Genome Biology最新文献

{"title":"Integrated large-scale metagenome assembly and multi-kingdom network analyses identify sex differences in the human nasal microbiome","authors":"Yanmei Ju, Zhe Zhang, Mingliang Liu, Shutian Lin, Qiang Sun, Zewei Song, Weiting Liang, Xin Tong, Zhuye Jie, Haorong Lu, Kaiye Cai, Peishan Chen, Xin Jin, Wenwei Zhang, Xun Xu, Huanming Yang, Jian Wang, Yong Hou, Liang Xiao, Huijue Jia, Tao Zhang, Ruijin Guo","doi":"10.1186/s13059-024-03389-2","DOIUrl":"https://doi.org/10.1186/s13059-024-03389-2","url":null,"abstract":"Respiratory diseases impose an immense health burden worldwide. Epidemiological studies have revealed extensive disparities in the incidence and severity of respiratory tract infections between men and women. It has been hypothesized that there might also be a nasal microbiome axis contributing to the observed sex disparities. Here, we study the nasal microbiome of healthy young adults in the largest cohort to date with 1593 individuals, using shotgun metagenomic sequencing. We compile the most comprehensive reference catalog for the nasal bacterial community containing 4197 metagenome-assembled genomes and integrate the mycobiome, to provide a valuable resource and a more holistic perspective for the understudied human nasal microbiome. We systematically evaluate sex differences and reveal extensive sex-specific features in both taxonomic and functional levels in the nasal microbiome. Through network analyses, we capture markedly higher ecological stability and antagonistic potentials in the female nasal microbiome compared to the male’s. The analysis of the keystone bacteria reveals that the sex-dependent evolutionary characteristics might have contributed to these differences. In summary, we construct the most comprehensive catalog of metagenome-assembled-genomes for the nasal bacterial community to provide a valuable resource for the understudied human nasal microbiome. On top of that, comparative analysis in relative abundance and microbial co-occurrence networks identify extensive sex differences in the respiratory tract community, which may help to further our understanding of the observed sex disparities in the respiratory diseases.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"122 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384437","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":"Optimizing and benchmarking polygenic risk scores with GWAS summary statistics","authors":"Zijie Zhao, Tim Gruenloh, Meiyi Yan, Yixuan Wu, Zhongxuan Sun, Jiacheng Miao, Yuchang Wu, Jie Song, Qiongshi Lu","doi":"10.1186/s13059-024-03400-w","DOIUrl":"https://doi.org/10.1186/s13059-024-03400-w","url":null,"abstract":"Polygenic risk score (PRS) is a major research topic in human genetics. However, a significant gap exists between PRS methodology and applications in practice due to often unavailable individual-level data for various PRS tasks including model fine-tuning, benchmarking, and ensemble learning. We introduce an innovative statistical framework to optimize and benchmark PRS models using summary statistics of genome-wide association studies. This framework builds upon our previous work and can fine-tune virtually all existing PRS models while accounting for linkage disequilibrium. In addition, we provide an ensemble learning strategy named PUMAS-ensemble to combine multiple PRS models into an ensemble score without requiring external data for model fitting. Through extensive simulations and analysis of many complex traits in the UK Biobank, we demonstrate that this approach closely approximates gold-standard analytical strategies based on external validation, and substantially outperforms state-of-the-art PRS methods. Our method is a powerful and general modeling technique that can continue to combine the best-performing PRS methods out there through ensemble learning and could become an integral component for all future PRS applications.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"12 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384434","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":"APC mutations dysregulate alternative polyadenylation in cancer","authors":"Austin M. Gabel, Andrea E. Belleville, James D. Thomas, Jose Mario Bello Pineda, Robert K. Bradley","doi":"10.1186/s13059-024-03406-4","DOIUrl":"https://doi.org/10.1186/s13059-024-03406-4","url":null,"abstract":"Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood. We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3′ UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations. As APC has been previously identified as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"54 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383956","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":"In vivo perturb-seq of cancer and microenvironment cells dissects oncologic drivers and radiotherapy responses in glioblastoma","authors":"S. John Liu, Christopher Zou, Joanna Pak, Alexandra Morse, Dillon Pang, Timothy Casey-Clyde, Ashir A. Borah, David Wu, Kyounghee Seo, Thomas O’Loughlin, Daniel A. Lim, Tomoko Ozawa, Mitchel S. Berger, Roarke A. Kamber, William A. Weiss, David R. Raleigh, Luke A. Gilbert","doi":"10.1186/s13059-024-03404-6","DOIUrl":"https://doi.org/10.1186/s13059-024-03404-6","url":null,"abstract":"Genetic perturbation screens with single-cell readouts have enabled rich phenotyping of gene function and regulatory networks. These approaches have been challenging in vivo, especially in adult disease models such as cancer, which include mixtures of malignant and microenvironment cells. Glioblastoma (GBM) is a fatal cancer, and methods of systematically interrogating gene function and therapeutic targets in vivo, especially in combination with standard of care treatment such as radiotherapy, are lacking. Here, we iteratively develop a multiplex in vivo perturb-seq CRISPRi platform for single-cell genetic screens in cancer and tumor microenvironment cells that leverages intracranial convection enhanced delivery of sgRNA libraries into mouse models of GBM. Our platform enables potent silencing of drivers of in vivo growth and tumor maintenance as well as genes that sensitize GBM to radiotherapy. We find radiotherapy rewires transcriptional responses to genetic perturbations in an in vivo-dependent manner, revealing heterogenous patterns of treatment sensitization or resistance in GBM. Furthermore, we demonstrate targeting of genes that function in the tumor microenvironment, enabling alterations of ligand-receptor interactions between immune and stromal cells following in vivo CRISPRi perturbations that can affect tumor cell phagocytosis. In sum, we demonstrate the utility of multiplexed perturb-seq for in vivo single-cell dissection of adult cancer and normal tissue biology across multiple cell types in the context of therapeutic intervention, a platform with potential for broad application.\u0000","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"12 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383957","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":"Assessing and mitigating batch effects in large-scale omics studies","authors":"Ying Yu, Yuanbang Mai, Yuanting Zheng, Leming Shi","doi":"10.1186/s13059-024-03401-9","DOIUrl":"https://doi.org/10.1186/s13059-024-03401-9","url":null,"abstract":"Batch effects in omics data are notoriously common technical variations unrelated to study objectives, and may result in misleading outcomes if uncorrected, or hinder biomedical discovery if over-corrected. Assessing and mitigating batch effects is crucial for ensuring the reliability and reproducibility of omics data and minimizing the impact of technical variations on biological interpretation. In this review, we highlight the profound negative impact of batch effects and the urgent need to address this challenging problem in large-scale omics studies. We summarize potential sources of batch effects, current progress in evaluating and correcting them, and consortium efforts aiming to tackle them.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"9 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369153","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":"Jointly benchmarking small and structural variant calls with vcfdist","authors":"Tim Dunn, Justin M. Zook, James M. Holt, Satish Narayanasamy","doi":"10.1186/s13059-024-03394-5","DOIUrl":"https://doi.org/10.1186/s13059-024-03394-5","url":null,"abstract":"In this work, we extend vcfdist to be the first variant call benchmarking tool to jointly evaluate phased single-nucleotide polymorphisms (SNPs), small insertions/deletions (INDELs), and structural variants (SVs) for the whole genome. First, we find that a joint evaluation of small and structural variants uniformly reduces measured errors for SNPs (− 28.9%), INDELs (− 19.3%), and SVs (− 52.4%) across three datasets. vcfdist also corrects a common flaw in phasing evaluations, reducing measured flip errors by over 50%. Lastly, we show that vcfdist is more accurate than previously published works and on par with the newest approaches while providing improved result interpretability.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"40 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363096","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 genome-wide association study reveals molecular mechanism underlying powdery mildew resistance in cucumber","authors":"Xuewen Xu, Yujiao Du, Suhao Li, Ming Tan, Hamza Sohail, Xueli Liu, Xiaohua Qi, Xiaodong Yang, Xuehao Chen","doi":"10.1186/s13059-024-03402-8","DOIUrl":"https://doi.org/10.1186/s13059-024-03402-8","url":null,"abstract":"Powdery mildew is a disease with one of the most substantial impacts on cucumber production globally. The most efficient approach for controlling powdery mildew is the development of genetic resistance; however, few genes associated with inherent variations in cucumber powdery mildew resistance have been identified as of yet. In this study, we re-sequence 299 cucumber accessions, which are divided into four geographical groups. A genome-wide association study identifies 50 sites significantly associated with natural variations in powdery mildew resistance. Linkage disequilibrium analysis further divides these 50 sites into 32 linkage disequilibrium blocks containing 41 putative genes. Virus-induced gene silencing and gene expression analysis implicate CsGy5G015960, which encodes a phosphate transporter, as the candidate gene regulating powdery mildew resistance. On the basis of the resequencing data, we generate five CsGy5G015960 haplotypes, identifying Hap.1 as the haplotype most likely associated with powdery mildew resistance. In addition, we determine that a 29-bp InDel in the 3′ untranslated region of CsGy5G015960 is responsible for mRNA stability. Overexpression of CsGy5G015960Hap.1 in the susceptible line enhances powdery mildew resistance and phosphorus accumulation. Further comparative RNA-seq analysis demonstrates that CsGy5G015960Hap.1 may regulate cucumber powdery mildew resistance by maintaining a higher H2O2 level through the depletion of multiple class III peroxidases. Here we identify a candidate powdery mildew-resistant gene in cucumber using GWAS. The identified gene may be a promising target for molecular breeding and genetic engineering in cucumber to enhance powdery mildew resistance.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"76 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363097","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":"Characterization of regeneration initiating cells during Xenopus laevis tail regeneration.","authors":"Radek Sindelka, Ravindra Naraine, Pavel Abaffy, Daniel Zucha, Daniel Kraus, Jiri Netusil, Karel Smetana, Lukas Lacina, Berwini Beduya Endaya, Jiri Neuzil, Martin Psenicka, Mikael Kubista","doi":"10.1186/s13059-024-03396-3","DOIUrl":"10.1186/s13059-024-03396-3","url":null,"abstract":"<p><strong>Background: </strong>Embryos are regeneration and wound healing masters. They rapidly close wounds and scarlessly remodel and regenerate injured tissue. Regeneration has been extensively studied in many animal models using new tools such as single-cell analysis. However, until now, they have been based primarily on experiments assessing from 1 day post injury.</p><p><strong>Results: </strong>In this paper, we reveal that critical steps initiating regeneration occur within hours after injury. We discovered the regeneration initiating cells (RICs) using single-cell and spatial transcriptomics of the regenerating Xenopus laevis tail. RICs are formed transiently from the basal epidermal cells, and their expression signature suggests they are important for modifying the surrounding extracellular matrix thus regulating development. The absence or deregulation of RICs leads to excessive extracellular matrix deposition and defective regeneration.</p><p><strong>Conclusion: </strong>RICs represent a newly discovered transient cell state involved in the initiation of the regeneration process.</p>","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"25 1","pages":"251"},"PeriodicalIF":10.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344911","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":"Massive detection of cryptic recessive genetic defects in dairy cattle mining millions of life histories","authors":"Florian Besnard, Ana Guintard, Cécile Grohs, Laurence Guzylack-Piriou, Margarita Cano, Clémentine Escouflaire, Chris Hozé, Hélène Leclerc, Thierry Buronfosse, Lucie Dutheil, Jeanlin Jourdain, Anne Barbat, Sébastien Fritz, Marie-Christine Deloche, Aude Remot, Blandine Gaussères, Adèle Clément, Marion Bouchier, Elise Contat, Anne Relun, Vincent Plassard, Julie Rivière, Christine Péchoux, Marthe Vilotte, Camille Eche, Claire Kuchly, Mathieu Charles, Arnaud Boulling, Guillaume Viard, Stéphanie Minéry, Sarah Barbey, Clément Birbes, Coralie Danchin-Burge, Frédéric Launay, Sophie Mattalia, Aurélie Allais-Bonnet, Bérangère Ravary, Yves Millemann, Raphaël Guatteo, Christophe Klopp, Christine Gaspin, Carole Iampietro, Cécile Donnadieu, Denis Milan, Marie-Anne Arcangioli, Mekki Boussaha, Gilles Foucras, Didier Boichard, Aurélien Capitan","doi":"10.1186/s13059-024-03384-7","DOIUrl":"https://doi.org/10.1186/s13059-024-03384-7","url":null,"abstract":"Dairy cattle breeds are populations of limited effective size, subject to recurrent outbreaks of recessive defects that are commonly studied using positional cloning. However, this strategy, based on the observation of animals with characteristic features, may overlook a number of conditions, such as immune or metabolic genetic disorders, which may be confused with pathologies of environmental etiology. We present a data mining framework specifically designed to detect recessive defects in livestock that have been previously missed due to a lack of specific signs, incomplete penetrance, or incomplete linkage disequilibrium. This approach leverages the massive data generated by genomic selection. Its basic principle is to compare the observed and expected numbers of homozygotes for sliding haplotypes in animals with different life histories. Within three cattle breeds, we report 33 new loci responsible for increased risk of juvenile mortality and present a series of validations based on large-scale genotyping, clinical examination, and functional studies for candidate variants affecting the NOA1, RFC5, and ITGB7 genes. In particular, we describe disorders associated with NOA1 and RFC5 mutations for the first time in vertebrates. The discovery of these many new defects will help to characterize the genetic basis of inbreeding depression, while their management will improve animal welfare and reduce losses to the industry.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"22 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330265","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":"Loss of Lateral suppressor gene is associated with evolution of root nodule symbiosis in Leguminosae","authors":"Tengfei Liu, Zhi Liu, Jingwei Fan, Yaqin Yuan, Haiyue Liu, Wenfei Xian, Shuaiying Xiang, Xia Yang, Yucheng Liu, Shulin Liu, Min Zhang, Yuannian Jiao, Shifeng Cheng, Jeff J. Doyle, Fang Xie, Jiayang Li, Zhixi Tian","doi":"10.1186/s13059-024-03393-6","DOIUrl":"https://doi.org/10.1186/s13059-024-03393-6","url":null,"abstract":"Root nodule symbiosis (RNS) is a fascinating evolutionary event. Given that limited genes conferring the evolution of RNS in Leguminosae have been functionally validated, the genetic basis of the evolution of RNS remains largely unknown. Identifying the genes involved in the evolution of RNS will help to reveal the mystery. Here, we investigate the gene loss event during the evolution of RNS in Leguminosae through phylogenomic and synteny analyses in 48 species including 16 Leguminosae species. We reveal that loss of the Lateral suppressor gene, a member of the GRAS-domain protein family, is associated with the evolution of RNS in Leguminosae. Ectopic expression of the Lateral suppressor (Ls) gene from tomato and its homolog MONOCULM 1 (MOC1) and Os7 from rice in soybean and Medicago truncatula result in almost completely lost nodulation capability. Further investigation shows that Lateral suppressor protein, Ls, MOC1, and Os7 might function through an interaction with NODULATION SIGNALING PATHWAY 2 (NSP2) and CYCLOPS to repress the transcription of NODULE INCEPTION (NIN) to inhibit the nodulation in Leguminosae. Additionally, we find that the cathepsin H (CTSH), a conserved protein, could interact with Lateral suppressor protein, Ls, MOC1, and Os7 and affect the nodulation. This study sheds light on uncovering the genetic basis of the evolution of RNS in Leguminosae and suggests that gene loss plays an essential role.\u0000","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"201 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330266","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}