Cell genomics最新文献

{"title":"Deciphering genetic regulation at single-cell resolution in gastric cancer.","authors":"Chengxuan Chen, Leng Han","doi":"10.1016/j.xgen.2025.100846","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100846","url":null,"abstract":"<p><p>Understanding cell-type-specific genetic regulation in gastric cancer is essential for uncovering disease susceptibility. By performing single-cell eQTL mapping in gastric tissues, Bian et al.¹ identified previously uncharacterized regulatory genetic mechanisms, risk genes, and co-localization signals associated with gastric cancer susceptibility, providing insights into its pathogenesis and potential therapeutic approaches.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":"5 4","pages":"100846"},"PeriodicalIF":11.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042706","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":"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":"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":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675089","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":"It's prime time for multiplexed prime editing.","authors":"Ke Wu, Francisco J Sánchez-Rivera","doi":"10.1016/j.xgen.2025.100852","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100852","url":null,"abstract":"<p><p>Prime editing screens allow precise and scalable studies of genetic variants in their native genomic context but are limited by variable editing efficiency. In this issue of Cell Genomics, Herger, Kajba, et al.¹ overcome these challenges by optimizing and applying prime editing screens to investigate variants in SMARCB1 and MLH1.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":"5 4","pages":"100852"},"PeriodicalIF":11.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054603","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":"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":"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":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671680","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":"Incorporating multiple functional annotations to improve polygenic risk prediction accuracy.","authors":"Zhonghe Shao, Wangxia Tang, Hongji Wu, Yifan Kong, Xingjie Hao","doi":"10.1016/j.xgen.2025.100850","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100850","url":null,"abstract":"<p><p>We present OmniPRS, a scalable biobank-scale framework that improves genetic risk prediction for complex traits by integrating genome-wide association study (GWAS) summary statistics and functional annotations. It employs a mixed model incorporating tissue-specific genetic variance components from annotations to re-estimate single-nucleotide polymorphism (SNP) effects and constructs tissue-specific polygenic risk scores (PRSs) and aggregates them into the final OmniPRS. Our experiments, encompassing 135 simulation scenarios and 11 representative traits, demonstrate that OmniPRS is flexible and robust, delivering efficient and accurate predictions comparable to ten leading PRS methods. For quantitative (binary) traits, OmniPRS achieved an average improvement of 52.31% (19.83%) versus the clumping and thresholding (C+T) method, 3.92% (1.31%) versus the annotation-integrated PRSs (LDpred-funct), and 8.44% (2.27%) versus the Bayesian-based PRSs (PRScs). Notably, it achieved 35× faster computation than the PRScs. This rapid, precise framework enables efficient polygenic risk scoring with multi-annotation integration for large-scale genomic studies.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100850"},"PeriodicalIF":11.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045624","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":"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":"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":"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":"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}