Genome research最新文献_第5页

Genotyping of selected germline adaptive immune system loci using short-read sequencing data 利用短读测序数据对选择的种系适应性免疫系统位点进行基因分型

IF 7 2区生物学

Genome research Pub Date : 2025-08-05 DOI: 10.1101/gr.280314.124

Michael K.B. Ford, Ananth Hari, Meredith Yeager, Lisa Mirabello, Stephen Chanock, Ibrahim Numanagić, COVNET Consortium, S. Cenk Sahinalp

{"title":"Genotyping of selected germline adaptive immune system loci using short-read sequencing data","authors":"Michael K.B. Ford, Ananth Hari, Meredith Yeager, Lisa Mirabello, Stephen Chanock, Ibrahim Numanagić, COVNET Consortium, S. Cenk Sahinalp","doi":"10.1101/gr.280314.124","DOIUrl":"https://doi.org/10.1101/gr.280314.124","url":null,"abstract":"As we enter the age of personalized medicine, healthcare is increasingly focused on tailoring diagnoses and treatments based on patients’ genetic and environmental circumstances. A critical component of a person's physiological makeup is their immune system, but individual genetic variation in many immune system genes has remained resistant to analysis using classical whole-genome or targeted sequencing approaches. In particular, germline adaptive immune system genes, like immunoglobulin (IG) and T cell receptor (TR) genes, are particularly hard to genotype using classic reference-based methods owing to their highly repetitive and homologous nature. In this paper, we present ImmunoTyper2, a new computational toolkit for genotyping the variable genes of the IG lambda and kappa, and the TR loci with short-read whole genome sequence data, using an integer linear programming formulation, as an update to the ImmunoTyper-SR suite, which focused on IGHV region only. We evaluate its genotyping performance using Mendelian concordance analysis in 590 trios from the 1000 Genomes Project, benchmarking 40 samples against HPRC assembly-derived genotypes, and assessing robustness through sequencing depth analysis and parameter sensitivity tests. We introduce allele call confidence metrics to help quantify reliability. We also perform a prospective disease association study, applying ImmunoTyper2 to a WGS data set from a cohort of 461 COVID-19 patients from the COVNET Consortium to demonstrate how it can be applied to investigate genetic associations with disease.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"11 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

High-resolution spatial transcriptomics in fixed tissue using a cost-effective PCL-seq workflow 高分辨率空间转录组学在固定组织中使用具有成本效益的PCL-seq工作流程

IF 7 2区生物学

Genome research Pub Date : 2025-08-05 DOI: 10.1101/gr.279906.124

Xue Dong, Mengzhu Hu, Xiaonan Cui, Wenjian Zhou, Jingtao Cai, Guangyao Mao, Weiyang Shi

{"title":"High-resolution spatial transcriptomics in fixed tissue using a cost-effective PCL-seq workflow","authors":"Xue Dong, Mengzhu Hu, Xiaonan Cui, Wenjian Zhou, Jingtao Cai, Guangyao Mao, Weiyang Shi","doi":"10.1101/gr.279906.124","DOIUrl":"https://doi.org/10.1101/gr.279906.124","url":null,"abstract":"The spatial heterogeneity of gene expression has driven the development of diverse spatial transcriptomics technologies. Here, we present photocleavage and ligation sequencing (PCL-seq), a spatial indexing method utilizing a light-controlled DNA labeling strategy applied to tissue sections. PCL-seq employs photocleavable oligonucleotides and ligation adapters to construct transcriptional profiles of specific regions of interest (ROIs) designated via microscopically controlled photo-illumination. In frozen mouse embryos, PCL-seq generates spatially aligned gene expression matrices and produces high-quality data, detecting approximately 170,000 unique molecular identifiers (UMIs) and 8600 genes (illumination diameter = 100 µm). Moreover, PCL-seq is compatible with formalin-fixed paraffin-embedded (FFPE) tissues, successfully identifying thousands of differentially enriched transcripts in the digits and vertebrae of mouse embryo FFPE sections. Additionally, PCL-seq achieves subcellular resolution, as demonstrated by differential expression profiling between nuclear and cytoplasmic compartments. These characteristics establish PCL-seq as an accessible and versatile workflow for spatial transcriptomic analyses in both frozen and FFPE tissues with subcellular resolution.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"159 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

3′-end ligation sequencing is a sensitive method to detect DNA nicks at potential sites of off-target activity induced by prime editors 3 '端结扎测序是一种灵敏的方法，用于检测由引物编辑器诱导的潜在脱靶活性位点的DNA缺口

IF 7 2区生物学

Genome research Pub Date : 2025-08-05 DOI: 10.1101/gr.280164.124

Jacob Stewart-Ornstein, Matthew J. Irby, Marina K. Lilieholm, Dylan Laprise, Maria D. Collier, Thomas Aunins, Dewi Harjanto, Aaron N. Chang, Deepak Reyon, Jeremy S. Duffield

{"title":"3′-end ligation sequencing is a sensitive method to detect DNA nicks at potential sites of off-target activity induced by prime editors","authors":"Jacob Stewart-Ornstein, Matthew J. Irby, Marina K. Lilieholm, Dylan Laprise, Maria D. Collier, Thomas Aunins, Dewi Harjanto, Aaron N. Chang, Deepak Reyon, Jeremy S. Duffield","doi":"10.1101/gr.280164.124","DOIUrl":"https://doi.org/10.1101/gr.280164.124","url":null,"abstract":"Gene editing makes precise changes in DNA to restore normal function or expression of genes; however, the advancement of gene editing to the clinic is limited by the potential genotoxicity of off-target editing. To comprehensively identify potential sites in the genome that may be recognized by gene editing agents, in vitro approaches, in which the editor is combined with human genomic DNA and sites where editing may occur are identified biochemically, are important tools. Existing biochemical approaches for off-target discovery recognize double-stranded breaks generated by nuclease-based gene editors such as SpCas9, but novel approaches are needed for new editing modalities, such as prime editing, that nick one strand of DNA. To fill this gap, we have developed 3′-end ligation sequencing (PEG-seq), which can identify prime editor–induced nicks throughout the genome on in vitro digested human genomic DNA to identify potential off-target sites. Here we show that PEG-seq is an important addition to the off-target detection toolkit, enabling off-target discovery for DNA nicking gene editors such as prime editors.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"30 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Interspecies systems biology links bacterial metabolic pathways to nematode gene expression, chemotaxis behavior, and survival 种间系统生物学将细菌代谢途径与线虫基因表达、趋化行为和生存联系起来

IF 7 2区生物学

Genome research Pub Date : 2025-08-05 DOI: 10.1101/gr.280848.125

Marina Athanasouli, Tobias Loschko, Christian Roedelsperger

{"title":"Interspecies systems biology links bacterial metabolic pathways to nematode gene expression, chemotaxis behavior, and survival","authors":"Marina Athanasouli, Tobias Loschko, Christian Roedelsperger","doi":"10.1101/gr.280848.125","DOIUrl":"https://doi.org/10.1101/gr.280848.125","url":null,"abstract":"All animals live in tight association with complex microbial communities, yet studying the effects of individual bacteria remains challenging. Bacterial feeding nematodes are powerful systems to study host microbe interactions as worms can be grown on monoxenic cultures. Here, we present three different types of resources that may assist future research of cross-species interactions in the nematode Pristionchus pacificus, but also in other organisms. First, by sequencing the genomes of 84 Pristionchus-associated bacteria, we establish a genomic basis to study host microbe interactions and we demonstrate its utility to identify candidate pathways in the bacteria affecting chemotaxis behavior and survival in the nematodes. Second, we generated nematode transcriptomes of P. pacificus nematodes on 38 bacterial diets and characterized 60 coexpression modules with differential responses to environmental microbiota. Third, we link the microbial genome and host transcriptome data by predicting a global map of more than 2,800 metabolic interactions. These interactions represent statistical associations between variation in bacterial metabolic potential and differential transcriptomic responses of coexpression modules in the nematode. Analysis of the interactome identifies several intestinal modules as the primary response layer to diverse microbiota and reveals a number of broadly conserved metabolic interactions. In summary, our study establishes a multiomic framework for future mechanistic studies in P. pacificus and may also be conceptually transferred and reimplemented in other organisms in order to investigate the evolution of the host microbe interactome.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"15 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

H3K27 and H3K9 methylation mask potential CTCF binding sites to maintain 3D genome integrity H3K27和H3K9甲基化掩盖潜在的CTCF结合位点，以维持三维基因组的完整性

IF 7 2区生物学

Genome research Pub Date : 2025-08-05 DOI: 10.1101/gr.280732.125

Kei Fukuda, Chikako Shimura, Yoichi Shinkai

{"title":"H3K27 and H3K9 methylation mask potential CTCF binding sites to maintain 3D genome integrity","authors":"Kei Fukuda, Chikako Shimura, Yoichi Shinkai","doi":"10.1101/gr.280732.125","DOIUrl":"https://doi.org/10.1101/gr.280732.125","url":null,"abstract":"The three-dimensional (3D) genome structure is essential for gene regulation and various genomic functions. CTCF plays a key role in organizing Topologically Associated Domains (TADs) and promoter-enhancer loops, contributing to proper cell differentiation and development. Although CTCF binds the genome with high sequence specificity, its binding sites are dynamically regulated during development, and aberrant CTCF binding is linked to diseases such as cancer and neurological disorders, and aging. However, the mechanisms controlling CTCF binding remain unclear. Here, we investigate the role of repressive chromatin modifications in CTCF binding using H3K9 methyltransferase-deficient immortalized mouse embryonic fibroblasts (iMEFs) and H3K27 methyltransferase EZH1/2 inhibitor. We find that H3K9 and H3K27 methylation regulate CTCF binding at distinct genomic regions, and their simultaneous loss induces drastic changes in CTCF binding. These changes are associated with alterations in 3D genome architecture and gene expression, suggesting that repressive chromatin modifications preserve proper chromatin organization by preventing aberrant CTCF binding. Additionally, while CTCF binding sites repressed by H3K9 methylation are bound by CTCF in early mouse embryos, those repressed by both H3K9 and H3K27 methylation remain inaccessible, with early embryonic-specific H3K27 methylation forming at these sites. These findings implicate that H3K27 methylation plays a role for restricting CTCF binding in early embryos, ensuring proper genome organization during development.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"26 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Epigenetic drift score captures directional methylation variability and links aging to transcriptional, metabolic, and genetic alterations 表观遗传漂变得分捕获定向甲基化变异性，并将衰老与转录、代谢和遗传改变联系起来

IF 7 2区生物学

Genome research Pub Date : 2025-08-01 DOI: 10.1101/gr.280155.124

Xiu Fan, Qili Qian, Wenran Li, Tianzi Liu, Changqing Zeng, Peilin Jia, Huandong Lin, Xin Gao, Li Jin, Mingfeng Xia, Sijia Wang, Fan Liu

{"title":"Epigenetic drift score captures directional methylation variability and links aging to transcriptional, metabolic, and genetic alterations","authors":"Xiu Fan, Qili Qian, Wenran Li, Tianzi Liu, Changqing Zeng, Peilin Jia, Huandong Lin, Xin Gao, Li Jin, Mingfeng Xia, Sijia Wang, Fan Liu","doi":"10.1101/gr.280155.124","DOIUrl":"https://doi.org/10.1101/gr.280155.124","url":null,"abstract":"Epigenetic drift refers to the gradual and stochastic accumulation of epigenetic changes, such as DNA methylation variability, with advancing age. Although increasingly recognized for its potential role in aging biology, its extent, biological significance, and population specificity remain insufficiently characterized. Here, we present the first comprehensive epigenome-wide drift study (EWDS) in a large Chinese cohort (n = 3,538), with replication in two independent Chinese (total n = 1,467) and two European cohorts (total n = 956), to investigate the scale and relevance of epigenetic drift across populations. Through simulation, we identified White's test as the most powerful method among four alternatives for detecting age-associated methylation variability. Our EWDS revealed that 10.8% (50,385 CpGs) of sites on the 850K EPIC array exhibited epigenome-wide significant drift, with 99% showing increased interindividual variability (positive drift) and 1% showing decreased variability (negative drift). Integration with single-cell RNA-seq data demonstrated that positive drift-CpGs are associated with increased transcriptional variability and upregulation in specific cell types, while negative drift-CpGs exhibit the opposite effect. We developed epigenetic drift scores (EDSs) to quantify individual drift burden; these scores are strongly age-associated and correlate with lipidomic profiles and clinical aging indicators. Longitudinal data confirm within-individual accumulation of drift over time. Finally, a GWAS of EDS identified genetic determinants of drift magnitude, including heritable loci (e.g., ASTN2, SOCS5). Collectively, these findings establish epigenetic drift as a pervasive, directional, and biologically meaningful feature of human aging.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"27 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Genotype imputation from low-coverage data for medical and population genetic analyses 基于低覆盖率数据的基因型输入，用于医学和群体遗传分析

IF 7 2区生物学

Genome research Pub Date : 2025-07-22 DOI: 10.1101/gr.280175.124

Simone Andrea Biagini, Sara Becelaere, Mio Aerden, Tatjana Jatsenko, Laurens Hannes, Philip Van Damme, Jeroen Breckpot, Koenraad Devriendt, Bernard Thienpont, Joris Robert Vermeesch, Isabelle Cleynen, Toomas Kivisild

{"title":"Genotype imputation from low-coverage data for medical and population genetic analyses","authors":"Simone Andrea Biagini, Sara Becelaere, Mio Aerden, Tatjana Jatsenko, Laurens Hannes, Philip Van Damme, Jeroen Breckpot, Koenraad Devriendt, Bernard Thienpont, Joris Robert Vermeesch, Isabelle Cleynen, Toomas Kivisild","doi":"10.1101/gr.280175.124","DOIUrl":"https://doi.org/10.1101/gr.280175.124","url":null,"abstract":"Genotype imputation from low-pass sequencing data presents unique opportunities for genomic analyses but comes with specific challenges. In this study, we explore the impact of quality filters on genetic ancestry and Polygenic Score (PGS) estimation after imputing 32,769 low-pass genome wide sequences (LPS) from noninvasive prenatal screening (NIPS) with an average autosomal sequence depth of ~0.15×. In scenarios involving ultra-low coverage sequences, conventional approaches to enhance accuracy may fail, especially when multiple samples are pooled. To enhance the proportion of high-quality genotypes in large datasets we introduce a filtering approach called GDI that combines genotype probability (GP), alternate allele dosage (DS), and INFO score filters. We demonstrate that imputation tools QUILT and GLIMPSE2 achieve similar accuracy, which is high enough for broad-scale ancestry mapping but insufficient for high resolution Principal Component Analysis (PCA), when applied without filters. With the GDI approach we can achieve quality that is adequate for such purposes. Furthermore, we explored the impact of imputation errors, choice of variants and filtering methods on PGS prediction for height in 1,911 subjects with height data. We show that polygenic scores predict 23.7% of variance in height in our imputed data and that, contrary to the effect on PCA, the GDI filter does not improve the performance of PGS in height prediction. These results highlight that imputed LPS data can be leveraged for further biomedical and population genetic use but there is a need to consider each downstream analysis tool individually for its imputation quality thresholds and filtering requirements.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"16 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The ggRibo single-gene viewer reveals insights into translatome and other nucleotide-resolution omics data grribo单基因查看器揭示了翻译组和其他核苷酸分辨率组学数据的见解

IF 7 2区生物学

Genome research Pub Date : 2025-07-22 DOI: 10.1101/gr.280480.125

Hsin-Yen Larry Wu, Isaiah D. Kaufman, Polly Yingshan Hsu

{"title":"The ggRibo single-gene viewer reveals insights into translatome and other nucleotide-resolution omics data","authors":"Hsin-Yen Larry Wu, Isaiah D. Kaufman, Polly Yingshan Hsu","doi":"10.1101/gr.280480.125","DOIUrl":"https://doi.org/10.1101/gr.280480.125","url":null,"abstract":"Visualizing Ribo-seq and other sequencing data within genes of interest is a powerful approach to studying gene expression, but its application is limited by a lack of robust tools. Here, we introduce ggRibo, a user-friendly R package for visualizing individual gene expression, integrating Ribo-seq, RNA-seq, and other genome-wide datasets with flexible scaling options. ggRibo visualizes 3-nucleotide periodicity, a hallmark of translating ribosomes, within a gene-structure context, including introns and untranslated regions, enabling the study of novel ORFs, translation of different isoforms, and mechanisms of translational regulation. ggRibo can plot multiple Ribo-seq/RNA-seq datasets from different conditions for comparison. It also contains functions for plotting single-transcript view, reading-frame decomposition, and RNA-seq coverage alone. Importantly, ggRibo supports the visualization of other omics datasets that could also be presented with single-nucleotide resolution, such as RNA degradome, transcription start sites, translation initiation sites, and epitranscriptomic modifications. We demonstrate its utility with examples of upstream ORFs, downstream ORFs, nested ORFs, and differential isoform translation in humans, Arabidopsis, tomato, and rice. We also provide examples of multiomic comparisons that reveal insights that connect the transcriptome, translatome, and degradome. In summary, ggRibo is an advanced single-gene viewer that offers a valuable resource for studying gene expression regulation through its intuitive and flexible platform.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"16 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Aggregation of recount3 RNA-seq data improves inference of consensus and tissue-specific gene coexpression networks 聚集的ret3 RNA-seq数据提高了共识和组织特异性基因共表达网络的推断

IF 7 2区生物学

Genome research Pub Date : 2025-07-17 DOI: 10.1101/gr.280808.125

Prashanthi Ravichandran, Princy Parsana, Rebecca Keener, Kasper Hansen, Alexis Battle

{"title":"Aggregation of recount3 RNA-seq data improves inference of consensus and tissue-specific gene coexpression networks","authors":"Prashanthi Ravichandran, Princy Parsana, Rebecca Keener, Kasper Hansen, Alexis Battle","doi":"10.1101/gr.280808.125","DOIUrl":"https://doi.org/10.1101/gr.280808.125","url":null,"abstract":"Gene coexpression networks (GCNs) describe relationships among genes that maintain cellular identity and homeostasis. However, typical RNA-seq experiments often lack sufficient sample sizes for reliable GCN inference. Recount3, a dataset with 316,443 processed human RNA-seq samples, provides an opportunity to improve network reconstruction. However, GCN inference from public data is challenged by confounders and inconsistent labeling. To address this, we developed a pipeline to annotate samples based on cell type composition. By comparing aggregation strategies, we found that regressing confounders within studies and prioritizing larger studies optimized network reconstruction. We applied these findings to infer three consensus networks (universal, cancer, non-cancer) and 27 context-specific networks. Central genes in consensus networks were enriched for evolutionarily constrained genes and ubiquitous biological pathways, while context-specific central nodes included tissue-specific transcription factors. The increased statistical power from data aggregation facilitated the derivation of variant annotations from context-specific networks, which were significantly enriched for complex-trait heritability independent of overlap with baseline functional genomic annotations. While data aggregation led to strictly increasing held-out log-likelihood, we observed diminishing marginal improvements, suggesting that integrating complementary modalities, such as Hi-C and ChIP-seq, could further refine network reconstruction. Our approach outlines best practices for GCN inference and highlights both the strengths and limitations of data aggregation.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations 易损运动神经元特有的转录调节可预测跨物种和SOD1突变的ALS

IF 7 2区生物学

Genome research Pub Date : 2025-07-17 DOI: 10.1101/gr.279501.124

Irene Mei, Susanne Nichterwitz, Melanie Leboeuf, Jik Nijssen, Isadora lenoel, Dirk Repsilber, Christian S Lobsiger, Eva Hedlund

{"title":"Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations","authors":"Irene Mei, Susanne Nichterwitz, Melanie Leboeuf, Jik Nijssen, Isadora lenoel, Dirk Repsilber, Christian S Lobsiger, Eva Hedlund","doi":"10.1101/gr.279501.124","DOIUrl":"https://doi.org/10.1101/gr.279501.124","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) that innervate skeletal muscles. However, certain MN groups including ocular MNs, are relatively resilient. To reveal key drivers of resilience versus vulnerability in ALS, we investigate the transcriptional dynamics of four distinct MN populations in SOD1G93A ALS mice using LCM-seq and single molecule fluorescent in situ hybridization. We find that resilient ocular MNs regulate few genes in response to disease. Instead, they exhibit high baseline gene expression of neuroprotective factors including En1, Pvalb, Cd63 and Gal, some of which vulnerable MNs upregulate during disease. Vulnerable motor neuron groups upregulate both detrimental and regenerative responses to ALS and share pathway activation, indicating that breakdown occurs through similar mechanisms across vulnerable neurons, albeit with distinct timing. Meta-analysis across four rodent mutant SOD1 MN transcriptome datasets identify a shared vulnerability code of 39 genes including Atf4, Nupr1, Ddit3, and Penk, involved in apoptosis as well as proregenerative and anti-apoptotic signature consisting of Atf3, Vgf, Ina, Sprr1a, Fgf21, Gap43, Adcyap1, and Mt1. Machine learning using genes upregulated in SOD1G93A spinal MN predicts disease in human stem cell-derived SOD1E100G MNs, and shows that dysregulation of VGF, INA, and PENK are strong disease-predictors across species and SOD1 mutations. Our study reveals MN population-specific gene expression and temporal disease-induced regulation that together provide a basis to explain ALS selective vulnerability and resilience and that can be used to predict disease.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"24 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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