Genome Biology最新文献

{"title":"SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation","authors":"Ryan T. Wagner, Ryan A. Hlady, Xiaoyu Pan, Liguo Wang, Sungho Kim, Xia Zhao, Louis Y. El Khoury, Shafiq Shaikh, Jian Zhong, Jeong-Heon Lee, Jolanta Grembecka, Tomasz Cierpicki, Thai H. Ho, Keith D. Robertson","doi":"10.1186/s13059-025-03483-z","DOIUrl":"https://doi.org/10.1186/s13059-025-03483-z","url":null,"abstract":"SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating cellular processes such as RNA splicing, DNA repair, and spurious transcription initiation underlies its broader tumor suppressor function. SETD2 mutation promotes the epithelial-mesenchymal transition and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. We employ an unbiased genome-wide synthetic lethal screen, which identifies another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction is performed in isogenic clear cell renal cell carcinoma and immortalized renal epithelial cell lines, in mouse and human backgrounds. Depletion of NSD1 using a CRISPRi targeting approach promotes the loss of SETD2-mutant cells coincident with elevated levels of DNA damage and apoptosis. Surprisingly, only suppression of NSD1, but not related H3K36-methyltransferases, promotes synthetic lethality in these models. Mapping of genomic H3K36me2 targeting by NSD1 and NSD2 individually highlights the independent functions of these epigenetic writers. Furthermore, as a proof-of-principle, we demonstrate the therapeutic feasibility of targeting this synthetic lethal interaction by recapitulating the phenotype using BT5, a first-in-class pharmacologic inhibitor against NSD1. These findings unify genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach to individualize therapies against a challenging loss-of-function SETD2 mutation in cancer.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"25 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125111","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":"MAAT: a new nonparametric Bayesian framework for incorporating multiple functional annotations in transcriptome-wide association studies","authors":"Han Wang, Xiang Li, Teng Li, Zhe Li, Pak Chung Sham, Yan Dora Zhang","doi":"10.1186/s13059-025-03485-x","DOIUrl":"https://doi.org/10.1186/s13059-025-03485-x","url":null,"abstract":"Transcriptome-wide association study (TWAS) has emerged as a powerful tool for translating the myriad variations identified by genome-wide association studies (GWAS) into regulated genes in the post-GWAS era. While integrating annotation information has been shown to enhance power, current annotation-assisted TWAS tools predominantly focus on epigenomic annotations. When including more annotations, the assumption of a positive correlation between annotation scores and SNPs’ effect sizes, as adopted by current methods, often falls short. Here, we propose MAAT expanding the horizons of existing TWAS studies, generating a new model incorporating multiple annotations into TWAS and a new metric indicating the most important annotation.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"24 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083379","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":"Engineering a bacterial toxin deaminase from the DYW-family into a novel cytosine base editor for plants and mammalian cells","authors":"Dingbo Zhang, Fiona Parth, Laura Matos da Silva, Teng-Cheong Ha, Axel Schambach, Jens Boch","doi":"10.1186/s13059-025-03478-w","DOIUrl":"https://doi.org/10.1186/s13059-025-03478-w","url":null,"abstract":"Base editors are precise editing tools that employ deaminases to modify target DNA bases. The DYW-family of cytosine deaminases is structurally and phylogenetically distinct and might be harnessed for genome editing tools. We report a novel CRISPR/Cas9-cytosine base editor using SsdA, a DYW-like deaminase and bacterial toxin. A G103S mutation in SsdA enhances C-to-T editing efficiency while reducing its toxicity. Truncations result in an extraordinarily small enzyme. The SsdA-base editor efficiently converts C-to-T in rice and barley protoplasts and induces mutations in rice plants and mammalian cells. The engineered SsdA is a highly efficient genome editing tool.\u0000","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"25 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077626","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":"A fully phased octoploid strawberry genome reveals the evolutionary dynamism of centromeric satellites","authors":"Xin Jin, Haiyuan Du, Maoxian Chen, Xu Zheng, Yiying He, Andan Zhu","doi":"10.1186/s13059-025-03482-0","DOIUrl":"https://doi.org/10.1186/s13059-025-03482-0","url":null,"abstract":"We systematically examine the application of different phasing strategies to decrypt strawberry genome organization and produce a fully phased and accurate reference genome for Fragaria x ananassa cv. “EA78” (2n = 8x = 56). We identify 147 bp canonical centromeric repeats across 50 strawberry chromosomes and uncover the formation of six neocentromeres through centromere turnover. Our findings indicate strawberry genomes have diverged centromeric satellite arrays among chromosomes, particularly across homoeologs, while maintaining high sequence similarity between homologs. We trace the evolutionary dynamics of centromeric repeats and find substantial centromere size expansion in wild and cultivated octoploids compared to the diploid ancestor, F. vesca.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"122 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077628","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":"A novel decomposer-exploiter interaction framework of plant residue microbial decomposition","authors":"Youzhi Miao, Wei Wang, Huanhuan Xu, Yanwei Xia, Qingxin Gong, Zhihui Xu, Nan Zhang, Weibing Xun, Qirong Shen, Ruifu Zhang","doi":"10.1186/s13059-025-03486-w","DOIUrl":"https://doi.org/10.1186/s13059-025-03486-w","url":null,"abstract":"Plant residue microbial decomposition, subject to significant environmental regulation, represents a crucial ecological process shaping and cycling the largest terrestrial soil organic carbon pool. However, the fundamental understanding of the functional dynamics and interactions between the principal participants, fungi and bacteria, in natural habitats remains limited. In this study, the evolution of fungal and bacterial communities and their functional interactions were elucidated during the degradation of complexity-gradient plant residues. The results reveal that with increasing residue complexity, fungi exhibit heightened adaptability, while bacterial richness declines sharply. The differential functional evolution of fungi and bacteria is driven by residue complexity but follows distinct trajectories. Fundamentally, fungi evolve towards promoting plant residue degradation and so consistently act as the dominant decomposers. Conversely, bacteria predominantly increase expression of genes of glycosidases to exploit fungal degradation products, thereby consistently acting as exploiters. The presence of fungi enables and endures bacterial exploitation. This study introduces a novel framework of fungal decomposers and bacterial exploiters during plant residue microbial decomposition, advancing our comprehensive understanding of microbial processes governing the organic carbon cycling.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"6 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077624","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":"Multi-INTACT: integrative analysis of the genome, transcriptome, and proteome identifies causal mechanisms of complex traits","authors":"Jeffrey Okamoto, Xianyong Yin, Brady Ryan, Joshua Chiou, Francesca Luca, Roger Pique-Regi, Hae Kyung Im, Jean Morrison, Charles Burant, Eric B. Fauman, Markku Laakso, Michael Boehnke, Xiaoquan Wen","doi":"10.1186/s13059-025-03480-2","DOIUrl":"https://doi.org/10.1186/s13059-025-03480-2","url":null,"abstract":"We present multi-integration of transcriptome-wide association studies and colocalization (Multi-INTACT), an algorithm that models multiple “gene products” (e.g., encoded RNA transcript and protein levels) to implicate causal genes and relevant gene products. In simulations, Multi-INTACT achieves higher power than existing methods, maintains calibrated false discovery rates, and detects the true causal gene product(s). We apply Multi-INTACT to GWAS on 1408 metabolites, integrating the GTEx expression and UK Biobank protein QTL datasets. Multi-INTACT infers 52 to 109% more metabolite causal genes than protein-alone or expression-alone analyses and indicates both gene products are relevant for most gene nominations.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"77 2 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077625","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":"Author Correction: X-Mapper: fast and accurate sequence alignment via gapped x-mers","authors":"Jeffry M. Gaston, Eric J. Alm, An-Ni Zhang","doi":"10.1186/s13059-025-03481-1","DOIUrl":"https://doi.org/10.1186/s13059-025-03481-1","url":null,"abstract":"<p><b>Correction</b><b>: </b><b>Genome Biol 26, 15 (2025)</b></p><p><b>https://doi.org/10.1186/s13059-024-03473-7</b></p><br/><p>Following publication of the original article [1], the authors identified that one of the headings in the results section is incorrect.</p><p>The incorrect heading is: Alignment accuracy of X‑Mapper in samples with various ties</p><p>The correct heading is: Alignment accuracy of X‑Mapper in samples with various complexities</p><p>The original article [1] has been updated.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Gaston JM, Alm EJ, Zhang AN. X-Mapper: fast and accurate sequence alignment via gapped x-mers. Genome Biol. 2025;26:15. https://doi.org/10.1186/s13059-024-03473-7.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><span>Author notes</span><ol><li><p>Jeffry M. Gaston and An-Ni Zhang contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Google, Cambridge, MA, USA</p><p>Jeffry M. Gaston</p></li><li><p>Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA</p><p>Eric J. Alm & An-Ni Zhang</p></li><li><p>School of Biological Sciences, Nanyang Technological University, Singapore, Singapore</p><p>Jeffry M. Gaston & An-Ni Zhang</p></li></ol><span>Authors</span><ol><li><span>Jeffry M. Gaston</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Eric J. Alm</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>An-Ni Zhang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding authors</h3><p>Correspondence to Eric J. Alm or An-Ni Zhang.</p><p><b>Open Access</b> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.</p>\u0000<p>","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"58 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044067","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":"Dynamic co-evolution of transposable elements and the piRNA pathway in African cichlid fishes","authors":"Miguel Vasconcelos Almeida, Moritz Blumer, Chengwei Ulrika Yuan, Pío Sierra, Jonathan L. Price, Fu Xiang Quah, Aleksandr Friman, Alexandra Dallaire, Grégoire Vernaz, Audrey L. K. Putman, Alan M. Smith, Domino A. Joyce, Falk Butter, Astrid D. Haase, Richard Durbin, M. Emília Santos, Eric A. Miska","doi":"10.1186/s13059-025-03475-z","DOIUrl":"https://doi.org/10.1186/s13059-025-03475-z","url":null,"abstract":"East African cichlid fishes have diversified in an explosive fashion, but the (epi)genetic basis of the phenotypic diversity of these fishes remains largely unknown. Although transposable elements (TEs) have been associated with phenotypic variation in cichlids, little is known about their transcriptional activity and epigenetic silencing. We set out to bridge this gap and to understand the interactions between TEs and their cichlid hosts. Here, we describe dynamic patterns of TE expression in African cichlid gonads and during early development. Orthology inference revealed strong conservation of TE silencing factors in cichlids, and an expansion of piwil1 genes in Lake Malawi cichlids, likely driven by PiggyBac TEs. The expanded piwil1 copies have signatures of positive selection and retain amino acid residues essential for catalytic activity. Furthermore, the gonads of African cichlids express a Piwi-interacting RNA (piRNA) pathway that targets TEs. We define the genomic sites of piRNA production in African cichlids and find divergence in closely related species, in line with fast evolution of piRNA-producing loci. Our findings suggest dynamic co-evolution of TEs and host silencing pathways in the African cichlid radiations. We propose that this co-evolution has contributed to cichlid genomic diversity.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"74 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992762","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":"X-Mapper: fast and accurate sequence alignment via gapped x-mers","authors":"Jeffry M. Gaston, Eric J. Alm, An-Ni Zhang","doi":"10.1186/s13059-024-03473-7","DOIUrl":"https://doi.org/10.1186/s13059-024-03473-7","url":null,"abstract":"Sequence alignment is foundational to many bioinformatic analyses. Many aligners start by splitting sequences into contiguous, fixed-length seeds, called k-mers. Alignment is faster with longer, unique seeds, but more accurate with shorter seeds avoiding mutations. Here, we introduce X-Mapper, aiming to offer high speed and accuracy via dynamic-length seeds containing gaps, called gapped x-mers. We observe 11–24-fold fewer suboptimal alignments analyzing a human reference and 3–579-fold lower inconsistency across bacterial references than other aligners, improving on 53% and 30% of reads aligned to non-target strains and species, respectively. Other seed-based analysis algorithms might benefit from gapped x-mers too.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"3 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992821","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":"MaveDB 2024: a curated community database with over seven million variant effects from multiplexed functional assays","authors":"Alan F. Rubin, Jeremy Stone, Aisha Haley Bianchi, Benjamin J. Capodanno, Estelle Y. Da, Mafalda Dias, Daniel Esposito, Jonathan Frazer, Yunfan Fu, Sally B. Grindstaff, Matthew R. Harrington, Iris Li, Abbye E. McEwen, Joseph K. Min, Nick Moore, Olivia G. Moscatelli, Jesslyn Ong, Polina V. Polunina, Joshua E. Rollins, Nathan J. Rollins, Ashley E. Snyder, Amy Tam, Matthew J. Wakefield, Shenyi Sunny Ye, Lea M. Starita, Vanessa L. Bryant, Debora S. Marks, Douglas M. Fowler","doi":"10.1186/s13059-025-03476-y","DOIUrl":"https://doi.org/10.1186/s13059-025-03476-y","url":null,"abstract":"Multiplexed assays of variant effect (MAVEs) are a critical tool for researchers and clinicians to understand genetic variants. Here we describe the 2024 update to MaveDB ( https://www.mavedb.org/ ) with four key improvements to the MAVE community’s database of record: more available data including over 7 million variant effect measurements, an improved data model supporting assays such as saturation genome editing, new built-in exploration and visualization tools, and powerful APIs for data federation and streamlined submission and access. Together these changes support MaveDB’s role as a hub for the analysis and dissemination of MAVEs now and into the future.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"162 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990650","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}