Pub Date : 2024-10-15DOI: 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.
{"title":"A genome-wide association analysis reveals new pathogenic pathways in gout*","authors":"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","doi":"10.1038/s41588-024-01921-5","DOIUrl":"https://doi.org/10.1038/s41588-024-01921-5","url":null,"abstract":"<p>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.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":30.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436343","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}
Pub Date : 2024-10-14DOI: 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.
{"title":"Parsing the spectrum of allelic architectures in diabetes","authors":"Yangxi Li, Constantin Polychronakos","doi":"10.1038/s41588-024-01950-0","DOIUrl":"https://doi.org/10.1038/s41588-024-01950-0","url":null,"abstract":"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.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":30.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430545","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}
Pub Date : 2024-10-14DOI: 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.
{"title":"Potential approaches to create ultimate genotypes in crops and livestock","authors":"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","doi":"10.1038/s41588-024-01942-0","DOIUrl":"https://doi.org/10.1038/s41588-024-01942-0","url":null,"abstract":"<p>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.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":30.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430547","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}
Pub Date : 2024-10-14DOI: 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.
{"title":"Mapping extrachromosomal DNA amplifications during cancer progression","authors":"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","doi":"10.1038/s41588-024-01949-7","DOIUrl":"https://doi.org/10.1038/s41588-024-01949-7","url":null,"abstract":"<p>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.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":30.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430546","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}
Pub Date : 2024-10-10DOI: 10.1038/s41588-024-01955-9
Kyle Vogan
{"title":"Autoreactive T cells target neoself-antigens in lupus","authors":"Kyle Vogan","doi":"10.1038/s41588-024-01955-9","DOIUrl":"10.1038/s41588-024-01955-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398525","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}
Pub Date : 2024-10-10DOI: 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。
{"title":"Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides","authors":"Marketa Tomkova, Michael John McClellan, Gilles Crevel, Akbar Muhammed Shahid, Nandini Mozumdar, Jakub Tomek, Emelie Shepherd, Sue Cotterill, Benjamin Schuster-Böckler, Skirmantas Kriaucionis","doi":"10.1038/s41588-024-01945-x","DOIUrl":"https://doi.org/10.1038/s41588-024-01945-x","url":null,"abstract":"<p>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.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":30.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397747","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}