Nature genetics最新文献_第9页

Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk 系统优先排序结直肠癌风险的功能变异和效应基因

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-16 DOI: 10.1038/s41588-024-01900-w

Philip J. Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T. Harris, Maria Mandelia, Charlie Mills, Malcolm G. Dunlop, Richard S. Houlston

{"title":"Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk","authors":"Philip J. Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T. Harris, Maria Mandelia, Charlie Mills, Malcolm G. Dunlop, Richard S. Houlston","doi":"10.1038/s41588-024-01900-w","DOIUrl":"10.1038/s41588-024-01900-w","url":null,"abstract":"Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer–gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment. This study uses a combination of in silico and experimental techniques to ascribe target genes to 170 risk loci for colorectal cancer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01900-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234445","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

Interpreting cis-regulatory interactions from large-scale deep neural networks 从大规模深度神经网络解读顺式调控相互作用

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-16 DOI: 10.1038/s41588-024-01923-3

Shushan Toneyan, Peter K. Koo

{"title":"Interpreting cis-regulatory interactions from large-scale deep neural networks","authors":"Shushan Toneyan, Peter K. Koo","doi":"10.1038/s41588-024-01923-3","DOIUrl":"10.1038/s41588-024-01923-3","url":null,"abstract":"The rise of large-scale, sequence-based deep neural networks (DNNs) for predicting gene expression has introduced challenges in their evaluation and interpretation. Current evaluations align DNN predictions with orthogonal experimental data, providing insights into generalization but offering limited insights into their decision-making process. Existing model explainability tools focus mainly on motif analysis, which becomes complex when interpreting longer sequences. Here we present cis-regulatory element model explanations (CREME), an in silico perturbation toolkit that interprets the rules of gene regulation learned by a genomic DNN. Applying CREME to Enformer, a state-of-the-art DNN, we identify cis-regulatory elements that enhance or silence gene expression and characterize their complex interactions. CREME can provide interpretations across multiple scales of genomic organization, from cis-regulatory elements to fine-mapped functional sequence elements within them, offering high-resolution insights into the regulatory architecture of the genome. CREME provides a powerful toolkit for translating the predictions of genomic DNNs into mechanistic insights of gene regulation. CREME is an extensible computational tool for investigating cis-regulation via in silico perturbations of neural network-based DNA sequence models such as Enformer, identifying complex interactions between a gene’s regulatory elements.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234509","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

Antagonism between H3K27me3 and genome–lamina association drives atypical spatial genome organization in the totipotent embryo H3K27me3 与基因组-拉米娜关联之间的拮抗作用驱动全能胚胎的非典型空间基因组组织

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-16 DOI: 10.1038/s41588-024-01902-8

Isabel Guerreiro, Franka J. Rang, Yumiko K. Kawamura, Carla Kroon-Veenboer, Jeroen Korving, Femke C. Groenveld, Ramada E. van Beek, Silke J. A. Lochs, Ellen Boele, Antoine H. M. F. Peters, Jop Kind

{"title":"Antagonism between H3K27me3 and genome–lamina association drives atypical spatial genome organization in the totipotent embryo","authors":"Isabel Guerreiro, Franka J. Rang, Yumiko K. Kawamura, Carla Kroon-Veenboer, Jeroen Korving, Femke C. Groenveld, Ramada E. van Beek, Silke J. A. Lochs, Ellen Boele, Antoine H. M. F. Peters, Jop Kind","doi":"10.1038/s41588-024-01902-8","DOIUrl":"10.1038/s41588-024-01902-8","url":null,"abstract":"In mammals, early embryonic development exhibits highly unusual spatial positioning of genomic regions at the nuclear lamina, but the mechanisms underpinning this atypical genome organization remain elusive. Here, we generated single-cell profiles of lamina-associated domains (LADs) coupled with transcriptomics, which revealed a striking overlap between preimplantation-specific LAD dissociation and noncanonical broad domains of H3K27me3. Loss of H3K27me3 resulted in a restoration of canonical LAD profiles, suggesting an antagonistic relationship between lamina association and H3K27me3. Tethering of H3K27me3 to the nuclear periphery showed that the resultant relocalization is partially dependent on the underlying DNA sequence. Collectively, our results suggest that the atypical organization of LADs in early developmental stages is the result of a tug-of-war between intrinsic affinity for the nuclear lamina and H3K27me3, constrained by the available space at the nuclear periphery. This study provides detailed insight into the molecular mechanisms regulating nuclear organization during early mammalian development. Single-cell profiling of lamina-associated domains (LADs) during early mouse development reveals an overlap between preimplantation-specific LAD dissociation and noncanonical broad H3K27me3 domains. Loss of H3K27me3 restores canonical LAD profiles.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01902-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234446","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

Widespread position-dependent transcriptional regulatory sequences in plants 植物中广泛存在的位置依赖性转录调控序列

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-12 DOI: 10.1038/s41588-024-01907-3

Yoav Voichek, Gabriela Hristova, Almudena Mollá-Morales, Detlef Weigel, Magnus Nordborg

{"title":"Widespread position-dependent transcriptional regulatory sequences in plants","authors":"Yoav Voichek, Gabriela Hristova, Almudena Mollá-Morales, Detlef Weigel, Magnus Nordborg","doi":"10.1038/s41588-024-01907-3","DOIUrl":"10.1038/s41588-024-01907-3","url":null,"abstract":"Much of what we know about eukaryotic transcription stems from animals and yeast; however, plants evolved separately for over a billion years, leaving ample time for divergence in transcriptional regulation. Here we set out to elucidate fundamental properties of cis-regulatory sequences in plants. Using massively parallel reporter assays across four plant species, we demonstrate the central role of sequences downstream of the transcription start site (TSS) in transcriptional regulation. Unlike animal enhancers that are position independent, plant regulatory elements depend on their position, as altering their location relative to the TSS significantly affects transcription. We highlight the importance of the region downstream of the TSS in regulating transcription by identifying a DNA motif that is conserved across vascular plants and is sufficient to enhance gene expression in a dose-dependent manner. The identification of a large number of position-dependent enhancers points to fundamental differences in gene regulation between plants and animals. Massively parallel reporter assays in four plant species show that transcriptional regulatory elements are position dependent with enrichment downstream of the transcription start site, particularly GATC motifs with strong effects in vascular plants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01907-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170997","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

Five latent factors underlie response to immunotherapy 免疫疗法反应的五个潜在因素

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-12 DOI: 10.1038/s41588-024-01899-0

Joseph Usset, Axel Rosendahl Huber, Maria A. Andrianova, Eduard Batlle, Joan Carles, Edwin Cuppen, Elena Elez, Enriqueta Felip, Marina Gómez-Rey, Deborah Lo Giacco, Francisco Martinez-Jimenez, Eva Muñoz-Couselo, Lillian L. Siu, Josep Tabernero, Ana Vivancos, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas

{"title":"Five latent factors underlie response to immunotherapy","authors":"Joseph Usset, Axel Rosendahl Huber, Maria A. Andrianova, Eduard Batlle, Joan Carles, Edwin Cuppen, Elena Elez, Enriqueta Felip, Marina Gómez-Rey, Deborah Lo Giacco, Francisco Martinez-Jimenez, Eva Muñoz-Couselo, Lillian L. Siu, Josep Tabernero, Ana Vivancos, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas","doi":"10.1038/s41588-024-01899-0","DOIUrl":"10.1038/s41588-024-01899-0","url":null,"abstract":"Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival. Analysis of human tumor datasets shows that all features that appear significantly associated with immunotherapy response and survival may be collapsed into five latent factors: tumor mutation burden, T cell effective infiltration, TGF-β activity in the microenvironment, prior treatment and tumor proliferative potential.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01899-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170845","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

Polygenic basis for seedless grapes 无籽葡萄的多基因基础

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-11 DOI: 10.1038/s41588-024-01926-0

Kyle Vogan

引用次数: 0

Human intestinal immuno-organoids 人体肠道免疫器官

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-11 DOI: 10.1038/s41588-024-01927-z

Chiara Anania

引用次数: 0

X chromosome dosage shapes renal cell carcinoma risk X 染色体剂量影响肾细胞癌风险

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-11 DOI: 10.1038/s41588-024-01924-2

Tiago Faial

引用次数: 0

The genomics of childhood T-lineage acute lymphoblastic leukemia 儿童 T 线型急性淋巴细胞白血病的基因组学

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-11 DOI: 10.1038/s41588-024-01928-y

Safia Danovi

引用次数: 0

Disease prediction with multi-omics and biomarkers empowers case–control genetic discoveries in the UK Biobank 利用多组学和生物标志物进行疾病预测有助于英国生物库中的病例对照基因发现

IF 31.7 1区生物学

Nature genetics Pub Date : 2024-09-11 DOI: 10.1038/s41588-024-01898-1

Manik Garg, Marcin Karpinski, Dorota Matelska, Lawrence Middleton, Oliver S. Burren, Fengyuan Hu, Eleanor Wheeler, Katherine R. Smith, Margarete A. Fabre, Jonathan Mitchell, Amanda O’Neill, Euan A. Ashley, Andrew R. Harper, Quanli Wang, Ryan S. Dhindsa, Slavé Petrovski, Dimitrios Vitsios

{"title":"Disease prediction with multi-omics and biomarkers empowers case–control genetic discoveries in the UK Biobank","authors":"Manik Garg, Marcin Karpinski, Dorota Matelska, Lawrence Middleton, Oliver S. Burren, Fengyuan Hu, Eleanor Wheeler, Katherine R. Smith, Margarete A. Fabre, Jonathan Mitchell, Amanda O’Neill, Euan A. Ashley, Andrew R. Harper, Quanli Wang, Ryan S. Dhindsa, Slavé Petrovski, Dimitrios Vitsios","doi":"10.1038/s41588-024-01898-1","DOIUrl":"10.1038/s41588-024-01898-1","url":null,"abstract":"The emergence of biobank-level datasets offers new opportunities to discover novel biomarkers and develop predictive algorithms for human disease. Here, we present an ensemble machine-learning framework (machine learning with phenotype associations, MILTON) utilizing a range of biomarkers to predict 3,213 diseases in the UK Biobank. Leveraging the UK Biobank’s longitudinal health record data, MILTON predicts incident disease cases undiagnosed at time of recruitment, largely outperforming available polygenic risk scores. We further demonstrate the utility of MILTON in augmenting genetic association analyses in a phenome-wide association study of 484,230 genome-sequenced samples, along with 46,327 samples with matched plasma proteomics data. This resulted in improved signals for 88 known (P < 1 × 10−8) gene–disease relationships alongside 182 gene–disease relationships that did not achieve genome-wide significance in the nonaugmented baseline cohorts. We validated these discoveries in the FinnGen biobank alongside two orthogonal machine-learning methods built for gene–disease prioritization. All extracted gene–disease associations and incident disease predictive biomarkers are publicly available ( http://milton.public.cgr.astrazeneca.com ). MILTON uses phenotype information in the UK Biobank to identify clinical biomarkers and other quantitative traits that characterize diseases. It then constructs augmented cohorts by predicting undiagnosed individuals, improving power to discover gene–disease relationships.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01898-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166305","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