首页 > 最新文献

Nature genetics最新文献

英文 中文
Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency CCDC201 停止-增益变异的同基因遗传会导致原发性卵巢功能不全。
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-27 DOI: 10.1038/s41588-024-01885-6
Asmundur Oddsson, Valgerdur Steinthorsdottir, Gudjon R. Oskarsson, Unnur Styrkarsdottir, Kristjan H. S. Moore, Salvor Isberg, Gisli H. Halldorsson, Gardar Sveinbjornsson, David Westergaard, Henriette Svarre Nielsen, Run Fridriksdottir, Brynjar O. Jensson, Gudny A. Arnadottir, Hakon Jonsson, Arni Sturluson, Audunn S. Snaebjarnarson, Ole A. Andreassen, G. Bragi Walters, Mette Nyegaard, Christian Erikstrup, Thora Steingrimsdottir, Rolv T. Lie, Pall Melsted, Ingileif Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Jona Saemundsdottir, Olafur Th. Magnusson, DBDS Genomic Consortium, Karina Banasik, Erik Sorensen, Gisli Masson, Ole Birger Pedersen, Laufey Tryggvadottir, Jan Haavik, Sisse Rye Ostrowski, Hreinn Stefansson, Hilma Holm, Thorunn Rafnar, Daniel F. Gudbjartsson, Patrick Sulem, Kari Stefansson
Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10−15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10−5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause. Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.
绝经年龄(AOM)对生育和疾病风险有很大影响。虽然在加性模型下通过全基因组关联研究(GWAS)发现了许多与绝经年龄相关的变异位点,但很少考虑其他遗传模型1。在此,我们通过对来自冰岛、丹麦、英国(UK;UK Biobank)和挪威的 174 329 名绝经后妇女进行隐性模型下的 GWAS 元分析,研究了对 AOM 影响较大的低频变异。我们发现,CCDC201(p.(Arg162Ter),小等位基因频率约为 1%)中的停止-增益变异 rs117316434 (A)的同源女性比其他女性提前 9 年绝经(P = 1.3 × 10-15)。北欧每 10,000 名妇女中就有一人存在这种基因型,其中近一半会导致原发性卵巢功能不全。因此,同型基因携带者生育的子女较少,末次生育年龄提前 5 年(P = 3.8 × 10-5)。CCDC201 基因于 2022 年才在人类中发现,在卵母细胞中高度表达。CCDC201功能缺失的同基因遗传对女性生殖健康有很大影响,同基因遗传者将受益于生殖咨询和更年期提前症状的治疗。
{"title":"Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency","authors":"Asmundur Oddsson, Valgerdur Steinthorsdottir, Gudjon R. Oskarsson, Unnur Styrkarsdottir, Kristjan H. S. Moore, Salvor Isberg, Gisli H. Halldorsson, Gardar Sveinbjornsson, David Westergaard, Henriette Svarre Nielsen, Run Fridriksdottir, Brynjar O. Jensson, Gudny A. Arnadottir, Hakon Jonsson, Arni Sturluson, Audunn S. Snaebjarnarson, Ole A. Andreassen, G. Bragi Walters, Mette Nyegaard, Christian Erikstrup, Thora Steingrimsdottir, Rolv T. Lie, Pall Melsted, Ingileif Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Jona Saemundsdottir, Olafur Th. Magnusson, DBDS Genomic Consortium, Karina Banasik, Erik Sorensen, Gisli Masson, Ole Birger Pedersen, Laufey Tryggvadottir, Jan Haavik, Sisse Rye Ostrowski, Hreinn Stefansson, Hilma Holm, Thorunn Rafnar, Daniel F. Gudbjartsson, Patrick Sulem, Kari Stefansson","doi":"10.1038/s41588-024-01885-6","DOIUrl":"10.1038/s41588-024-01885-6","url":null,"abstract":"Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10−15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10−5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause. Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01885-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081006","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
Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences 462,666 个英国生物库全基因组序列中端粒长度的遗传结构。
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-27 DOI: 10.1038/s41588-024-01884-7
Oliver S. Burren, Ryan S. Dhindsa, Sri V. V. Deevi, Sean Wen, Abhishek Nag, Jonathan Mitchell, Fengyuan Hu, Douglas P. Loesch, Katherine R. Smith, Neetu Razdan, Henric Olsson, Adam Platt, Dimitrios Vitsios, Qiang Wu, AstraZeneca Genomics Initiative, Veryan Codd, Christopher P. Nelson, Nilesh J. Samani, Ruth E. March, Sebastian Wasilewski, Keren Carss, Margarete Fabre, Quanli Wang, Menelas N. Pangalos, Slavé Petrovski
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis. Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.
端粒保护染色体末端免受损伤,端粒长度与人类疾病和衰老有关。我们开发了一种联合端粒长度度量方法,将定量 PCR 和全基因组测序测量结果相结合,这些测量结果来自 462,666 名英国生物库参与者。该指标提高了SNP遗传率,表明它能更好地捕捉端粒长度的遗传调控。全外显子罕见变体和基因水平的折叠关联研究发现了与端粒长度显著相关的64个变体和30个基因,包括ACD和RTEL1中的等位基因系列。值得注意的是,这些基因中有 16% 是已知的克隆造血的驱动因素--一种与年龄相关的体细胞镶嵌现象,与骨髓癌和一些非恶性疾病相关。体细胞变异分析揭示了基因与端粒长度的特异性关联,包括SRSF2基因突变克隆大的个体端粒变长,而其他基因驱动的克隆扩增个体端粒变短。总之,我们的研究结果表明了罕见变异对端粒长度的影响,在与克隆造血相关的基因中观察到了更大的影响。
{"title":"Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences","authors":"Oliver S. Burren, Ryan S. Dhindsa, Sri V. V. Deevi, Sean Wen, Abhishek Nag, Jonathan Mitchell, Fengyuan Hu, Douglas P. Loesch, Katherine R. Smith, Neetu Razdan, Henric Olsson, Adam Platt, Dimitrios Vitsios, Qiang Wu, AstraZeneca Genomics Initiative, Veryan Codd, Christopher P. Nelson, Nilesh J. Samani, Ruth E. March, Sebastian Wasilewski, Keren Carss, Margarete Fabre, Quanli Wang, Menelas N. Pangalos, Slavé Petrovski","doi":"10.1038/s41588-024-01884-7","DOIUrl":"10.1038/s41588-024-01884-7","url":null,"abstract":"Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis. Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01884-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081005","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
Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases 对不同祖先的精细图谱绘制推动了人类复杂性状和疾病的潜在因果变异的发现。
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-26 DOI: 10.1038/s41588-024-01870-z
Kai Yuan, Ryan J. Longchamps, Antonio F. Pardiñas, Mingrui Yu, Tzu-Ting Chen, Shu-Chin Lin, Yu Chen, Max Lam, Ruize Liu, Yan Xia, Zhenglin Guo, Wenzhao Shi, Chengguo Shen, The Schizophrenia Workgroup of Psychiatric Genomics Consortium, Mark J. Daly, Benjamin M. Neale, Yen-Chen A. Feng, Yen-Feng Lin, Chia-Yen Chen, Michael C. O’Donovan, Tian Ge, Hailiang Huang
Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping. SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and linkage disequilibrium patterns, accounts for multiple causal variants in a genomic region and can be applied to GWAS summary statistics. We comprehensively assessed the performance of SuSiEx using simulations. We further showed that SuSiEx improves the fine-mapping of a range of quantitative traits available in both the UK Biobank and Taiwan Biobank, and improves the fine-mapping of schizophrenia-associated loci by integrating GWAS across East Asian and European ancestries. The cross-population Sum of Single Effects (SuSiEx) model is a robust and computationally efficient method for conducting multi-ancestry fine-mapping of genome-wide association signals, producing smaller credible sets and capturing population-specific causal variants.
对人类复杂性状或疾病进行的全基因组关联研究(GWAS)往往涉及到数百或数千个基因变异的遗传位点,其中许多变异具有相似的统计意义。虽然欧洲血统个体的统计精细图谱已经取得了重要发现,但跨人群精细图谱有可能通过利用不同血统的基因组多样性来提高研究效率和分辨率。在这里,我们介绍一种精确且计算效率高的跨人群精细图谱绘制方法--SuSiEx。SuSiEx 整合了来自任意数量祖先的数据,明确地模拟了特定人群的等位基因频率和连锁不平衡模式,考虑了基因组区域中的多个因果变异,并可应用于 GWAS 的汇总统计。我们通过模拟全面评估了 SuSiEx 的性能。我们进一步表明,SuSiEx 改善了英国生物库和台湾生物库中一系列数量性状的精细图谱,并通过整合东亚和欧洲血统的 GWAS 改善了精神分裂症相关位点的精细图谱。
{"title":"Fine-mapping across diverse ancestries drives the discovery of putative causal variants underlying human complex traits and diseases","authors":"Kai Yuan, Ryan J. Longchamps, Antonio F. Pardiñas, Mingrui Yu, Tzu-Ting Chen, Shu-Chin Lin, Yu Chen, Max Lam, Ruize Liu, Yan Xia, Zhenglin Guo, Wenzhao Shi, Chengguo Shen, The Schizophrenia Workgroup of Psychiatric Genomics Consortium, Mark J. Daly, Benjamin M. Neale, Yen-Chen A. Feng, Yen-Feng Lin, Chia-Yen Chen, Michael C. O’Donovan, Tian Ge, Hailiang Huang","doi":"10.1038/s41588-024-01870-z","DOIUrl":"10.1038/s41588-024-01870-z","url":null,"abstract":"Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping. SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and linkage disequilibrium patterns, accounts for multiple causal variants in a genomic region and can be applied to GWAS summary statistics. We comprehensively assessed the performance of SuSiEx using simulations. We further showed that SuSiEx improves the fine-mapping of a range of quantitative traits available in both the UK Biobank and Taiwan Biobank, and improves the fine-mapping of schizophrenia-associated loci by integrating GWAS across East Asian and European ancestries. The cross-population Sum of Single Effects (SuSiEx) model is a robust and computationally efficient method for conducting multi-ancestry fine-mapping of genome-wide association signals, producing smaller credible sets and capturing population-specific causal variants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073305","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
Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules 基因组尺度量化和预测小分子致病终止密码子读穿
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-22 DOI: 10.1038/s41588-024-01878-5
Ignasi Toledano, Fran Supek, Ben Lehner
Premature termination codons (PTCs) cause ~10–20% of inherited diseases and are a major mechanism of tumor suppressor gene inactivation in cancer. A general strategy to alleviate the effects of PTCs would be to promote translational readthrough. Nonsense suppression by small molecules has proven effective in diverse disease models, but translation into the clinic is hampered by ineffective readthrough of many PTCs. Here we directly tackle the challenge of defining drug efficacy by quantifying the readthrough of ~5,800 human pathogenic stop codons by eight drugs. We find that different drugs promote the readthrough of complementary subsets of PTCs defined by local sequence context. This allows us to build interpretable models that accurately predict drug-induced readthrough genome-wide, and we validate these models by quantifying endogenous stop codon readthrough. Accurate readthrough quantification and prediction will empower clinical trial design and the development of personalized nonsense suppression therapies. Small molecules can promote translational readthrough of premature termination codons, reducing their pathological effect. This study quantifies the readthrough of ~5,800 human pathogenic stop codons by eight drugs and builds models to predict drug-induced readthrough genome-wide.
过早终止密码子(PTC)导致约 10-20% 的遗传性疾病,也是癌症中抑癌基因失活的主要机制。减轻过早终止密码子影响的一般策略是促进翻译通读。小分子的有义抑制已被证明在多种疾病模型中有效,但由于许多 PTCs 的无效通读,将其转化为临床应用受到了阻碍。在这里,我们通过量化八种药物对约 5,800 个人类致病终止密码子的读通情况,直接解决了界定药物疗效的难题。我们发现,不同的药物会促进由局部序列上下文定义的 PTC 互补子集的读通。这使我们能够建立可解释的模型,准确预测药物诱导的全基因组读通,我们还通过量化内源性终止密码子读通验证了这些模型。准确的读穿量化和预测将有助于临床试验设计和个性化无意义抑制疗法的开发。
{"title":"Genome-scale quantification and prediction of pathogenic stop codon readthrough by small molecules","authors":"Ignasi Toledano, Fran Supek, Ben Lehner","doi":"10.1038/s41588-024-01878-5","DOIUrl":"10.1038/s41588-024-01878-5","url":null,"abstract":"Premature termination codons (PTCs) cause ~10–20% of inherited diseases and are a major mechanism of tumor suppressor gene inactivation in cancer. A general strategy to alleviate the effects of PTCs would be to promote translational readthrough. Nonsense suppression by small molecules has proven effective in diverse disease models, but translation into the clinic is hampered by ineffective readthrough of many PTCs. Here we directly tackle the challenge of defining drug efficacy by quantifying the readthrough of ~5,800 human pathogenic stop codons by eight drugs. We find that different drugs promote the readthrough of complementary subsets of PTCs defined by local sequence context. This allows us to build interpretable models that accurately predict drug-induced readthrough genome-wide, and we validate these models by quantifying endogenous stop codon readthrough. Accurate readthrough quantification and prediction will empower clinical trial design and the development of personalized nonsense suppression therapies. Small molecules can promote translational readthrough of premature termination codons, reducing their pathological effect. This study quantifies the readthrough of ~5,800 human pathogenic stop codons by eight drugs and builds models to predict drug-induced readthrough genome-wide.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01878-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021886","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
Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus 生物新陈代谢调节正常食管中致癌 PIK3CA 突变克隆的扩增
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-21 DOI: 10.1038/s41588-024-01891-8
Albert Herms, Bartomeu Colom, Gabriel Piedrafita, Argyro Kalogeropoulou, Ujjwal Banerjee, Charlotte King, Emilie Abby, Kasumi Murai, Irene Caseda, David Fernandez-Antoran, Swee Hoe Ong, Michael W. J. Hall, Christopher Bryant, Roshan K. Sood, Joanna C. Fowler, Albert Pol, Christian Frezza, Bart Vanhaesebroeck, Philip H. Jones
Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3caH1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K–mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3caH1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues. Reducing the competitive advantage conferred by driver mutations can abrogate expansions of mutant clones in healthy tissue in mice. This suggests ways to prevent cancer and other diseases that are associated with somatic mutations in humans.
致癌的 PIK3CA 突变会在衰老的人类食管中产生大量克隆。在这里,我们研究了 Pik3ca 突变克隆在转基因小鼠正常食管上皮细胞中的行为。杂合子 Pik3caH1047R 突变的表达通过使细胞命运向增殖方向倾斜来驱动克隆扩增。CRISPR筛选和抑制剂处理原代食管角质细胞证实,PI3K-mTOR通路增加了突变细胞的竞争适应性。抗糖尿病药物二甲双胍降低了突变细胞在体内和体外的优势。相反,代谢条件(如 1 型糖尿病或饮食引起的肥胖)增强了 Pik3caH1047R 细胞的竞争适应性。同样,与体重正常的人相比,我们在体重指数高的人的食管中发现了更高密度的 PIK3CA 功能增益突变。我们的结论是,代谢环境会选择性地影响正常上皮细胞突变的演变。临床上可行的干预措施可以平衡野生型细胞和突变细胞之间的信号传导失衡,从而限制致癌突变体在正常组织中的扩展。
{"title":"Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus","authors":"Albert Herms, Bartomeu Colom, Gabriel Piedrafita, Argyro Kalogeropoulou, Ujjwal Banerjee, Charlotte King, Emilie Abby, Kasumi Murai, Irene Caseda, David Fernandez-Antoran, Swee Hoe Ong, Michael W. J. Hall, Christopher Bryant, Roshan K. Sood, Joanna C. Fowler, Albert Pol, Christian Frezza, Bart Vanhaesebroeck, Philip H. Jones","doi":"10.1038/s41588-024-01891-8","DOIUrl":"10.1038/s41588-024-01891-8","url":null,"abstract":"Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3caH1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K–mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3caH1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues. Reducing the competitive advantage conferred by driver mutations can abrogate expansions of mutant clones in healthy tissue in mice. This suggests ways to prevent cancer and other diseases that are associated with somatic mutations in humans.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01891-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013806","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
Harnessing cancer genomes for precision oncology 利用癌症基因组开展精准肿瘤学研究
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-20 DOI: 10.1038/s41588-024-01879-4
Stephen J. Chanock
Precision oncology has just received a boost: a report on the prevalence of mutations in cancer driver genes based on whole genome sequencing of 10,000 clinical cases. The challenge ahead lies in how to explore the data to accelerate new discoveries in cancer biology while advancing precision oncology.
精准肿瘤学刚刚获得了一份推动力:一份基于 10,000 例临床病例全基因组测序的癌症驱动基因突变发生率报告。未来的挑战在于如何探索这些数据,以加快癌症生物学的新发现,同时推进精准肿瘤学的发展。
{"title":"Harnessing cancer genomes for precision oncology","authors":"Stephen J. Chanock","doi":"10.1038/s41588-024-01879-4","DOIUrl":"10.1038/s41588-024-01879-4","url":null,"abstract":"Precision oncology has just received a boost: a report on the prevalence of mutations in cancer driver genes based on whole genome sequencing of 10,000 clinical cases. The challenge ahead lies in how to explore the data to accelerate new discoveries in cancer biology while advancing precision oncology.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007353","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
Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes 多发性骨髓瘤的全面分子图谱分析确定了精细的拷贝数和表达亚型
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-19 DOI: 10.1038/s41588-024-01853-0
Sheri Skerget, Daniel Penaherrera, Ajai Chari, Sundar Jagannath, David S. Siegel, Ravi Vij, Gregory Orloff, Andrzej Jakubowiak, Ruben Niesvizky, Darla Liles, Jesus Berdeja, Moshe Levy, Jeffrey Wolf, Saad Z. Usmani, The MMRF CoMMpass Network, Austin W. Christofferson, Sara Nasser, Jessica L. Aldrich, Christophe Legendre, Brooks Benard, Chase Miller, Bryce Turner, Ahmet Kurdoglu, Megan Washington, Venkata Yellapantula, Jonathan R. Adkins, Lori Cuyugan, Martin Boateng, Adrienne Helland, Shari Kyman, Jackie McDonald, Rebecca Reiman, Kristi Stephenson, Erica Tassone, Alex Blanski, Brianne Livermore, Meghan Kirchhoff, Daniel C. Rohrer, Mattia D’Agostino, Manuela Gamella, Kimberly Collison, Jennifer Stumph, Pam Kidd, Andrea Donnelly, Barbara Zaugg, Maureen Toone, Kyle McBride, Mary DeRome, Jennifer Rogers, David Craig, Winnie S. Liang, Norma C. Gutierrez, Scott D. Jewell, John Carpten, Kenneth C. Anderson, Hearn Jay Cho, Daniel Auclair, Sagar Lonial, Jonathan J. Keats
Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation’s Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option. Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.
多发性骨髓瘤是一种可治疗但目前无法治愈的浆细胞血液恶性肿瘤,其特点是肿瘤遗传学多样而复杂,目前尚缺乏精准的治疗方法。多发性骨髓瘤研究基金会的 "多发性骨髓瘤临床结果与个人遗传特征评估相关性研究"(NCT01454297)是一项纵向观察性临床研究,研究对象是新诊断的多发性骨髓瘤患者(n = 1,143),在诊断和病情进展时使用全基因组测序、全外显子组测序和 RNA 测序对肿瘤样本进行特征描述,每 3 个月收集一次临床数据。对基线队列的分析确定了反复发生功能增益和功能缺失事件的靶基因。共识聚类分别确定了骨髓瘤的8种和12种独特拷贝数亚型和表达亚型,确定了高风险基因亚型,并阐明了这些独特生物群体的许多分子基础。对序列样本的分析表明,25.5%的患者在病情进展时转变为高风险表达亚型。我们观察到这一亚型中免疫疗法靶点的强表达,这表明这是一种潜在的治疗选择。
{"title":"Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes","authors":"Sheri Skerget, Daniel Penaherrera, Ajai Chari, Sundar Jagannath, David S. Siegel, Ravi Vij, Gregory Orloff, Andrzej Jakubowiak, Ruben Niesvizky, Darla Liles, Jesus Berdeja, Moshe Levy, Jeffrey Wolf, Saad Z. Usmani, The MMRF CoMMpass Network, Austin W. Christofferson, Sara Nasser, Jessica L. Aldrich, Christophe Legendre, Brooks Benard, Chase Miller, Bryce Turner, Ahmet Kurdoglu, Megan Washington, Venkata Yellapantula, Jonathan R. Adkins, Lori Cuyugan, Martin Boateng, Adrienne Helland, Shari Kyman, Jackie McDonald, Rebecca Reiman, Kristi Stephenson, Erica Tassone, Alex Blanski, Brianne Livermore, Meghan Kirchhoff, Daniel C. Rohrer, Mattia D’Agostino, Manuela Gamella, Kimberly Collison, Jennifer Stumph, Pam Kidd, Andrea Donnelly, Barbara Zaugg, Maureen Toone, Kyle McBride, Mary DeRome, Jennifer Rogers, David Craig, Winnie S. Liang, Norma C. Gutierrez, Scott D. Jewell, John Carpten, Kenneth C. Anderson, Hearn Jay Cho, Daniel Auclair, Sagar Lonial, Jonathan J. Keats","doi":"10.1038/s41588-024-01853-0","DOIUrl":"10.1038/s41588-024-01853-0","url":null,"abstract":"Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation’s Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option. Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01853-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002648","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
A telomere-to-telomere cotton genome assembly reveals centromere evolution and a Mutator transposon-linked module regulating embryo development 端粒到端粒的棉花基因组组装揭示了中心粒的进化和调控胚胎发育的突变体转座子关联模块
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-15 DOI: 10.1038/s41588-024-01877-6
Gai Huang, Zhigui Bao, Li Feng, Jixian Zhai, Jonathan F. Wendel, Xiaofeng Cao, Yuxian Zhu
Assembly of complete genomes can reveal functional genetic elements missing from draft sequences. Here we present the near-complete telomere-to-telomere and contiguous genome of the cotton species Gossypium raimondii. Our assembly identified gaps and misoriented or misassembled regions in previous assemblies and produced 13 centromeres, with 25 chromosomal ends having telomeres. In contrast to satellite-rich Arabidopsis and rice centromeres, cotton centromeres lack phased CENH3 nucleosome positioning patterns and probably evolved by invasion from long terminal repeat retrotransposons. In-depth expression profiling of transposable elements revealed a previously unannotated DNA transposon (MuTC01) that interacts with miR2947 to produce trans-acting small interfering RNAs (siRNAs), one of which targets the newly evolved LEC2 (LEC2b) to produce phased siRNAs. Systematic genome editing experiments revealed that this tripartite module, miR2947–MuTC01–LEC2b, controls the morphogenesis of complex folded embryos characteristic of Gossypium and its close relatives in the cotton tribe. Our study reveals a trans-acting siRNA-based tripartite regulatory pathway for embryo development in higher plants. A telomere-to-telomere genome assembly of the diploid cotton species Gossypium raimondii reveals centromere evolution and a Mutator transposon-linked tripartite module, miR2947–MuTC01–LEC2b that regulates cotton embryo development.
组装完整的基因组可以揭示序列草案中缺失的功能遗传元件。在这里,我们展示了近乎完整的棉花物种 Gossypium raimondii 的端粒到端粒和连续基因组。我们的组配发现了之前组配中的缺口和定向错误或组装错误的区域,并产生了 13 个中心粒,25 个染色体末端具有端粒。与卫星丰富的拟南芥和水稻中心粒相比,棉花中心粒缺乏分阶段的CENH3核小体定位模式,可能是由长末端重复反转座子入侵进化而来。对转座元件的深入表达谱分析发现了一个以前未注明的DNA转座子(MuTC01),它与miR2947相互作用产生反式作用的小干扰RNA(siRNA),其中一个靶标是新进化的LEC2(LEC2b),以产生分阶段的siRNA。系统的基因组编辑实验显示,这个三方模块(miR2947-MuTC01-LEC2b)控制着棉花及其近亲的复杂折叠胚的形态发生。我们的研究揭示了一种基于 siRNA 的反式作用的三方调控途径,可用于高等植物的胚胎发育。
{"title":"A telomere-to-telomere cotton genome assembly reveals centromere evolution and a Mutator transposon-linked module regulating embryo development","authors":"Gai Huang, Zhigui Bao, Li Feng, Jixian Zhai, Jonathan F. Wendel, Xiaofeng Cao, Yuxian Zhu","doi":"10.1038/s41588-024-01877-6","DOIUrl":"10.1038/s41588-024-01877-6","url":null,"abstract":"Assembly of complete genomes can reveal functional genetic elements missing from draft sequences. Here we present the near-complete telomere-to-telomere and contiguous genome of the cotton species Gossypium raimondii. Our assembly identified gaps and misoriented or misassembled regions in previous assemblies and produced 13 centromeres, with 25 chromosomal ends having telomeres. In contrast to satellite-rich Arabidopsis and rice centromeres, cotton centromeres lack phased CENH3 nucleosome positioning patterns and probably evolved by invasion from long terminal repeat retrotransposons. In-depth expression profiling of transposable elements revealed a previously unannotated DNA transposon (MuTC01) that interacts with miR2947 to produce trans-acting small interfering RNAs (siRNAs), one of which targets the newly evolved LEC2 (LEC2b) to produce phased siRNAs. Systematic genome editing experiments revealed that this tripartite module, miR2947–MuTC01–LEC2b, controls the morphogenesis of complex folded embryos characteristic of Gossypium and its close relatives in the cotton tribe. Our study reveals a trans-acting siRNA-based tripartite regulatory pathway for embryo development in higher plants. A telomere-to-telomere genome assembly of the diploid cotton species Gossypium raimondii reveals centromere evolution and a Mutator transposon-linked tripartite module, miR2947–MuTC01–LEC2b that regulates cotton embryo development.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986309","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
Chloroplast and whole-genome sequencing shed light on the evolutionary history and phenotypic diversification of peanuts 叶绿体和全基因组测序揭示了花生的进化历史和表型多样性
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-13 DOI: 10.1038/s41588-024-01876-7
Zheng Zheng, Ziqi Sun, Feiyan Qi, Yuanjin Fang, Ke Lin, Stefano Pavan, Bingyan Huang, Wenzhao Dong, Pei Du, Mengdi Tian, Lei Shi, Jing Xu, Suoyi Han, Hua Liu, Li Qin, Zhongxin Zhang, Xiaodong Dai, Lijuan Miao, Ruifang Zhao, Juan Wang, Yanlin Liao, Alun Li, Jue Ruan, Chiara Delvento, Riccardo Aiese Cigliano, Chris Maliepaard, Yuling Bai, Richard G. F. Visser, Xinyou Zhang
Cultivated peanut (Arachis hypogaea L.) is a widely grown oilseed crop worldwide; however, the events leading to its origin and diversification are not fully understood. Here by combining chloroplast and whole-genome sequence data from a large germplasm collection, we show that the two subspecies of A. hypogaea (hypogaea and fastigiata) likely arose from distinct allopolyploidization and domestication events. Peanut genetic clusters were then differentiated in relation to dissemination routes and breeding efforts. A combination of linkage mapping and genome-wide association studies allowed us to characterize genes and genomic regions related to main peanut morpho-agronomic traits, namely flowering pattern, inner tegument color, growth habit, pod/seed weight and oil content. Together, our findings shed light on the evolutionary history and phenotypic diversification of peanuts and might be of broad interest to plant breeders. Chloroplast and whole-genome sequencing of a global germplasm panel of 355 Arachis accessions encompassing various species sheds light on the evolutionary history and phenotypic diversification of peanuts.
栽培花生(Arachis hypogaea L.)是世界上广泛种植的油料作物;然而,导致其起源和多样化的事件并不完全清楚。在这里,我们通过结合来自大型种质资源库的叶绿体和全基因组序列数据,表明花生的两个亚种(hypogaea 和 fastigiata)很可能是由不同的异源多倍体化和驯化事件产生的。然后,根据传播途径和育种工作对花生遗传集群进行了区分。结合连锁图谱和全基因组关联研究,我们确定了与花生主要形态学特征(即开花模式、内表皮颜色、生长习性、荚果/种子重量和含油量)相关的基因和基因组区域的特征。我们的研究结果揭示了花生的进化历史和表型多样化,可能会引起植物育种者的广泛兴趣。
{"title":"Chloroplast and whole-genome sequencing shed light on the evolutionary history and phenotypic diversification of peanuts","authors":"Zheng Zheng, Ziqi Sun, Feiyan Qi, Yuanjin Fang, Ke Lin, Stefano Pavan, Bingyan Huang, Wenzhao Dong, Pei Du, Mengdi Tian, Lei Shi, Jing Xu, Suoyi Han, Hua Liu, Li Qin, Zhongxin Zhang, Xiaodong Dai, Lijuan Miao, Ruifang Zhao, Juan Wang, Yanlin Liao, Alun Li, Jue Ruan, Chiara Delvento, Riccardo Aiese Cigliano, Chris Maliepaard, Yuling Bai, Richard G. F. Visser, Xinyou Zhang","doi":"10.1038/s41588-024-01876-7","DOIUrl":"10.1038/s41588-024-01876-7","url":null,"abstract":"Cultivated peanut (Arachis hypogaea L.) is a widely grown oilseed crop worldwide; however, the events leading to its origin and diversification are not fully understood. Here by combining chloroplast and whole-genome sequence data from a large germplasm collection, we show that the two subspecies of A. hypogaea (hypogaea and fastigiata) likely arose from distinct allopolyploidization and domestication events. Peanut genetic clusters were then differentiated in relation to dissemination routes and breeding efforts. A combination of linkage mapping and genome-wide association studies allowed us to characterize genes and genomic regions related to main peanut morpho-agronomic traits, namely flowering pattern, inner tegument color, growth habit, pod/seed weight and oil content. Together, our findings shed light on the evolutionary history and phenotypic diversification of peanuts and might be of broad interest to plant breeders. Chloroplast and whole-genome sequencing of a global germplasm panel of 355 Arachis accessions encompassing various species sheds light on the evolutionary history and phenotypic diversification of peanuts.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01876-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973778","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
A Genomics England haplotype reference panel and imputation of UK Biobank 英格兰基因组学单倍型参考面板和英国生物数据库的估算
IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-08-12 DOI: 10.1038/s41588-024-01868-7
Sinan Shi, Simone Rubinacci, Sile Hu, Loukas Moutsianas, Alex Stuckey, Anna C. Need, Pier Francesco Palamara, Mark Caulfield, Jonathan Marchini, Simon Myers
We built a reference panel with 342 million autosomal variants using 78,195 individuals from the Genomics England (GEL) dataset, achieving a phasing switch error rate of 0.18% for European samples and imputation quality of r2 = 0.75 for variants with minor allele frequencies as low as 2 × 10−4 in white British samples. The GEL-imputed UK Biobank genome-wide association analysis identified 70% of associations found by direct exome sequencing (P < 2.18 × 10−11), while extending testing of rare variants to the entire genome. Coding variants dominated the rare-variant genome-wide association results, implying less disruptive effects of rare non-coding variants. A Genomics England haplotype reference panel constructed using sequence data from 78,195 individuals improves phasing and imputation accuracy. Imputation of the UK Biobank using this panel enables genome-wide rare-variant association analyses.
我们利用英格兰基因组学(Genomics England,GEL)数据集中的 78195 个个体建立了一个包含 3.42 亿个常染色体变异的参考面板,欧洲样本的相位切换错误率为 0.18%,英国白人样本中小等位基因频率低至 2 × 10-4 的变异的估算质量为 r2 = 0.75。GEL 估算的英国生物库全基因组关联分析确定了直接外显子组测序发现的关联的 70%(P < 2.18 × 10-11),同时将罕见变异的测试扩展到了整个基因组。编码变异在罕见变异全基因组关联结果中占主导地位,这意味着罕见非编码变异的破坏性影响较小。
{"title":"A Genomics England haplotype reference panel and imputation of UK Biobank","authors":"Sinan Shi,&nbsp;Simone Rubinacci,&nbsp;Sile Hu,&nbsp;Loukas Moutsianas,&nbsp;Alex Stuckey,&nbsp;Anna C. Need,&nbsp;Pier Francesco Palamara,&nbsp;Mark Caulfield,&nbsp;Jonathan Marchini,&nbsp;Simon Myers","doi":"10.1038/s41588-024-01868-7","DOIUrl":"10.1038/s41588-024-01868-7","url":null,"abstract":"We built a reference panel with 342 million autosomal variants using 78,195 individuals from the Genomics England (GEL) dataset, achieving a phasing switch error rate of 0.18% for European samples and imputation quality of r2 = 0.75 for variants with minor allele frequencies as low as 2 × 10−4 in white British samples. The GEL-imputed UK Biobank genome-wide association analysis identified 70% of associations found by direct exome sequencing (P &lt; 2.18 × 10−11), while extending testing of rare variants to the entire genome. Coding variants dominated the rare-variant genome-wide association results, implying less disruptive effects of rare non-coding variants. A Genomics England haplotype reference panel constructed using sequence data from 78,195 individuals improves phasing and imputation accuracy. Imputation of the UK Biobank using this panel enables genome-wide rare-variant association analyses.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01868-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918820","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
期刊
Nature genetics
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1