Cell genomics最新文献

{"title":"Multiomic QTL mapping reveals phenotypic complexity of GWAS loci and prioritizes putative causal variants.","authors":"Timothy D Arthur, Jennifer P Nguyen, Benjamin A Henson, Agnieszka D'Antonio-Chronowska, Jeffrey Jaureguy, Nayara Silva, Athanasia D Panopoulos, Juan Carlos Izpisua Belmonte, Matteo D'Antonio, Graham McVicker, Kelly A Frazer","doi":"10.1016/j.xgen.2025.100775","DOIUrl":"10.1016/j.xgen.2025.100775","url":null,"abstract":"<p><p>Most GWAS loci are presumed to affect gene regulation; however, only ∼43% colocalize with expression quantitative trait loci (eQTLs). To address this colocalization gap, we map eQTLs, chromatin accessibility QTLs (caQTLs), and histone acetylation QTLs (haQTLs) using molecular samples from three early developmental-like tissues. Through colocalization, we annotate 10.4% (n = 540) of GWAS loci in 15 traits by QTL phenotype, temporal specificity, and complexity. We show that integration of chromatin QTLs results in a 2.3-fold higher annotation rate of GWAS loci because they capture distal GWAS loci missed by eQTLs, and that 5.4% (n = 13) of GWAS colocalizing eQTLs are early developmental specific. Finally, we utilize the iPSCORE multiomic QTLs to prioritize putative causal variants overlapping transcription factor motifs to elucidate the potential genetic underpinnings of 296 GWAS-QTL colocalizations.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100775"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity.","authors":"Kyuto Sonehara, Yoshifumi Uwamino, Ryunosuke Saiki, Masaru Takeshita, Shinichi Namba, Shunsuke Uno, Tomoko Nakanishi, Tomoyasu Nishimura, Tatsuhiko Naito, Go Sato, Masahiro Kanai, Aoxing Liu, Sho Uchida, Toshinobu Kurafuji, Akiko Tanabe, Tomoko Arai, Akemi Ohno, Ayako Shibata, Shiho Tanaka, Masatoshi Wakui, Shoko Kashimura, Chiharu Tomi, Akemi Hara, Shiori Yoshikawa, Keiko Gotanda, Kana Misawa, Hiromu Tanaka, Shuhei Azekawa, Qingbo S Wang, Ryuya Edahiro, Yuya Shirai, Kenichi Yamamoto, Genta Nagao, Takuo Suzuki, Masato Kiyoshi, Akiko Ishii-Watabe, Shinichi Higashiue, Shuzo Kobayashi, Hiroki Yamaguchi, Yasushi Okazaki, Naoyuki Matsumoto, Akihide Masumoto, Hidenobu Koga, Akinori Kanai, Yoshiya Oda, Yutaka Suzuki, Koichi Matsuda, Yuko Kitagawa, Ryuji Koike, Akinori Kimura, Atsushi Kumanogoh, Akihiko Yoshimura, Seiya Imoto, Satoru Miyano, Takanori Kanai, Koichi Fukunaga, Naoki Hasegawa, Mitsuru Murata, Hiromichi Matsushita, Seishi Ogawa, Yukinori Okada, Ho Namkoong","doi":"10.1016/j.xgen.2025.100783","DOIUrl":"10.1016/j.xgen.2025.100783","url":null,"abstract":"<p><p>Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = -0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves' disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100783"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A roadmap toward genome-wide CRISPR screening throughout the organism.","authors":"Tess K Fallon, Kristin A Knouse","doi":"10.1016/j.xgen.2025.100777","DOIUrl":"10.1016/j.xgen.2025.100777","url":null,"abstract":"<p><p>Genome-wide CRISPR screening in the organism has tremendous potential to answer long-standing questions of mammalian physiology and disease. However, bringing this powerful technology in vivo presents unique challenges, including delivering a genome-wide sgRNA library to the appropriate cell type, achieving sufficient coverage of the library, and selecting for the phenotype of interest. In this review, we highlight recent advances in sgRNA delivery, library design, and phenotypic readout that can help overcome these technical challenges and thereby bring high-throughput genetic dissection to an increasing number of tissues and questions. We are excited about the potential for ongoing innovation in these areas to ultimately enable genome-wide CRISPR screening in any cell type of interest in the organism, allowing for unprecedented investigation into diverse questions of mammalian physiology and disease.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100777"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics identifies novel Pseudomonas aeruginosa virulence factors.","authors":"Hao Zhou, Oscar Negrón, Serena Abbondante, Michaela Marshall, Brandon Jones, Edison Ong, Nicole Chumbler, Christopher Tunkey, Groves Dixon, Haining Lin, Obadiah Plante, Eric Pearlman, Mihaela Gadjeva","doi":"10.1016/j.xgen.2025.100805","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100805","url":null,"abstract":"<p><p>To examine host-pathogen interactions, we leveraged a dual spatial transcriptomics approach that simultaneously captures the expression of Pseudomonas aeruginosa genes alongside the entire host transcriptome using a murine model of ocular infection. This method revealed differential pathogen- and host-specific gene expression patterns in infected corneas, which generated a unified transcriptional map of infection. By integrating these data, we developed a predictive ridge regression model trained on images from infected tissues. The model achieved an R² score of 0.923 in predicting bacterial burden distributions and identifying novel biomarkers associated with disease severity. Among iron acquisition pathogen-specific gene transcripts that showed significant enrichment at the host-pathogen interface, we discovered the novel virulence mediator PA2590, which was required for bacterial virulence. This study therefore highlights the power of combining bacterial and host spatial transcriptomics to uncover complex host-pathogen interactions and identify potentially druggable targets.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":"5 3","pages":"100805"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The breaking point where repeat expansion triggers neuronal collapse in Huntington's disease.","authors":"Michael D Flower, Sarah J Tabrizi","doi":"10.1016/j.xgen.2025.100816","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100816","url":null,"abstract":"<p><p>Somatic CAG expansion drives neuronal loss in Huntington's disease (HD), but how expansion results in pathogenesis has remained unclear. Handsaker et al.¹ use single-cell RNA and repeat length sequencing to reveal a phased model of expansion and toxicity, highlighting a critical tipping point beyond 150 CAG repeats where neuronal identity collapses and cells die.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":"5 3","pages":"100816"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"National investment case development for pathogen genomics.","authors":"Yoong Khean Khoo, Suci Wulandari, Marya Getchell, La Moe, Shurendar Selva Kumar, Elyssa Jiawen Liu, Yimei Sun, Junxiong Pang, Swapnil Mishra, Hannah Clapham, Ben Marais, Vitali Sintchenko, Ruklanthi de Alwis, David Hipgrave, Paul Michael Pronyk","doi":"10.1016/j.xgen.2025.100781","DOIUrl":"10.1016/j.xgen.2025.100781","url":null,"abstract":"<p><p>Sustaining and expanding genomic surveillance capacity requires broader investment in genomics that target both novel and pandemic pathogens. Currently, there is no standardized methodology to evaluate the cost and benefit of a multi-pathogen surveillance system. We propose a framework for pathogen genomic surveillance that links public health and systems considerations to a stepwise approach.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100781"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of germline and somatic mutations to risk of neuromyelitis optica spectrum disorder.","authors":"Tomohiro Yata, Go Sato, Kotaro Ogawa, Tatsuhiko Naito, Kyuto Sonehara, Ryunosuke Saiki, Ryuya Edahiro, Shinichi Namba, Mitsuru Watanabe, Yuya Shirai, Kenichi Yamamoto, Ho NamKoong, Tomoko Nakanishi, Yuji Yamamoto, Akiko Hosokawa, Mamoru Yamamoto, Eri Oguro-Igashira, Takuro Nii, Yuichi Maeda, Kimiko Nakajima, Rika Nishikawa, Hiroaki Tanaka, Shingo Nakayamada, Koichi Matsuda, Chikako Nishigori, Shigetoshi Sano, Makoto Kinoshita, Ryuji Koike, Akinori Kimura, Seiya Imoto, Satoru Miyano, Koichi Fukunaga, Masahito Mihara, Yuko Shimizu, Izumi Kawachi, Katsuichi Miyamoto, Yoshiya Tanaka, Atsushi Kumanogoh, Masaaki Niino, Yuji Nakatsuji, Seishi Ogawa, Takuya Matsushita, Jun-Ichi Kira, Hideki Mochizuki, Noriko Isobe, Tatsusada Okuno, Yukinori Okada","doi":"10.1016/j.xgen.2025.100776","DOIUrl":"10.1016/j.xgen.2025.100776","url":null,"abstract":"<p><p>Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by optic neuritis and transverse myelitis, with an unclear genetic background. A genome-wide meta-analysis of NMOSD in Japanese individuals (240 patients and 50,578 controls) identified significant associations with the major histocompatibility complex region and a common variant close to CCR6 (rs12193698; p = 1.8 × 10^-8, odds ratio [OR] = 1.73). In single-cell RNA sequencing (scRNA-seq) analysis (25 patients and 101 controls), the CCR6 risk variant showed disease-specific expression quantitative trait loci effects in CD4⁺ T (CD4T) cell subsets. Furthermore, we detected somatic mosaic chromosomal alterations (mCAs) in various autoimmune diseases and found that mCAs increase the risk of NMOSD (OR = 3.37 for copy number alteration). In scRNA-seq data, CD4T cells with 21q loss, a recurrently observed somatic event in NMOSD, showed dysregulation of type I interferon-related genes. Our integrated study identified novel germline and somatic mutations associated with NMOSD pathogenesis.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100776"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning imputes DNA methylation states in single cells and enhances the detection of epigenetic alterations in schizophrenia.","authors":"Jiyun Zhou, Chongyuan Luo, Hanqing Liu, Matthew G Heffel, Richard E Straub, Joel E Kleinman, Thomas M Hyde, Joseph R Ecker, Daniel R Weinberger, Shizhong Han","doi":"10.1016/j.xgen.2025.100774","DOIUrl":"10.1016/j.xgen.2025.100774","url":null,"abstract":"<p><p>DNA methylation (DNAm) is a key epigenetic mark with essential roles in gene regulation, mammalian development, and human diseases. Single-cell technologies enable profiling DNAm at cytosines in individual cells, but they often suffer from low coverage for CpG sites. We introduce scMeFormer, a transformer-based deep learning model for imputing DNAm states at each CpG site in single cells. Comprehensive evaluations across five single-nucleus DNAm datasets from human and mouse demonstrate scMeFormer's superior performance over alternative models, achieving high-fidelity imputation even with coverage reduced to 10% of original CpG sites. Applying scMeFormer to a single-nucleus DNAm dataset from the prefrontal cortex of patients with schizophrenia and controls identified thousands of schizophrenia-associated differentially methylated regions that would have remained undetectable without imputation and added granularity to our understanding of epigenetic alterations in schizophrenia. We anticipate that scMeFormer will be a valuable tool for advancing single-cell DNAm studies.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100774"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Missing regulatory effects on complex traits: Contribution of distal variants.","authors":"Sool Lee, Hakhamanesh Mostafavi","doi":"10.1016/j.xgen.2025.100809","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100809","url":null,"abstract":"<p><p>Most genetic effects on complex traits lie in non-coding regions, yet many show no regulatory activity in standard gene expression assays. In this issue of Cell Genomics, Arthur et al.¹ add early development-like cell types and chromatin assays, showing that distal variants missed in expression assays partly explain this discrepancy.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":"5 3","pages":"100809"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Centromeric transposable elements and epigenetic status drive karyotypic variation in the eastern hoolock gibbon.","authors":"Gabrielle A Hartley, Mariam Okhovat, Savannah J Hoyt, Emily Fuller, Nicole Pauloski, Nicolas Alexandre, Ivan Alexandrov, Ryan Drennan, Danilo Dubocanin, David M Gilbert, Yizi Mao, Christine McCann, Shane Neph, Fedor Ryabov, Takayo Sasaki, Jessica M Storer, Derek Svendsen, William Troy, Jackson Wells, Leighton Core, Andrew Stergachis, Lucia Carbone, Rachel J O'Neill","doi":"10.1016/j.xgen.2025.100808","DOIUrl":"10.1016/j.xgen.2025.100808","url":null,"abstract":"<p><p>Great apes have maintained a stable karyotype with few large-scale rearrangements; in contrast, gibbons have undergone a high rate of chromosomal rearrangements coincident with rapid centromere turnover. Here, we characterize fully assembled centromeres in the eastern hoolock gibbon, Hoolock leuconedys (HLE), finding a diverse group of transposable elements (TEs) that differ from the canonical alpha-satellites found across centromeres of other apes. We find that HLE centromeres contain a CpG methylation centromere dip region, providing evidence that this epigenetic feature is conserved in the absence of satellite arrays. We uncovered a variety of atypical centromeric features, including protein-coding genes and mismatched replication timing. Further, we identify duplications and deletions in HLE centromeres that distinguish them from other gibbons. Finally, we observed differentially methylated TEs, topologically associated domain boundaries, and segmental duplications at chromosomal breakpoints, and thus propose that a combination of multiple genomic attributes with propensities for chromosome instability shaped gibbon centromere evolution.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100808"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}