Nature genetics最新文献

{"title":"Context transcription factors establish cooperative environments and mediate enhancer communication","authors":"Judith F. Kribelbauer-Swietek, Olga Pushkarev, Vincent Gardeux, Katerina Faltejskova, Julie Russeil, Guido van Mierlo, Bart Deplancke","doi":"10.1038/s41588-024-01892-7","DOIUrl":"10.1038/s41588-024-01892-7","url":null,"abstract":"Many enhancers control gene expression by assembling regulatory factor clusters, also referred to as condensates. This process is vital for facilitating enhancer communication and establishing cellular identity. However, how DNA sequence and transcription factor (TF) binding instruct the formation of high regulatory factor environments remains poorly understood. Here we developed a new approach leveraging enhancer-centric chromatin accessibility quantitative trait loci (caQTLs) to nominate regulatory factor clusters genome-wide. By analyzing TF-binding signatures within the context of caQTLs and comparing episomal versus endogenous enhancer activities, we discovered a class of regulators, ‘context-only’ TFs, that amplify the activity of cell type-specific caQTL-binding TFs, that is, ‘context-initiator’ TFs. Similar to super-enhancers, enhancers enriched for context-only TF-binding sites display high coactivator binding and sensitivity to bromodomain-inhibiting molecules. We further show that binding sites for context-only and context-initiator TFs underlie enhancer coordination, providing a mechanistic rationale for how a loose TF syntax confers regulatory specificity. This study identifies context-only transcription factors (TFs), a TF class that enhances DNA accessibility initiated by cell type-specific TFs and establishes cooperative environments. Enhancers enriched with motifs of both TF classes show high coactivator binding, enhanced coordination and sensitivity to bromodomain inhibitors.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2199-2212"},"PeriodicalIF":31.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01892-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368958","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}

{"title":"Pan-African analysis identifies genetic differences in prostate cancer risk","authors":"","doi":"10.1038/s41588-024-01932-2","DOIUrl":"10.1038/s41588-024-01932-2","url":null,"abstract":"To understand the genetic basis of disease, it is essential to study diverse populations. We conducted the largest study to date of African men to evaluate the evolutionary genetics and causes of prostate cancer. Our findings reveal novel genetic associations, including those that were not observed in studies of non-African populations.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2006-2007"},"PeriodicalIF":31.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369924","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}

{"title":"Standardizing variant naming in literature with VariantValidator to increase diagnostic rates","authors":"Peter J. Freeman, John F. Wagstaff, Ivo F. A. C. Fokkema, Garry R. Cutting, Heidi L. Rehm, Angela C. Davies, Johan T. den Dunnen, Liam J. Gretton, Raymond Dalgleish","doi":"10.1038/s41588-024-01938-w","DOIUrl":"10.1038/s41588-024-01938-w","url":null,"abstract":"Accurate naming of genetic variants is essential to identify clinical data that interpret the consequences of such variants. In partnership with the Human Genome Organization, we advocate for integration of VariantValidator in publishing of journals and databases, to improve the quality of shared genetic data and ultimately patient outcomes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2284-2286"},"PeriodicalIF":31.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362745","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}

{"title":"MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution","authors":"Clare Puttick, Thomas P. Jones, Michelle M. Leung, Felipe Galvez-Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Oriol Pich, Carlos Martinez-Ruiz, Robert Bentham, Krijn K. Dijkstra, James R. M. Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A. Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A. Quezada, TRACERx Consortium, Charles Swanton, Nicholas McGranahan","doi":"10.1038/s41588-024-01883-8","DOIUrl":"10.1038/s41588-024-01883-8","url":null,"abstract":"Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution. Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2121-2131"},"PeriodicalIF":31.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01883-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362747","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}

{"title":"Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa","authors":"Rohini Janivara, Wenlong C. Chen, Ujani Hazra, Shakuntala Baichoo, Ilir Agalliu, Paidamoyo Kachambwa, Corrine N. Simonti, Lyda M. Brown, Saanika P. Tambe, Michelle S. Kim, Maxine Harlemon, Mohamed Jalloh, Dillon Muzondiwa, Daphne Naidoo, Olabode O. Ajayi, Nana Yaa Snyper, Lamine Niang, Halimatou Diop, Medina Ndoye, James E. Mensah, Afua O. D. Abrahams, Richard Biritwum, Andrew A. Adjei, Akindele O. Adebiyi, Olayiwola Shittu, Olufemi Ogunbiyi, Sikiru Adebayo, Maxwell M. Nwegbu, Hafees O. Ajibola, Olabode P. Oluwole, Mustapha A. Jamda, Audrey Pentz, Christopher A. Haiman, Petrus V. Spies, André van der Merwe, Michael B. Cook, Stephen J. Chanock, Sonja I. Berndt, Stephen Watya, Alexander Lubwama, Mazvita Muchengeti, Sean Doherty, Natalie Smyth, David Lounsbury, Brian Fortier, Thomas E. Rohan, Judith S. Jacobson, Alfred I. Neugut, Ann W. Hsing, Alexander Gusev, Oseremen I. Aisuodionoe-Shadrach, Maureen Joffe, Ben Adusei, Serigne M. Gueye, Pedro W. Fernandez, Jo McBride, Caroline Andrews, Lindsay N. Petersen, Joseph Lachance, Timothy R. Rebbeck","doi":"10.1038/s41588-024-01931-3","DOIUrl":"10.1038/s41588-024-01931-3","url":null,"abstract":"Men of African descent have the highest prostate cancer incidence and mortality rates, yet the genetic basis of prostate cancer in African men has been understudied. We used genomic data from 3,963 cases and 3,509 controls from Ghana, Nigeria, Senegal, South Africa and Uganda to infer ancestry-specific genetic architectures and fine-map disease associations. Fifteen independent associations at 8q24.21, 6q22.1 and 11q13.3 reached genome-wide significance, including four new associations. Intriguingly, multiple lead associations are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of prostate cancer differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African prostate cancer associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations. Genome-wide association analyses of prostate cancer in men from sub-Saharan Africa identify population-specific risk variants and regional differences in effect sizes. Founder effects contribute to continental differences in the genetic architecture of prostate cancer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2093-2103"},"PeriodicalIF":31.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362867","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}

{"title":"Aneuploidy as a driver of human cancer","authors":"Eran Sdeor, Hajime Okada, Ron Saad, Tal Ben-Yishay, Uri Ben-David","doi":"10.1038/s41588-024-01916-2","DOIUrl":"10.1038/s41588-024-01916-2","url":null,"abstract":"Aneuploidy, an abnormal chromosome composition, is a major contributor to cancer development and progression and an important determinant of cancer therapeutic responses and clinical outcomes. Despite being recognized as a hallmark of human cancer, the exact role of aneuploidy as a ‘driver’ of cancer is still largely unknown. Identifying the specific genetic elements that underlie the recurrence of common aneuploidies remains a major challenge of cancer genetics. In this Review, we discuss recurrent aneuploidies and their function as drivers of tumor development. We then delve into the context-dependent identification and functional characterization of the driver genes underlying driver aneuploidies and examine emerging strategies to uncover these driver genes using cancer genomics data and cancer models. Lastly, we explore opportunities for targeting driver aneuploidies in cancer by leveraging the functional consequences of these common genetic alterations. This Review discusses recurrent aneuploidies driving human cancer, methods to identify them and strategies to uncover underlying driver genes. It highlights genomic and experimental approaches to study and ultimately target driver aneuploidies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2014-2026"},"PeriodicalIF":31.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362746","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}

{"title":"Genetic and non-genetic HLA disruption is widespread in lung and breast tumors","authors":"","doi":"10.1038/s41588-024-01886-5","DOIUrl":"10.1038/s41588-024-01886-5","url":null,"abstract":"Immune recognition of cancers can be inhibited if the molecules that present cancer cell-specific antigens are disrupted. We have developed a tool that can detect four different types of disruption. Overall, we find that both genetic and non-genetic disruption of these molecules is common in lung and breast tumors.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2008-2009"},"PeriodicalIF":31.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362865","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}

{"title":"Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome","authors":"Sanghyeon Park, Soyeon Kim, Beomsu Kim, Dan Say Kim, Jaeyoung Kim, Yeeun Ahn, Hyejin Kim, Minku Song, Injeong Shim, Sang-Hyuk Jung, Chamlee Cho, Soohyun Lim, Sanghoon Hong, Hyeonbin Jo, Akl C. Fahed, Pradeep Natarajan, Patrick T. Ellinor, Ali Torkamani, Woong-Yang Park, Tae Yang Yu, Woojae Myung, Hong-Hee Won","doi":"10.1038/s41588-024-01933-1","DOIUrl":"10.1038/s41588-024-01933-1","url":null,"abstract":"Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (nobserved = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS. Large-scale multivariate analyses across populations of European ancestry identify risk loci for the metabolic syndrome, improving polygenic prediction models and highlighting associations with diverse traits beyond cardiometabolic diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2380-2391"},"PeriodicalIF":31.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01933-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329658","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}

{"title":"Valid inference for machine learning-assisted genome-wide association studies","authors":"Jiacheng Miao, Yixuan Wu, Zhongxuan Sun, Xinran Miao, Tianyuan Lu, Jiwei Zhao, Qiongshi Lu","doi":"10.1038/s41588-024-01934-0","DOIUrl":"10.1038/s41588-024-01934-0","url":null,"abstract":"Machine learning (ML) has become increasingly popular in almost all scientific disciplines, including human genetics. Owing to challenges related to sample collection and precise phenotyping, ML-assisted genome-wide association study (GWAS), which uses sophisticated ML techniques to impute phenotypes and then performs GWAS on the imputed outcomes, have become increasingly common in complex trait genetics research. However, the validity of ML-assisted GWAS associations has not been carefully evaluated. Here, we report pervasive risks for false-positive associations in ML-assisted GWAS and introduce Post-Prediction GWAS (POP-GWAS), a statistical framework that redesigns GWAS on ML-imputed outcomes. POP-GWAS ensures valid and powerful statistical inference irrespective of imputation quality and choice of algorithm, requiring only GWAS summary statistics as input. We employed POP-GWAS to perform a GWAS of bone mineral density derived from dual-energy X-ray absorptiometry imaging at 14 skeletal sites, identifying 89 new loci and revealing skeletal site-specific genetic architecture. Our framework offers a robust analytic solution for future ML-assisted GWAS. Post-prediction genome-wide association study (POP-GWAS) is a statistical framework that uses summary statistics from labeled samples with both observed and imputed phenotypes to debias single-nucleotide polymorphism effect size estimates for unlabeled samples with imputed phenotypes only, leading to valid and powerful inference.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2361-2369"},"PeriodicalIF":31.7,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329615","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}

{"title":"Structural remodeling of the inactive X chromosome during early mouse development","authors":"Edda G. Schulz, Alexandra Martitz","doi":"10.1038/s41588-024-01936-y","DOIUrl":"10.1038/s41588-024-01936-y","url":null,"abstract":"The mammalian inactive X chromosome shows unusual folding dominated by large-scale structures. A study finds a megadomain structure with a boundary at the Xist locus, preceding the well-known Dxz4-separated megadomains in somatic cells.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 10","pages":"2004-2005"},"PeriodicalIF":31.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321964","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}