Genome research最新文献_第2页

Recalibrating differential gene expression by genetic dosage variance prioritizes functionally relevant genes 通过基因剂量方差重新校准差异基因表达优先考虑功能相关基因

IF 7 2区生物学

Genome research Pub Date : 2025-09-17 DOI: 10.1101/gr.280360.124

Philipp Rentzsch, Aaron Kollotzek, Kaushik Ram Ganapathy, Pejman Mohammadi, Tuuli Lappalainen

{"title":"Recalibrating differential gene expression by genetic dosage variance prioritizes functionally relevant genes","authors":"Philipp Rentzsch, Aaron Kollotzek, Kaushik Ram Ganapathy, Pejman Mohammadi, Tuuli Lappalainen","doi":"10.1101/gr.280360.124","DOIUrl":"https://doi.org/10.1101/gr.280360.124","url":null,"abstract":"Differential expression (DE) analysis is a widely used method for identifying genes that are functionally relevant for an observed phenotype or biological response. However, typical DE analysis includes selection of genes based on a threshold of fold change in expression under the implicit assumption that all genes are equally sensitive to dosage changes of their transcripts. This tends to favor highly variable genes over more constrained genes where even small changes in expression may be biologically relevant. To address this limitation, we have developed a method to recalibrate each gene's DE fold change based on genetic expression variance observed in the human population. The newly established metric ranks statistically differentially expressed genes, not by nominal change of expression, but by relative change in comparison to natural dosage variation for each gene. We apply our method to RNA sequencing data sets from in vitro stimulus response and neuropsychiatric disease experiments. Compared to the standard approach, our method adjusts the bias in discovery toward highly variable genes and enriches for pathways and biological processes related to metabolic and regulatory activity, indicating a prioritization of functionally relevant driver genes. Tissue-specific recalibration increases detection of known disease-relevant processes. Altogether, our method provides a novel view on DE and contributes toward bridging the existing gap between statistical and biological significance. We believe that this approach will simplify the identification of disease-causing molecular processes and enhance the discovery of therapeutic targets.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"53 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077422","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

Analyzing the large and complex SFARI autism cohort data using the Genotypes and Phenotypes in Families (GPF) platform 使用家族基因型和表型（GPF）平台分析大量复杂的SFARI自闭症队列数据

IF 7 2区生物学

Genome research Pub Date : 2025-09-16 DOI: 10.1101/gr.280356.124

Liubomir Chorbadjiev, Murat Cokol, Zohar Weinstein, Kevin Shi, Christopher Fleisch, Nikolay Dimitrov, Svetlin Mladenov, Ivo Todorov, Iordan Ivanov, Simon Xu, Steven Ford, Yoon-ha Lee, Boris Yamrom, Steven Marks, Adriana Munoz, Alex Lash, Natalia Volfovsky, Ivan Iossifov

{"title":"Analyzing the large and complex SFARI autism cohort data using the Genotypes and Phenotypes in Families (GPF) platform","authors":"Liubomir Chorbadjiev, Murat Cokol, Zohar Weinstein, Kevin Shi, Christopher Fleisch, Nikolay Dimitrov, Svetlin Mladenov, Ivo Todorov, Iordan Ivanov, Simon Xu, Steven Ford, Yoon-ha Lee, Boris Yamrom, Steven Marks, Adriana Munoz, Alex Lash, Natalia Volfovsky, Ivan Iossifov","doi":"10.1101/gr.280356.124","DOIUrl":"https://doi.org/10.1101/gr.280356.124","url":null,"abstract":"The exploration of genotypic variants impacting phenotypes is a cornerstone in genetics research. The emergence of vast collections containing deeply genotyped and phenotyped families has made it possible to pursue the search for variants associated with complex diseases. However, managing these large-scale data sets requires specialized computational tools to organize and analyze the extensive data. Genotypes and Phenotypes in Families (GPF) is an open-source platform that manages genotypes and phenotypes derived from collections of families. GPF allows interactive exploration of genetic variants, enrichment analysis for de novo mutations, phenotype/genotype association tools, and secure data sharing. GPF is used to disseminate two family collection data sets, SSC and SPARK, for the study of autism, built by the Simons Foundation. The GPF instance at the Simons Foundation (GPF-SFARI) provides protected access to comprehensive genotypic and phenotypic data for SSC and SPARK. GPF-SFARI also provides public access to an extensive collection of de novo mutations from individuals with autism and related disorders and to gene-level statistics of the protected data sets characterizing the genes’ roles in autism. However, GPF is versatile and can manage genotypic data from other small or large family collections. Here, we highlight the primary features of GPF within the context of GPF-SFARI.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"37 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145072494","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

Long-read sequencing reveals HBV integration patterns and oncogenic impact on early-onset hepatocellular carcinoma 长读序列揭示了HBV整合模式和对早发性肝细胞癌的致癌影响

IF 7 2区生物学

Genome research Pub Date : 2025-09-16 DOI: 10.1101/gr.279889.124

Yao Wang, Dong Yu, Yue Mei, Zhida Fu, Jian Lin, Di Wu, Yuan Yang, Hongli Yan

{"title":"Long-read sequencing reveals HBV integration patterns and oncogenic impact on early-onset hepatocellular carcinoma","authors":"Yao Wang, Dong Yu, Yue Mei, Zhida Fu, Jian Lin, Di Wu, Yuan Yang, Hongli Yan","doi":"10.1101/gr.279889.124","DOIUrl":"https://doi.org/10.1101/gr.279889.124","url":null,"abstract":"Hepatitis B virus (HBV) integration is a key driver of hepatocellular carcinoma (HCC) occurrence and progression; however, its oncogenic mechanisms remain incompletely understood because of limitations in detection methods and sample availability. In this study, we employed Oxford Nanopore Technologies (ONT) whole-genome sequencing and full-length transcriptome sequencing to characterize HBV integration events at the genomic and transcriptomic levels, along with their regulatory effects on structural variations (SVs) and gene expression. Functional validation was performed using dual-luciferase assays and cell-based experiments. Our findings revealed that integrated HBV sequences form long concatemers, mediating inter- and intrachromosomal recombination in the human genome. Notably, integrated HBV enhancer I (HBV-Enh I) was detected in 6 of 7 tumor tissues and was associated with aberrant gene expression. HBV integration induced oncogenic SVs, such as focal MYC amplification and NAV2 deletion, and directly modulated gene expression. Additionally, ectopic overexpression of MYOCD, driven by HBV-Enh I integration, promoted HCC cell migration and invasion. In summary, HBV integration acts as a major driver of large-scale genomic SVs and transcriptomic dysregulation, through either direct alterations in genome dosage or cis-regulatory mechanisms. HBV-Enh I is frequently integrated in HCC and might play a pivotal role in abnormal gene expression, highlighting its potential as a therapeutic target.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"46 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067702","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

T2T-CHM13 improves read mapping and detection of clinically relevant genetic variation in the Swedish population T2T-CHM13改善了瑞典人群中临床相关遗传变异的读取定位和检测

IF 7 2区生物学

Genome research Pub Date : 2025-09-16 DOI: 10.1101/gr.279320.124

Daniel Schmitz, Adam Ameur, Åsa Johansson

{"title":"T2T-CHM13 improves read mapping and detection of clinically relevant genetic variation in the Swedish population","authors":"Daniel Schmitz, Adam Ameur, Åsa Johansson","doi":"10.1101/gr.279320.124","DOIUrl":"https://doi.org/10.1101/gr.279320.124","url":null,"abstract":"The T2T-CHM13 reference genome, released in March 2022, fills in the 8% of the human genome that were not resolved in GRCh38 and reconstructs large parts of the known genome. The more accurate and complete reference genome is expected to improve the quality of read mapping and variant calling. Even though whole genome sequencing (WGS)-based approaches have become the golden standard in medical genetics, the extent of these benefits still remains unclear. In this study, we aim to evaluate mapping quality and variant call performance with T2T-CHM13 as a reference using a cross-sectional Swedish cohort (SweGen) comprising 1000 individuals with short-read Illumina WGS data available. Remapping and variant calling was performed using the nf-core/sarek pipeline. T2T-CHM13 improved a wide range of mapping and variant calling related metrics, including a higher fraction of properly paired reads, lower mismatch rate, and more uniform coverage of coding regions. Moreover, the fraction of ambiguous alignments was higher, reflecting segmental duplications that were incorrectly collapsed in GRCh37 and GRCh38. In comparison to GRCh38, we identified 10 million additional variants in the cohort, including 5.5 million singletons, and observed an increased sensitivity for rare variants. SnpEff assigned impact ratings of moderate or high to 13% more variants in T2T-CHM13 than GRCh38. In summary, we conclude that T2T-CHM13 improves alignment metrics with higher mapping quality, better variant calling performance and confidence, including for rare and deleterious variants. The T2T-CHM13 genome reference thus facilitates enhanced discovery of new disease-causing variation, benefiting, for example, rare-disease diagnostics.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"321 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067755","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

Dynamic evolution of satellite DNAs drastically differentiates the genomes of Tribolium sibling species 卫星dna的动态进化极大地区分了Tribolium兄弟物种的基因组

IF 7 2区生物学

Genome research Pub Date : 2025-09-16 DOI: 10.1101/gr.280516.125

Damira Veseljak, Evelin Despot-Slade, Marin Volarić, Lucija Horvat, Tanja Vojvoda Zeljko, Nevenka Meštrović, Brankica Mravinac

{"title":"Dynamic evolution of satellite DNAs drastically differentiates the genomes of Tribolium sibling species","authors":"Damira Veseljak, Evelin Despot-Slade, Marin Volarić, Lucija Horvat, Tanja Vojvoda Zeljko, Nevenka Meštrović, Brankica Mravinac","doi":"10.1101/gr.280516.125","DOIUrl":"https://doi.org/10.1101/gr.280516.125","url":null,"abstract":"Tandemly repeated satellite DNAs (satDNAs) are among the most abundant and fastest-evolving eukaryotic sequences, but the way they model genomes is still elusive. Here, we investigate the evolutionary dynamics of satDNAs in the extremely satDNA-rich genomes of two closely related Tribolium insects that produce sterile hybrids. In Tribolium freemani, we identify 135 satDNAs, accounting for 38.7% of the genome. Comparative analysis with the Tribolium castaneum satellitome reveals that the drastic difference occurred in their centromeric regions, which share orthologous organization characterized by totally different major satDNAs but related minor satDNAs. The T. freemani male sex chromosome, which lacks the major satDNA but contains a minor-like satDNA, further highlighted the question of which satDNA is centromere-competent. By analyzing the long-range organization of the centromeric regions, we discover that both the major and minor satDNA arrays exhibit a strong tendency toward macro-dyad symmetry, suggesting that the secondary structures in the centromeres may be more important than the primary sequence itself. We find evidence that the centromeric satDNAs of T. freemani occur in extrachromosomal circular DNAs, which may contribute to their expansion and homogenization between nonhomologous chromosomes. We also identify numerous low-copy-number satDNAs that are orthologous between the siblings, some of which are associated with transposable elements, highlighting transposition as a mechanism of their spreading. The dynamic evolution of satDNAs has clearly influenced the differentiation of Tribolium genomes, but the question remains whether the differences in their satDNA profiles are a cause or consequence of speciation.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"17 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067703","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

Mapping multitissue regulatory variants reveals a liver-centric coexpression network associated with duck egg-laying performance 绘制多组织调控变异揭示了与鸭产蛋性能相关的肝脏中心共表达网络

IF 7 2区生物学

Genome research Pub Date : 2025-09-10 DOI: 10.1101/gr.280345.124

Yang Xi, Jingjing Qi, Zhao Yang, Yutian Zeng, Huicong Zhang, Qiuyu Tao, Mengru Xu, Anqi Huang, Shenqiang Hu, Chunchun Han, Lili Bai, Jiwei Hu, Jiwen Wang, Liang Li, Lingzhao Fang, Hehe Liu

{"title":"Mapping multitissue regulatory variants reveals a liver-centric coexpression network associated with duck egg-laying performance","authors":"Yang Xi, Jingjing Qi, Zhao Yang, Yutian Zeng, Huicong Zhang, Qiuyu Tao, Mengru Xu, Anqi Huang, Shenqiang Hu, Chunchun Han, Lili Bai, Jiwei Hu, Jiwen Wang, Liang Li, Lingzhao Fang, Hehe Liu","doi":"10.1101/gr.280345.124","DOIUrl":"https://doi.org/10.1101/gr.280345.124","url":null,"abstract":"Poultry egg production is shaped by the intertwined action of multiple physiological systems, greatly magnifying the complexity of its underlying genetic regulation. Although multitissue mapping of regulatory variants offers a powerful route to untangle this complexity, comprehensive data sets in ducks remain scarce. Meanwhile, the contributions of peripheral systems beyond neuroendocrine regulation on poultry egg production are still largely unexplored. Here, we generate 979 RNA-seq samples from the liver, ovary, oviduct shell gland, and spleen, along with matched whole-genome sequencing data from 307 egg-laying ducks. We map cis-regulatory variants associated with gene expression (eQTL), alternative splicing (sQTL), and 3′ alternative polyadenylation (apaQTL), yielding 14,074, 6267, and 4994 genes with at least one significant eQTL, sQTL, and apaQTL, respectively. By integrating this resource and GWAS results, we confirm that ABCG2 expression in the shell gland specifically regulates eggshell color, with additional involvement of ENOPH1’s 3′APA sites in both the shell gland and liver. In addition, expression of LOC101800576 and LOC101790890 in the shell gland, of LOC119713219 in the ovary, and of GLP2R in the spleen is causally linked to declining egg production at peak laying. Last, we delineate a cross-tissue regulatory landscape underlying duck egg production and identify liver-derived modules, particularly Liver_ME1, which is mainly involved in cell cycle regulation, as central hubs coordinating with peripheral tissues affecting duck egg production. This work delivers a key resource and fresh perspectives for the genetic mechanism dissection of duck egg production and for future studies on cross-tissue regulation of reproduction.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031923","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

ScisTree2 enables large-scale inference of cell lineage trees and genotype calling using efficient local search ScisTree2可以通过高效的局部搜索实现细胞谱系树和基因型调用的大规模推断

IF 7 2区生物学

Genome research Pub Date : 2025-09-03 DOI: 10.1101/gr.280542.125

Haotian Zhang, Yiming Zhang, Teng Gao, Yufeng Wu

{"title":"ScisTree2 enables large-scale inference of cell lineage trees and genotype calling using efficient local search","authors":"Haotian Zhang, Yiming Zhang, Teng Gao, Yufeng Wu","doi":"10.1101/gr.280542.125","DOIUrl":"https://doi.org/10.1101/gr.280542.125","url":null,"abstract":"In a multicellular organism, cell lineages share a common evolutionary history. Knowing this history can facilitate the study of development, aging, and cancer. Cell lineage trees represent the evolutionary history of cells sampled from an organism. Recent developments in single-cell sequencing have greatly facilitated the inference of cell lineage trees. However, single-cell data are sparse and noisy, and the size of single-cell data is increasing rapidly. Accurate inference of cell lineage tree from large single-cell data is computationally challenging. In this paper, we present ScisTree2, a fast and accurate cell lineage tree inference and genotype calling approach based on the infinite-sites model. ScisTree2 relies on an efficient local search approach to find optimal trees. ScisTree2 also calls single-cell genotypes based on the inferred cell lineage tree. Experiments on simulated and real biological data show that ScisTree2 achieves better overall accuracy while being significantly more efficient than existing methods. To the best of our knowledge, ScisTree2 is the first model-based cell lineage tree inference and genotype calling approach that is capable of handling datasets from tens of thousands of cells or more.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"24 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987594","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

APOBEC3A drives deaminase mutagenesis in human gastric epithelium APOBEC3A驱动人胃上皮脱氨酶突变

IF 7 2区生物学

Genome research Pub Date : 2025-08-26 DOI: 10.1101/gr.280338.124

Yohan An, Ji-Hyun Lee, Joonoh Lim, Jeonghwan Youk, Seongyeol Park, Ji-Hyung Park, Kijong Yi, Taewoo Kim, Chang Hyun Nam, Won Hee Lee, Soo A Oh, Yoo Jin Bae, Thomas M. Klompstra, Haeun Lee, Jinju Han, Junehwak Lee, Jung Woo Park, Jie-Hyun Kim, Hyunki Kim, Hugo Snippert, Bon-Kyoung Koo, Young Seok Ju

{"title":"APOBEC3A drives deaminase mutagenesis in human gastric epithelium","authors":"Yohan An, Ji-Hyun Lee, Joonoh Lim, Jeonghwan Youk, Seongyeol Park, Ji-Hyung Park, Kijong Yi, Taewoo Kim, Chang Hyun Nam, Won Hee Lee, Soo A Oh, Yoo Jin Bae, Thomas M. Klompstra, Haeun Lee, Jinju Han, Junehwak Lee, Jung Woo Park, Jie-Hyun Kim, Hyunki Kim, Hugo Snippert, Bon-Kyoung Koo, Young Seok Ju","doi":"10.1101/gr.280338.124","DOIUrl":"https://doi.org/10.1101/gr.280338.124","url":null,"abstract":"Cancer genomes frequently carry APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like)-associated DNA mutations, suggesting APOBEC enzymes as innate mutagens during cancer initiation and evolution. However, the pure mutagenic impacts of the specific enzymes among this family remain unclear in human normal cell lineages. Here, we investigated the comparative mutagenic activities of APOBEC3A and APOBEC3B, through whole-genome sequencing of human normal gastric organoid lines carrying doxycycline-inducible APOBEC expression cassettes. Our findings demonstrated that transcriptional upregulation of APOBEC3A led to the acquisition of a massive number of genomic mutations in just a few cell cycles. By contrast, despite clear deaminase activity and DNA damage, APOBEC3B upregulation did not generate a significant increase in mutations in the gastric epithelium. APOBEC3B-associated mutagenesis remained minimal even in the context of TP53 inactivation. Further analysis of the mutational landscape following APOBEC3A upregulation revealed a detailed spectrum of APOBEC3A-associated mutations, including indels, primarily 1 bp deletions, clustered mutations, and evidence of selective pressures acting on cells carrying the mutations. Our observations provide a clear foundation for understanding the mutational impact of APOBEC enzymes in human cells.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"15 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898382","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

Molecular and genetic landscapes of retina and brain microglia in neurodegenerative diseases 神经退行性疾病中视网膜和脑小胶质细胞的分子和遗传景观

IF 7 2区生物学

Genome research Pub Date : 2025-08-26 DOI: 10.1101/gr.280554.125

Khang Ma, Rinki Ratnapriya

{"title":"Molecular and genetic landscapes of retina and brain microglia in neurodegenerative diseases","authors":"Khang Ma, Rinki Ratnapriya","doi":"10.1101/gr.280554.125","DOIUrl":"https://doi.org/10.1101/gr.280554.125","url":null,"abstract":"Microglia-driven dysregulation has emerged as a significant underlying mechanism in many neurodegenerative diseases, such as Age-related Macular Degeneration (AMD) and Alzheimer's disease (AD). While both brain and retinal microglia originate from the yolk sac, it is uncertain whether they share molecular similarities or genetic and molecular foundations related to neurodegenerative diseases. In this study, we examine the transcriptomic and epigenetic profiles of retina and brain microglia through integrative analyses of single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) from 97 independent human samples across eleven different studies. Our findings reveal that retina and brain microglia share similar expression and regulatory profiles when compared to other cell types in retina and brain. By integrating genome-wide association studies (GWAS) data with gene expression profiles, we demonstrate that genetic variants associated with AMD and AD are linked to microglia-specific gene signatures. Furthermore, integrating regulatory annotations with GWAS data shows that susceptibility loci for both AMD and AD are notably enriched in the open chromatin regions of microglia from brain and retina, emphasizing their relevance to these neurodegenerative conditions. Finally, a comparison with microglia annotations from other tissues highlights the specific enrichment of microglia in relation to neurodegenerative diseases. These findings contribute to the understanding of the role of microglia in AMD and AD pathogenesis and offer an opportunity to utilize resources from both retinal and brain microglia to deepen our understanding of their contributions to genetic variations in neurodegenerative diseases.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"43 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898379","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

Widespread specific intron-retention events in nuclear RNA complexes identified by sedimentation analysis of pluripotent cellular extracts 通过多能细胞提取物的沉淀分析鉴定核RNA复合物中广泛的特异性内含子保留事件

IF 7 2区生物学

Genome research Pub Date : 2025-08-26 DOI: 10.1101/gr.280431.125

Isabela T Pereira, Izabela Mamede, Paulo de Paiva Amaral, Gloria Regina Franco, John L Rinn

{"title":"Widespread specific intron-retention events in nuclear RNA complexes identified by sedimentation analysis of pluripotent cellular extracts","authors":"Isabela T Pereira, Izabela Mamede, Paulo de Paiva Amaral, Gloria Regina Franco, John L Rinn","doi":"10.1101/gr.280431.125","DOIUrl":"https://doi.org/10.1101/gr.280431.125","url":null,"abstract":"Many essential cellular processes require RNA to interact with protein(s) to form ribonucleic protein complexes (RNPs). For example, all cellular proteins are produced by the ribosome - a large and stable RNP, gene splicing requires a choreography of numerous small and large RNPs, even the replication of telomeric DNA requires an RNP. All these examples are stable RNPs that exhibit specific sedimentation rates (e.g., in a sucrose gradient) based on the composition of RNA and protein. In this study we aimed to identify RNA components of discrete RNPs on a transcriptome-wide scale. Using sucrose-gradient sedimentation followed by sequencing, we identified 1,057 RNA transcripts, both coding and noncoding, that are likely to be components of cellular RNPs. We named these transcripts Gradient Enriched Transcripts (GETs). GETs were predominantly nuclear, metabolically stable, and they were not the major splice isoforms but instead each contained a specific retained intron. Collectively our study reveals a widespread phenomenon of a specific intron being retained in a stable nuclear RNPs.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"23 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898383","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