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A genome-wide association analysis reveals new pathogenic pathways in gout* 全基因组关联分析揭示了痛风的新致病途径*。
IF 30.8 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-15 DOI: 10.1038/s41588-024-01921-5
Tanya J. Major, Riku Takei, Hirotaka Matsuo, Megan P. Leask, Nicholas A. Sumpter, Ruth K. Topless, Yuya Shirai, Wei Wang, Murray J. Cadzow, Amanda J. Phipps-Green, Zhiqiang Li, Aichang Ji, Marilyn E. Merriman, Emily Morice, Eric E. Kelley, Wen-Hua Wei, Sally P. A. McCormick, Matthew J. Bixley, Richard J. Reynolds, Kenneth G. Saag, Tayaza Fadason, Evgenia Golovina, Justin M. O’Sullivan, Lisa K. Stamp, Nicola Dalbeth, Abhishek Abhishek, Michael Doherty, Edward Roddy, Lennart T. H. Jacobsson, Meliha C. Kapetanovic, Olle Melander, Mariano Andrés, Fernando Pérez-Ruiz, Rosa J. Torres, Timothy Radstake, Timothy L. Jansen, Matthijs Janssen, Leo A. B. Joosten, Ruiqi Liu, Orsolya I. Gaal, Tania O. Crişan, Simona Rednic, Fina Kurreeman, Tom W. J. Huizinga, René Toes, Frédéric Lioté, Pascal Richette, Thomas Bardin, Hang Korng Ea, Tristan Pascart, Geraldine M. McCarthy, Laura Helbert, Blanka Stibůrková, Anne-K. Tausche, Till Uhlig, Véronique Vitart, Thibaud S. Boutin, Caroline Hayward, Philip L. Riches, Stuart H. Ralston, Archie Campbell, Thomas M. MacDonald, Akiyoshi Nakayama, Tappei Takada, Masahiro Nakatochi, Seiko Shimizu, Yusuke Kawamura, Yu Toyoda, Hirofumi Nakaoka, Ken Yamamoto, Keitaro Matsuo, Nariyoshi Shinomiya, Kimiyoshi Ichida, Chaeyoung Lee, Linda A. Bradbury, Matthew A. Brown, Philip C. Robinson, Russell R. C. Buchanan, Catherine L. Hill, Susan Lester, Malcolm D. Smith, Maureen Rischmueller, Hyon K. Choi, Eli A. Stahl, Jeff N. Miner, Daniel H. Solomon, Jing Cui, Kathleen M. Giacomini, Deanna J. Brackman, Eric M. Jorgenson, Hongbo Liu, Katalin Susztak, Suyash Shringarpure, Alexander So, Yukinori Okada, Changgui Li, Yongyong Shi, Tony R. Merriman

Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.

痛风是一种慢性疾病,是在高尿酸血症的情况下对沉积的单钠尿酸盐结晶的先天性免疫反应引起的。在这里,我们通过一项对 260 万人(包括 120,295 名痛风患者)进行的全基因组关联研究(GWAS),深入探讨了痛风中鲜为人知的炎症成分的分子机制。我们发现了 377 个基因位点和 410 个基因独立信号(149 个以前未报道过的尿酸盐和痛风基因位点)。此外,我们还发现了 65 个在尿酸盐中有信号的位点(来自 630,117 人的 GWAS),但在痛风中没有信号。一个优先排序方案确定了痛风炎症过程中的候选基因,包括参与表观遗传重塑、细胞渗透压和 NOD 样受体蛋白 3 (NLRP3) 炎症小体活性调节的基因。孟德尔随机分析提供了证据,证明具有不确定潜能的克隆造血在痛风中起着因果作用。我们的研究确定了痛风炎症发病机制中适合后续研究的候选基因和分子过程。
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引用次数: 0
Parsing the spectrum of allelic architectures in diabetes 解析糖尿病等位基因结构谱
IF 30.8 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-14 DOI: 10.1038/s41588-024-01950-0
Yangxi Li, Constantin Polychronakos
Distinguishing ordinary diabetes from its monogenic forms has been one of the challenges in optimally managing the disease. Using high-quality imputation of rare variants and large databases, a study now defines the gray zone between the two and lays down a blueprint for objectively evaluating the related variants.
区分普通糖尿病和单基因糖尿病一直是优化糖尿病管理的挑战之一。现在,一项研究利用罕见变异的高质量归因和大型数据库,界定了两者之间的灰色地带,并为客观评估相关变异绘制了蓝图。
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引用次数: 0
Potential approaches to create ultimate genotypes in crops and livestock 创造作物和牲畜终极基因型的潜在方法
IF 30.8 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-14 DOI: 10.1038/s41588-024-01942-0
Ben J. Hayes, Timothy J. Mahony, Kira Villiers, Christie Warburton, Kathryn E. Kemper, Eric Dinglasan, Hannah Robinson, Owen Powell, Kai Voss-Fels, Ian D. Godwin, Lee T. Hickey

Many thousands and, in some cases, millions of individuals from the major crop and livestock species have been genotyped and phenotyped for the purpose of genomic selection. ‘Ultimate genotypes’, in which the marker allele haplotypes with the most favorable effects on a target trait or traits in the population are combined together in silico, can be constructed from these datasets. Ultimate genotypes display up to six times the performance of the current best individuals in the population, as demonstrated for net profit in dairy cattle (incorporating a range of economic traits), yield in wheat and 100-seed weight in chickpea. However, current breeding strategies that aim to assemble ultimate genotypes through conventional crossing take many generations. As a hypothetical thought piece, here, we contemplate three future pathways for rapidly achieving ultimate genotypes: accelerated recombination with gene editing, direct editing of whole-genome haplotype sequences and synthetic biology.

为了进行基因组选育,已经对主要农作物和牲畜物种的成千上万个个体进行了基因分型和表型分析,在某些情况下甚至达到了数百万个个体。终极基因型 "是指在群体中对目标性状具有最有利影响的标记等位基因单倍型,可以从这些数据集中构建出来。终极基因型的表现可达目前种群中最佳个体的六倍,奶牛的净利润(包括一系列经济性状)、小麦的产量和鹰嘴豆的百粒重都证明了这一点。然而,目前的育种策略旨在通过常规杂交培育终极基因型,这需要很多代人的努力。作为一个假设性的想法,我们在此设想了未来快速实现终极基因型的三种途径:基因编辑加速重组、直接编辑全基因组单倍型序列和合成生物学。
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引用次数: 0
Mapping extrachromosomal DNA amplifications during cancer progression 绘制癌症进展过程中染色体外 DNA 扩增的图谱
IF 30.8 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-14 DOI: 10.1038/s41588-024-01949-7
Hoon Kim, Soyeon Kim, Taylor Wade, Eunchae Yeo, Anuja Lipsa, Anna Golebiewska, Kevin C. Johnson, Sepil An, Junyong Ko, Yoonjoo Nam, Hwa Yeon Lee, Seunghyun Kang, Heesuk Chung, Simone P. Niclou, Hyo-Eun Moon, Sun Ha Paek, Vineet Bafna, Jens Luebeck, Roel G. W. Verhaak

To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers. In particular, tubulin inhibition associated with ecDNA increases, suggesting a role for ecDNA in treatment response. In longitudinally matched tumor samples, ecDNAs were more likely to be retained compared to chromosomal amplifications. EcDNAs shared between time points, and ecDNAs in advanced cancers were more likely to harbor localized hypermutation events compared to private ecDNAs and ecDNAs in newly diagnosed tumors. Relatively high variant allele fractions of ecDNA localized hypermutations implicated early ecDNA mutagenesis. Our findings nominate ecDNAs to provide tumors with competitive advantages during cancer progression and metastasis.

为了了解染色体外DNA(ecDNA)扩增在癌症进展中的作用,我们检测了8060例新诊断的原发性癌症、未治疗的转移瘤和重度预处理肿瘤中的病灶扩增并对其进行了分类。与新诊断的癌症相比,在未经治疗的转移瘤和预处理肿瘤中检测到的 ecDNAs 频率明显更高。与未经治疗的癌症相比,化疗预处理患者的肿瘤显示出更高的 ecDNA 频率。特别是,微管蛋白抑制与 ecDNA 的增加有关,表明 ecDNA 在治疗反应中的作用。在纵向匹配的肿瘤样本中,与染色体扩增相比,ecDNA更有可能被保留下来。ecDNA在不同时间点之间共享,晚期癌症中的ecDNA与私人ecDNA和新诊断肿瘤中的ecDNA相比,更有可能携带局部高突变事件。ecDNA局部高突变的变异等位基因比例相对较高,这与早期ecDNA突变有关。我们的研究结果表明,ecDNA 在癌症进展和转移过程中为肿瘤提供了竞争优势。
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引用次数: 0
Reprogramming-based gene therapy promotes anti-tumor immunity in vivo 基于重编程的基因疗法促进体内抗肿瘤免疫力
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-10 DOI: 10.1038/s41588-024-01956-8
Chiara Anania
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引用次数: 0
Personalizing pangenome graphs with k-mers 利用 k-mers 个性化庞基因组图谱
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-10 DOI: 10.1038/s41588-024-01954-w
Wei Li
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引用次数: 0
Autoreactive T cells target neoself-antigens in lupus 自反应 T 细胞靶向狼疮中的新自身抗原
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-10 DOI: 10.1038/s41588-024-01955-9
Kyle Vogan
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引用次数: 0
Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides 人类 DNA 聚合酶 ε 是 CpG 二核苷酸上 C>T 突变的来源之一
IF 30.8 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-10 DOI: 10.1038/s41588-024-01945-x
Marketa Tomkova, Michael John McClellan, Gilles Crevel, Akbar Muhammed Shahid, Nandini Mozumdar, Jakub Tomek, Emelie Shepherd, Sue Cotterill, Benjamin Schuster-Böckler, Skirmantas Kriaucionis

C-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism.

CpG 二核苷酸的 C-T 转换是人类癌症和遗传疾病中最常见的突变。这些突变归因于 5-甲基胞嘧啶(5mC)的脱氨基作用,5-甲基胞嘧啶是 CpGs 上的一种表观遗传修饰。我们最近将 CpG>TpG 突变与复制联系起来,并假设聚合酶 ε(Pol ε)引入的错误可能是突变的另一个来源。在这里,我们提出了一种称为聚合酶错误率测序(PER-seq)的新方法,用于单独测量 DNA 聚合酶的错误谱。我们发现,最常见的人类癌症相关 Pol ε 突变体(P286R)产生了过多的 CpG>TpG 错误,表征了携带这种突变和错配修复缺陷的肿瘤的突变谱。值得注意的是,我们还发现野生型 Pol ε 复制 5mCpG 时的错误率比其他情况下的 C 高七倍。我们从 PER-seq 和人类癌症中获得的结果共同证明,复制错误是复制细胞中 CpG>TpG 诱变的主要因素,从根本上改变了我们对这一重要致病突变机制的认识。
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引用次数: 0
Defining genome access of transcription factors 定义转录因子的基因组访问
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-10 DOI: 10.1038/s41588-024-01953-x
Petra Gross
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引用次数: 0
DNA polymerase ε produces elevated C-to-T mutations at methylated CpG dinucleotides. DNA 聚合酶 ε 会在甲基化的 CpG 二核苷酸上产生较高的 C-T 突变。
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-10-09 DOI: 10.1038/s41588-024-01946-w
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引用次数: 0
期刊
Nature genetics
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