Cell genomics最新文献

{"title":"Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations.","authors":"Jeannette L Tenthorey, Serena Del Banco, Ishrak Ramzan, Hayley Klingenberg, Chang Liu, Michael Emerman, Harmit S Malik","doi":"10.1016/j.xgen.2025.100818","DOIUrl":"10.1016/j.xgen.2025.100818","url":null,"abstract":"<p><p>Antiviral proteins often evolve rapidly at virus-binding interfaces to defend against new viruses. We investigated whether antiviral adaptation via missense mutations might face limits, which insertion or deletion mutations (indels) could overcome. Using high-throughput saturation missense mutagenesis, we identify one such case of a nearly insurmountable evolutionary challenge: the human anti-retroviral protein TRIM5α requires more than five missense mutations in its specificity-determining v1 loop to restrict a divergent simian immunodeficiency virus (SIV). However, through a novel saturating indel scanning methodology, we find that duplicating just one amino acid in v1 enables human TRIM5α to potently restrict SIV in a single evolutionary step. Moreover, natural primate TRIM5α v1 loops have evolved indels that confer novel antiviral specificities. Thus, indels enable antiviral proteins to overcome viral challenges otherwise inaccessible by missense mutations. Our findings reveal the potential of often-overlooked indel mutations in driving protein innovation.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100818"},"PeriodicalIF":11.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733475","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":"Single-cell eQTL mapping reveals cell-type-specific genes associated with the risk of gastric cancer.","authors":"Lijun Bian, Beiping Hu, Fengyuan Li, Yuanliang Gu, Caihong Hu, Yuheng Chen, Bin Deng, Haisheng Fang, Xia Zhu, Yan Chen, Xiangjin Fu, Tianpei Wang, Qiang She, Meng Zhu, Yue Jiang, Juncheng Dai, Hao Xu, Hongxia Ma, Zekuan Xu, Zhibin Hu, Hongbing Shen, Yanbing Ding, Caiwang Yan, Guangfu Jin","doi":"10.1016/j.xgen.2025.100812","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100812","url":null,"abstract":"<p><p>Most expression quantitative trait locus (eQTL) analyses have been conducted in heterogeneous gastric tissues, limiting understanding of cell-type-specific regulatory mechanisms. Here, we employed a pooled multiplexing strategy to profile 399,683 gastric cells from 203 Chinese individuals using single-cell RNA sequencing (scRNA-seq). We identified 19 distinct gastric cell types and performed eQTL analyses, uncovering 8,498 independent eQTLs, with a considerable fraction (81%, 6,909/8,498) exhibiting cell-type-specific effects. Integration of these eQTLs with genome-wide association studies for gastric cancer (GC) revealed four co-localization signals in specific cell types. Genetically predicted cell-type-specific gene expression identified 15 genes associated with GC risk, including the upregulation of MUC1 exclusively in parietal cells, linked to decreased GC risk. Our findings highlight substantial heterogeneity in the genetic regulation of gene expression across gastric cell types and provide critical cell-type-specific annotations of genetic variants associated with GC risk, offering new molecular insights underlying GC.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100812"},"PeriodicalIF":11.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671680","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":"Recurrent breakpoints in the BRD4 locus reduce toxicity associated with gene amplification.","authors":"Jeremiah Wala, Simona Dalin, Sophie Webster, Ofer Shapira, John Busanovich, Shahab Sarmashghi, Rameen Beroukhim, Pratiti Bandopadhayay, Veronica Rendo","doi":"10.1016/j.xgen.2025.100815","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100815","url":null,"abstract":"<p><p>Recent work by the ICGC-PCAWG consortium identified recurrent focal deletions in the BRD4 gene, decreasing expression despite increased copy number. We show that these focal deletions occur in the context of cyclin E1 amplification in breast, ovarian, and endometrial cancers, and serve to disrupt BRD4 regulatory regions and gene expression across isoforms. We analyze open reading frame screen data and find that overexpression of BRD4 long (BRD4-L) and short isoform BRD4-S(a) impairs cell growth across cell lines. We confirm these results in OVSAHO ovarian cancer cells, where the overexpression of BRD4 isoforms significantly reduces tumor growth. Next, we mimic BRD4 focal deletions using CRISPR-Cas9 technology and show that these focal deletions rescue ovarian cancer cells from toxicity associated with BRD4 overexpression, suggesting that BRD4 levels must be fine-tuned for cancer cell proliferation. Our study provides experimental evidence for the first recurrent deletion reducing toxicity in cancer, expanding the landscape of cancer progression mechanisms.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100815"},"PeriodicalIF":11.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671675","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":"Strategic targeting of Cas9 nickase expands tandem gene arrays.","authors":"Hiroaki Takesue, Satoshi Okada, Goro Doi, Yuki Sugiyama, Emiko Kusumoto, Takashi Ito","doi":"10.1016/j.xgen.2025.100811","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100811","url":null,"abstract":"<p><p>Expanding tandem gene arrays facilitates adaptation through dosage effects and gene family formation via sequence diversification. However, experimental induction of such expansions remains challenging. Here, we introduce a method termed break-induced replication (BIR)-mediated tandem repeat expansion (BITREx) to address this challenge. BITREx places Cas9 nickase adjacent to a tandem gene array to break the replication fork that has just replicated the array, forming a single-ended double-strand break. This break is subsequently end-resected to become single stranded. Since there is no repeat unit downstream of the break, the single-stranded DNA often invades an upstream unit to initiate ectopic BIR, resulting in array expansion. BITREx has successfully expanded gene arrays in budding yeast, with the CUP1 array reaching ∼1 Mb. Furthermore, appropriate splint DNAs allow BITREx to generate tandem arrays de novo from single-copy genes. We have also demonstrated BITREx in mammalian cells. Therefore, BITREx will find various unique applications in genome engineering.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100811"},"PeriodicalIF":11.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675089","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}