和肿瘤发生中的作用尚不清楚。有关 Pik3caH1047R 突变食管克隆行为的新研究表明,宿主依赖性代谢特征是其扩张的基础。
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引用次数: 0
Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank 英国生物库中基因组、外显子组和估算的遗传关联信号的产量
IF 30.8 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-25 DOI: 10.1038/s41588-024-01930-4
Sheila M. Gaynor, Tyler Joseph, Xiaodong Bai, Yuxin Zou, Boris Boutkov, Evan K. Maxwell, Olivier Delaneau, Robin J. Hofmeister, Olga Krasheninina, Suganthi Balasubramanian, Anthony Marcketta, Joshua Backman, Jeffrey G. Reid, John D. Overton, Luca A. Lotta, Jonathan Marchini, William J. Salerno, Aris Baras, Goncalo R. Abecasis, Timothy A. Thornton

Whole-genome sequencing (WGS), whole-exome sequencing (WES) and array genotyping with imputation (IMP) are common strategies for assessing genetic variation and its association with medically relevant phenotypes. To date, there has been no systematic empirical assessment of the yield of these approaches when applied to hundreds of thousands of samples to enable the discovery of complex trait genetic signals. Using data for 100 complex traits from 149,195 individuals in the UK Biobank, we systematically compare the relative yield of these strategies in genetic association studies. We find that WGS and WES combined with arrays and imputation (WES + IMP) have the largest association yield. Although WGS results in an approximately fivefold increase in the total number of assayed variants over WES + IMP, the number of detected signals differed by only 1% for both single-variant and gene-based association analyses. Given that WES + IMP typically results in savings of lab and computational time and resources expended per sample, we evaluate the potential benefits of applying WES + IMP to larger samples. When we extend our WES + IMP analyses to 468,169 UK Biobank individuals, we observe an approximately fourfold increase in association signals with the threefold increase in sample size. We conclude that prioritizing WES + IMP and large sample sizes rather than contemporary short-read WGS alternatives will maximize the number of discoveries in genetic association studies.

全基因组测序(WGS)、全外显子组测序(WES)和带归因的阵列基因分型(IMP)是评估遗传变异及其与医学相关表型关联的常用策略。迄今为止,这些方法在应用于数十万样本以发现复杂性状遗传信号时的收益还没有系统的实证评估。利用英国生物库中 149195 个个体的 100 个复杂性状的数据,我们系统地比较了这些策略在遗传关联研究中的相对收益。我们发现,WGS 和 WES 结合阵列和归因(WES + IMP)的关联收益最大。虽然与 WES + IMP 相比,WGS 使检测变体总数增加了约五倍,但在单变体和基于基因的关联分析中,检测到的信号数量仅相差 1%。鉴于 WES + IMP 通常可以节省每个样本的实验室和计算时间及资源,我们评估了将 WES + IMP 应用于更大样本的潜在优势。当我们将 WES + IMP 分析扩展到 468,169 个英国生物库个体时,我们发现随着样本量增加三倍,关联信号增加了约四倍。我们的结论是,优先考虑 WES + IMP 和大样本量,而不是当代的短读数 WGS,将最大限度地增加遗传关联研究的发现数量。
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引用次数: 0
Integration of variant annotations using deep set networks boosts rare variant association testing 利用深度集网络整合变异注释可促进罕见变异关联测试
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-25 DOI: 10.1038/s41588-024-01919-z
Brian Clarke, Eva Holtkamp, Hakime Öztürk, Marcel Mück, Magnus Wahlberg, Kayla Meyer, Felix Munzlinger, Felix Brechtmann, Florian R. Hölzlwimmer, Jonas Lindner, Zhifen Chen, Julien Gagneur, Oliver Stegle
Rare genetic variants can have strong effects on phenotypes, yet accounting for rare variants in genetic analyses is statistically challenging due to the limited number of allele carriers and the burden of multiple testing. While rich variant annotations promise to enable well-powered rare variant association tests, methods integrating variant annotations in a data-driven manner are lacking. Here we propose deep rare variant association testing (DeepRVAT), a model based on set neural networks that learns a trait-agnostic gene impairment score from rare variant annotations and phenotypes, enabling both gene discovery and trait prediction. On 34 quantitative and 63 binary traits, using whole-exome-sequencing data from UK Biobank, we find that DeepRVAT yields substantial gains in gene discoveries and improved detection of individuals at high genetic risk. Finally, we demonstrate how DeepRVAT enables calibrated and computationally efficient rare variant tests at biobank scale, aiding the discovery of genetic risk factors for human disease traits. Deep rare variant association testing (DeepRVAT) is a deep set neural network model that flexibly integrates rare variant annotations into a trait-agnostic gene impairment score. These scores improve association testing and polygenic risk prediction.
罕见遗传变异对表型有很大影响,但由于等位基因携带者数量有限和多重测试的负担,在遗传分析中考虑罕见变异在统计学上具有挑战性。虽然丰富的变异注释有望实现强大的罕见变异关联测试,但目前还缺乏以数据驱动方式整合变异注释的方法。在此,我们提出了深度罕见变异关联测试(DeepRVAT),这是一种基于集合神经网络的模型,它能从罕见变异注释和表型中学习与性状无关的基因损伤评分,从而实现基因发现和性状预测。我们利用英国生物库的全外显子测序数据对 34 个定量性状和 63 个二元性状进行了分析,发现 DeepRVAT 在发现基因和检测高遗传风险个体方面都有显著提高。最后,我们展示了 DeepRVAT 如何在生物库规模上实现校准和计算高效的罕见变异测试,从而帮助发现人类疾病特征的遗传风险因素。
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引用次数: 0
Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution 定义体细胞进化过程中细胞表型的遗传性、可塑性和过渡动力学
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-24 DOI: 10.1038/s41588-024-01920-6
Joshua S. Schiffman, Andrew R. D’Avino, Tamara Prieto, Yakun Pang, Yilin Fan, Srinivas Rajagopalan, Catherine Potenski, Toshiro Hara, Mario L. Suvà, Charles Gawad, Dan A. Landau
Single-cell sequencing has characterized cell state heterogeneity across diverse healthy and malignant tissues. However, the plasticity or heritability of these cell states remains largely unknown. To address this, we introduce PATH (phylogenetic analysis of trait heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers. Altogether, PATH replaces qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution. Phylogenetic analysis of trait heritability (PATH) applies phylogenetic correlations to single-cell lineage tracing data, quantifying cell state plasticity and transition probabilities. PATH offers insights into cell state heritability and transition dynamics in cancers.
单细胞测序技术描述了各种健康和恶性组织的细胞状态异质性。然而,这些细胞状态的可塑性或遗传性在很大程度上仍然未知。为了解决这个问题,我们引入了 PATH(性状遗传性系统发育分析),这是一个量化细胞状态遗传性与可塑性的框架,可以从单细胞系追踪数据推断细胞状态的转变和增殖动态。我们将 PATH 应用于小鼠胰腺癌模型,观察到上皮细胞向间质细胞转变谱两端的遗传性,而中间状态的可塑性更高。在原发性胶质母细胞瘤中,我们发现了干细胞和间充质样细胞之间的双向转变,这种转变以星形胶质细胞样状态为中介。最后,我们从 B 细胞急性淋巴细胞白血病的单细胞全基因组测序中重建了系统发育,并描述了与遗传驱动因素相关的 B 细胞分化状态的遗传性。总之,PATH 以定量测量取代了可塑性的定性概念,为研究体细胞进化提供了一个框架。
{"title":"Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution","authors":"Joshua S. Schiffman,&nbsp;Andrew R. D’Avino,&nbsp;Tamara Prieto,&nbsp;Yakun Pang,&nbsp;Yilin Fan,&nbsp;Srinivas Rajagopalan,&nbsp;Catherine Potenski,&nbsp;Toshiro Hara,&nbsp;Mario L. Suvà,&nbsp;Charles Gawad,&nbsp;Dan A. Landau","doi":"10.1038/s41588-024-01920-6","DOIUrl":"10.1038/s41588-024-01920-6","url":null,"abstract":"Single-cell sequencing has characterized cell state heterogeneity across diverse healthy and malignant tissues. However, the plasticity or heritability of these cell states remains largely unknown. To address this, we introduce PATH (phylogenetic analysis of trait heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers. Altogether, PATH replaces qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution. Phylogenetic analysis of trait heritability (PATH) applies phylogenetic correlations to single-cell lineage tracing data, quantifying cell state plasticity and transition probabilities. PATH offers insights into cell state heritability and transition dynamics in cancers.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance 对来自 1 405 人的血液 eQTL 和 pQTL 进行统计和功能精细映射,揭示了不同的调控模式和疾病相关性
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-24 DOI: 10.1038/s41588-024-01896-3
Qingbo S. Wang, Takanori Hasegawa, Ho Namkoong, Ryunosuke Saiki, Ryuya Edahiro, Kyuto Sonehara, Hiromu Tanaka, Shuhei Azekawa, Shotaro Chubachi, Yugo Takahashi, Saori Sakaue, Shinichi Namba, Kenichi Yamamoto, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Hideki Makishima, Yasuhito Nannya, Zicong Zhang, Rika Tsujikawa, Ryuji Koike, Tomomi Takano, Makoto Ishii, Akinori Kimura, Fumitaka Inoue, Takanori Kanai, Koichi Fukunaga, Seishi Ogawa, Seiya Imoto, Satoru Miyano, Yukinori Okada, Japan COVID-19 Task Force
Studying the genetic regulation of protein expression (through protein quantitative trait loci (pQTLs)) offers a deeper understanding of regulatory variants uncharacterized by mRNA expression regulation (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood mRNA and 2,932 plasma samples of protein expression, as part of the Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 variants validated with a massively parallel reporter assay. Fine-mapped pQTLs (n = 582) were enriched for missense variations on structured and extracellular domains, although the possibility of epitope-binding artifacts remains. Trans-eQTL and trans-pQTL analysis highlighted associations of class I HLA allele variation with KIR genes. We contrast the multi-tissue origin of plasma protein with blood mRNA, contributing to the limited colocalization level, distinct regulatory mechanisms and trait relevance of eQTLs and pQTLs. We report a negative correlation between ABO mRNA and protein expression because of linkage disequilibrium between distinct nearby eQTLs and pQTLs. Statistical fine-mapping of mRNA and protein quantitative trait loci in blood samples from the Japan COVID-19 Task Force sheds light on regulatory mechanisms and disease associations.
通过蛋白质定量性状位点(pQTLs)研究蛋白质表达的遗传调控,可以更深入地了解 mRNA 表达调控(表达 QTLs (eQTLs))研究中未表征的调控变异。作为日本 COVID-19 特别工作组(JCTF)的一部分,我们在此报告了从 1,405 份血液 mRNA 基因分型样本和 2,932 份血浆蛋白质表达样本中获得的顺式-eQTL 和顺式-pQTL 统计精细图谱。精细映射的 eQTL(n = 3,464)富集了 932 个变体,并通过大规模并行报告检测进行了验证。结构域和细胞外结构域上的错义变异富集了精细映射 pQTLs(n = 582),但仍存在表位结合假象的可能性。反式-eQTL 和反式-pQTL 分析强调了 I 类 HLA 等位基因变异与 KIR 基因的关联。我们对比了血浆蛋白与血液 mRNA 的多组织来源,这导致了 eQTL 和 pQTL 有限的共定位水平、不同的调控机制和性状相关性。我们报告了 ABO mRNA 和蛋白质表达之间的负相关,这是因为附近不同的 eQTL 和 pQTL 之间存在连锁不平衡。
{"title":"Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance","authors":"Qingbo S. Wang,&nbsp;Takanori Hasegawa,&nbsp;Ho Namkoong,&nbsp;Ryunosuke Saiki,&nbsp;Ryuya Edahiro,&nbsp;Kyuto Sonehara,&nbsp;Hiromu Tanaka,&nbsp;Shuhei Azekawa,&nbsp;Shotaro Chubachi,&nbsp;Yugo Takahashi,&nbsp;Saori Sakaue,&nbsp;Shinichi Namba,&nbsp;Kenichi Yamamoto,&nbsp;Yuichi Shiraishi,&nbsp;Kenichi Chiba,&nbsp;Hiroko Tanaka,&nbsp;Hideki Makishima,&nbsp;Yasuhito Nannya,&nbsp;Zicong Zhang,&nbsp;Rika Tsujikawa,&nbsp;Ryuji Koike,&nbsp;Tomomi Takano,&nbsp;Makoto Ishii,&nbsp;Akinori Kimura,&nbsp;Fumitaka Inoue,&nbsp;Takanori Kanai,&nbsp;Koichi Fukunaga,&nbsp;Seishi Ogawa,&nbsp;Seiya Imoto,&nbsp;Satoru Miyano,&nbsp;Yukinori Okada,&nbsp;Japan COVID-19 Task Force","doi":"10.1038/s41588-024-01896-3","DOIUrl":"10.1038/s41588-024-01896-3","url":null,"abstract":"Studying the genetic regulation of protein expression (through protein quantitative trait loci (pQTLs)) offers a deeper understanding of regulatory variants uncharacterized by mRNA expression regulation (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood mRNA and 2,932 plasma samples of protein expression, as part of the Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 variants validated with a massively parallel reporter assay. Fine-mapped pQTLs (n = 582) were enriched for missense variations on structured and extracellular domains, although the possibility of epitope-binding artifacts remains. Trans-eQTL and trans-pQTL analysis highlighted associations of class I HLA allele variation with KIR genes. We contrast the multi-tissue origin of plasma protein with blood mRNA, contributing to the limited colocalization level, distinct regulatory mechanisms and trait relevance of eQTLs and pQTLs. We report a negative correlation between ABO mRNA and protein expression because of linkage disequilibrium between distinct nearby eQTLs and pQTLs. Statistical fine-mapping of mRNA and protein quantitative trait loci in blood samples from the Japan COVID-19 Task Force sheds light on regulatory mechanisms and disease associations.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01896-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations 对来自不同人群的 29 745 名发育障碍患者的常染色体隐性编码变异进行联合分析
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-23 DOI: 10.1038/s41588-024-01910-8
V. Kartik Chundru, Zhancheng Zhang, Klaudia Walter, Sarah J. Lindsay, Petr Danecek, Ruth Y. Eberhardt, Eugene J. Gardner, Daniel S. Malawsky, Emilie M. Wigdor, Rebecca Torene, Kyle Retterer, Caroline F. Wright, Hildur Ólafsdóttir, Maria J. Guillen Sacoto, Akif Ayaz, Ismail Hakki Akbeyaz, Dilşad Türkdoğan, Aaisha Ibrahim Al Balushi, Aida Bertoli-Avella, Peter Bauer, Emmanuelle Szenker-Ravi, Bruno Reversade, Kirsty McWalter, Eamonn Sheridan, Helen V. Firth, Matthew E. Hurles, Kaitlin E. Samocha, Vincent D. Ustach, Hilary C. Martin
Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2–19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16. This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes. Analysis of autosomal recessive coding variants in 29,745 trios from the DDD study and GeneDx provides insights into the genetic architecture of developmental disorders across ancestrally diverse populations.
常染色体隐性编码变异是导致罕见疾病的众所周知的原因。我们在一个由 29,745 人组成的大型祖先多样性队列中量化了这些变异对发育障碍的贡献,其中 20.4% 的人的遗传推断祖先为非欧洲人。据估计,全外显子常染色体隐性编码变异导致的患者比例在各遗传推断祖先群体中介于~2%-19%之间,并与平均自身杂合度显著相关。已确定的常染色体隐性发育障碍相关基因(ARDD)占常染色体隐性编码负担总量的 84.0%,而这些已确定基因中 34.4% 的负担是由 ClinVar 中尚未报告为致病的变异所造成的。统计分析发现了两个新的 ARDD 基因:KBTBD2 和 ZDHHC16。这项研究拓展了我们对不同遗传推断祖先群体发育障碍遗传结构的了解,并表明改进已知 ARDD 基因中错义变异的解释策略可能比发现其余基因更有助于诊断更多患者。
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引用次数: 0
Self-sustaining long-term 3D epithelioid cultures reveal drivers of clonal expansion in esophageal epithelium 自我维持的长期三维上皮细胞培养揭示食管上皮细胞克隆扩增的驱动因素
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-09-23 DOI: 10.1038/s41588-024-01875-8
Albert Herms, David Fernandez-Antoran, Maria P. Alcolea, Argyro Kalogeropoulou, Ujjwal Banerjee, Gabriel Piedrafita, Emilie Abby, Jose Antonio Valverde-Lopez, Inês S. Ferreira, Irene Caseda, Maria T. Bejar, Stefan C. Dentro, Sara Vidal-Notari, Swee Hoe Ong, Bartomeu Colom, Kasumi Murai, Charlotte King, Krishnaa Mahbubani, Kourosh Saeb-Parsy, Alan R. Lowe, Moritz Gerstung, Philip H. Jones
Aging epithelia are colonized by somatic mutations, which are subjected to selection influenced by intrinsic and extrinsic factors. The lack of suitable culture systems has slowed the study of this and other long-term biological processes. Here, we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least 1 year, maintaining a three-dimensional structure with proliferative basal cells that differentiate into suprabasal cells, which eventually shed and retain genomic stability. Live imaging over 5 months showed that epithelioids replicate in vivo cell dynamics. Epithelioids support genetic manipulation and enable the study of mutant cell competition and selection in three-dimensional epithelia, and show how anti-cancer treatments modulate competition between transformed and wild-type cells. Finally, a targeted CRISPR–Cas9 screen shows that epithelioids recapitulate mutant gene selection in aging human esophagus and identifies additional drivers of clonal expansion, resolving the genetic networks underpinning competitive fitness. Epithelioids are genetically stable, self-sustaining three-dimensional cultures. They may be used to investigate various aspects of epithelial biology over several months without need for passaging. In this paper, mouse epithelioids are used to identify drivers of clonal expansion in the esophagus.
衰老的上皮受到体细胞突变的影响,而体细胞突变又受到内在和外在因素的选择。由于缺乏合适的培养系统,对这一过程和其他长期生物学过程的研究进展缓慢。在这里,我们描述了上皮细胞,这是一种培养多种小鼠和人类上皮细胞的简便、经济有效的方法。食管上皮细胞无需传代就能自我维持至少 1 年,保持三维结构,基底细胞增生分化为上基底细胞,最终脱落并保持基因组稳定性。超过 5 个月的实时成像显示,上皮细胞复制了体内细胞的动态变化。上皮细胞支持遗传操作,能够在三维上皮细胞中研究突变细胞的竞争和选择,并展示抗癌治疗如何调节转化细胞和野生型细胞之间的竞争。最后,一项有针对性的CRISPR-Cas9筛选显示,上皮细胞再现了衰老人类食管中的突变基因选择,并确定了克隆扩增的其他驱动因素,解决了支撑竞争性适存的遗传网络问题。
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引用次数: 0
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Nature genetics
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