PLoS Genetics最新文献

{"title":"The chitin synthase regulator CSR-3 promotes cellular integrity during cell-cell fusion in the filamentous ascomycete fungus Neurospora crassa.","authors":"Stephanie Herzog, Tanja N Sedlacek, Kristian D R Roth, Manuel Reuning, Ulrike Brandt, André Fleißner","doi":"10.1371/journal.pgen.1011891","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011891","url":null,"abstract":"<p><p>Cell-cell fusion in plants and fungi requires localized cell wall dissolution at the contact site to allow direct plasma membrane contact and subsequent membrane merger. Since cell wall removal carries the risk of cell rupture, the process must be tightly regulated to permit localized fusion pore formation while preserving cellular integrity. While the molecular events guiding cell-cell signaling leading to contact between fusing fungal cells have begun to unfold, the post-contact mechanisms stabilizing the forming fusion pore remain largely unknown. Here, we identify the chitin synthase regulator CSR-3 as a molecular factor promoting stable pore formation during somatic fusion in the fungal cell fusion model Neurospora crassa. CSR-3 specifically accumulates at the contact zones of fusing cells and contributes to fusion fidelity by preventing membrane rupture and lysis, particularly under calcium-limited conditions. Loss of CSR-3 leads to elevated fusion-induced lysis, a phenotype rescued by osmotic stabilization, suggesting a cell wall defect. Beyond fusion, CSR-3 is involved in septum formation, septal pore plugging, conidiation, and the response to biotic and abiotic cell wall stress. These observations support a broader role for CSR-3 in chitin-mediated cell wall remodeling. Our data indicate that CSR-3 dynamics at fusion sites depend on the MAP kinase MAK-1, implicating cell wall integrity signaling in post-contact fusion events. Consistent with this finding, phospho-mimetic analysis suggests a regulatory role for CSR-3 phosphorylation. Co-localization and genetic analyses identify the chitin synthase CHS-2 as a likely downstream target of CSR-3, with both proteins functioning in the same pathway. Together, our findings reveal that CSR-3 coordinates cell wall remodeling during cell fusion and stress responses, uncovering a crucial regulatory layer that safeguards fungal cellular integrity during dynamic developmental processes. Our observations support a model in which cell wall biosynthesis plays a critical role in cell wall remodeling during fusion pore formation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011891"},"PeriodicalIF":3.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276421","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}

{"title":"VAB-8/KIF26, LIN-17/Frizzled, and EFN-4/Ephrin, control distinct stages of posterior neuroblast migration downstream of the MAB-5/Hox transcription factor in Caenorhabditis elegans.","authors":"Vedant D Jain, Erik A Lundquist","doi":"10.1371/journal.pgen.1011906","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011906","url":null,"abstract":"<p><p>Hox transcription factors are involved in neuronal and neural crest development and differentiation, including migration, but the genetic programs employed by Hox genes to regulate terminal differentiation remain to be defined. In C. elegans, the Antennapedia-like Hox factor MAB-5 is both necessary and sufficient to induce posterior migration of the Q lineage neuroblasts and neurons downstream of canonical Wnt signaling. Q lineage fluorescence-activated cell sorting and RNA seq in mab-5 loss-of-function and gain-of-function backgrounds revealed genes with expression in the Q lineage dependent upon MAB-5. Here, the roles of three mab-5-regulated genes in QL lineage posterior migration are delineated, vab-8/KIF26, lin-17/Fz, and efn-4/Ephrin. Live, time-lapse imaging of QL.a and QL.ap posterior migration revealed that this migration occurs in three distinct stages: QL.a migration posterior to QL.p (1st stage); after QL.a division, posterior migration of QL.ap to a region immediately anterior to the anus (2nd stage); and final migration of QL.ap posterior to the final position where it differentiates into the PQR neuron (3rd stage). vab-8 affected each of the three stages, lin-17 affected stages two and three, and efn-4 was required for the third stage of posterior QL.ap migration. Thus, different MAB-5-regulated genes control distinct stages of posterior migration. mab-20/Semaphorin, a known interaction partner with efn-4, also affected only the third stage similar to efn-4. Suppression of mab-5 gof posterior migration confirmed that these genes act downstream of mab-5 in posterior migration. Possibly, VAB-8/KIF26 helps deliver distinct molecules to the plasma membrane that mediate distinct stages of migration, including LIN-17/Fz and EFN-4. Surprisingly, failure of stages two and three led to the premature extension of a posterior dendritic protrusion, which normally forms after QL.ap had migrated to its final position and PQR differentiation begins. This suggests a link between migration and differentiation, where differentiation is delayed while migration proceeds. In sum, this work delineates a transcriptional program downstream of mab-5/Hox that controls posterior neuroblast migration, in response to Wnt signaling.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011906"},"PeriodicalIF":3.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276456","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}

{"title":"Convergent evolution of H4K16ac-mediated dosage compensation in the ZW species Artemia franciscana.","authors":"Frederic Zimmer, Annika Maria Fox, Qiaowei Pan, Frank Rühle, Peter Andersen, Ann-Kathrin Huylmans, Tanja Schwander, M Felicia Basilicata, Claudia Isabelle Keller Valsecchi","doi":"10.1371/journal.pgen.1011895","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011895","url":null,"abstract":"<p><p>Sex chromosomes impact chromatin organization and histone modification dynamics differently between males and females, particularly those involved in dosage compensation (DC). The evolutionary diversity, as well as the tissue- and age-dependent variations of DC mechanisms are incompletely understood. Here, we investigate the occurrence of histone H4 lysine 16 acetylation (H4K16ac), previously known for its role in sex chromosome DC in the male-heterogametic fruit fly Drosophila melanogaster and the green anole lizard Anolis carolinensis. By sampling multiple arthropods, we find the convergent evolution of H4K16ac for DC in a female-heterogametic (ZW) species, the crustacean Artemia franciscana. CUT&Tag analysis demonstrates that H4K16ac is confined to the non-recombining stratum of the Z chromosome in females. H4K16ac-mediated DC is established during embryogenesis. In aged individuals, we observe an overall decline in nuclear organization, disrupted H4K16ac territories and increased variability in local acetylation levels on the female Z chromosome. Our findings shed light on the evolutionary diversity of DC across species and raise the possibility of sex-specific histone acetylation contributing to male-female differences in lifespan.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011895"},"PeriodicalIF":3.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259928","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}

{"title":"A genetic screen reveals a key role for Reg1 in 2-deoxyglucose sensing and yeast AMPK inhibition.","authors":"Alberto Ballin, Véronique Albanèse, Samia Miled, Véronique Legros, Guillaume Chevreux, Agathe Verraes, Anne Friedrich, Sébastien Léon","doi":"10.1371/journal.pgen.1011896","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011896","url":null,"abstract":"<p><p>The yeast Saccharomyces cerevisiae thrives in sugar-rich environments by rapidly consuming glucose and favoring alcoholic fermentation. This strategy is tightly regulated by the glucose repression pathway, which prevents the expression of genes required for the utilization of alternative carbon source. Central to this regulatory network is the yeast ortholog of the heterotrimeric 5'AMP-activated protein kinase (AMPK), which adjusts gene expression in response to glucose availability. The activity of the yeast AMPK complex is primarily regulated by the phosphorylation state of its catalytic subunit Snf1, a process orchestrated by a balance between upstream kinases and phosphatases. Among the latter, the Protein Phosphatase 1 (PP1) complex Reg1/Glc7 plays a critical role in inhibiting Snf1 activity under glucose-rich conditions. Despite its importance, the precise mechanism by which glucose availability leads to Snf1 inhibition remains incompletely understood. Evidence suggests that hexokinase 2 (Hxk2) participates in this pathway, potentially coupling the early steps of glucose metabolism to Snf1 signaling. Notably, the toxic glucose analog 2-deoxyglucose (2DG)- which is phosphorylated by Hxk2 but not further metabolized- mimics glucose in its ability to repress Snf1, implicating glucose or 2DG phosphorylation as a key regulatory signal. Additionally, yeast AMPK activity correlates with 2DG resistance through mechanisms that are incompletely described. In this study, we performed a large-scale 2DG-resistance genetic screen to explore both the molecular basis of 2DG resistance and AMPK regulation in yeast. The identified mutations confer resistance either by reducing 2DG phosphorylation (e.g., mutations in HXK2) or by enhancing constitutive Snf1 activity, via gain-of-function alleles in AMPK subunits or loss-of-function mutations in REG1 and GLC7. We also describe a novel series of REG1 missense mutations, including reg1-W165G, that maintain basal, glucose-regulated Snf1 activity but fail to mediate 2DG-induced Snf1 inhibition. These findings position Reg1 as a central mediator in glucose sensing, possibly by sensing 2DG-derived -and by extension, glucose-derived- metabolites.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011896"},"PeriodicalIF":3.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259976","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}

{"title":"Probing the molecular determinants of Ty1 retrotransposon restriction specificity in yeast.","authors":"Sean L Beckwith, Matthew A Cottee, J Adam Hannon-Hatfield, Abigail C Newman, Emma C Walker, Justin R Romero, Jonathan P Stoye, Ian A Taylor, David J Garfinkel","doi":"10.1371/journal.pgen.1011898","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011898","url":null,"abstract":"<p><p>The evolutionary history of retrotransposons and their hosts shapes the dynamics of transposition and restriction. The Pseudoviridae of yeast includes multiple Ty1 LTR-retrotransposon subfamilies. Saccharomyces cerevisiae prevents uncontrolled retrotransposition of Ty1 subfamilies using distinct mechanisms: canonical Ty1 is inhibited by a self-encoded restriction factor, p22/p18, whereas Ty1' is inhibited by an endogenized restriction factor, Drt2. The minimal inhibitory fragment of both restriction factors (p18m and Drt2m) is a conserved C-terminal capsid domain. Here, we use biophysical and genetic approaches to demonstrate that p18m and Drt2m are highly specific to their subfamilies. Although the crystal structures of p18m and Drt2m are similar, three divergent residues found in a conserved hydrophobic interface direct restriction specificity. By mutating these three residues, we re-target each restriction factor to the opposite transposon. Our work highlights how a common lattice-poisoning mechanism of restriction evolved from independent evolutionary trajectories in closely related retrotransposon subfamilies. These data raise the possibility that similar capsid-capsid interactions may exist in other transposons/viruses and that highly specific inhibitors could be engineered to target capsid interfaces.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011898"},"PeriodicalIF":3.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259956","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}

{"title":"Immunophenotypic changes in the tumor and tumor microenvironment during progression to multiple myeloma.","authors":"Isabelle Bergiers, Murat Cem Köse, Sheri Skerget, Milan Malfait, Nele Fourneau, Jenna-Claire Ellis, Greet Vanhoof, Tina Smets, Bie Verbist, Dries De Maeyer, Jeroen Van Houdt, Koen Van der Borght, Raluca Verona, Bradley Heidrich, William Kurth, Michel Delforge, Nathalie Meuleman, Jan Van Droogenbroeck, Philip Vlummens, Christoph J Heuck, Yves Beguin, Nizar Bahlis, Tineke Casneuf, Jo Caers","doi":"10.1371/journal.pgen.1011848","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011848","url":null,"abstract":"<p><p>Investigation of the cellular and molecular mechanisms of disease progression from precursor plasma cell disorders to active disease increases our understanding of multiple myeloma (MM) pathogenesis and supports the development of novel therapeutic strategies. In this analysis, single-cell RNA sequencing, surface protein profiling, and B lymphocyte antigen receptor profiling of unsorted, whole bone marrow (BM) mononuclear cell samples was used to study molecular changes in tumor cells and the tumor microenvironment (TME). A cell atlas of the BM microenvironment was generated from 123 subjects including healthy volunteers and patients with monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM), and MM. These analyses revealed commonalities in molecular pathways, including MYC signaling, E2F targets and interferon alpha response, that were altered during disease progression. Evidence of early dysregulation of the immune system in MGUS and SMM, which increases and impacts many cell types as the disease progresses, was found. In parallel with disease progression, population shifts in CD8 + T cells, macrophages, and classical dendritic cells were observed, and the resulting differences in CD8 + T cells and macrophages were associated with poor overall survival outcomes. Potential ligand-receptor interactions that may play a role during the transition from precursor stages to MM were identified, along with potential biomarkers of disease progression, some of which may represent novel therapeutic targets. MIF, IL15, CD320, HGF and FAM3C were detected as potential regulators of the TME by plasma cells, while SERPINA1 and BAFF (TNFSF13B) were found to have the highest potential to contribute to the downstream changes observed between precursor stage and MM cells. These findings demonstrate that myeloma tumorigenesis is associated with dysregulation of molecular pathways driven by gradually occurring immunophenotypic changes in the tumor and TME. Trial registration: This project has been registered at EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with protocol number NOPRODMMY0001 and EudraCT Number 2018-004443-23 on 12 December 2018.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011848"},"PeriodicalIF":3.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245303","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}

{"title":"PP6 phosphatase and Elongator contribute to kinesin 5-dependent spindle assembly by controlling microtubule regulators levels.","authors":"Laura Marín, Jorge Castro-Sangrador, Marta Hoya, Shara Tello, Pedro M Coll, Javier Encinar Del Dedo, Alfonso Fernández-Álvarez, Juan C Ribas, Phong T Tran, Sergio A Rincon","doi":"10.1371/journal.pgen.1011596","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011596","url":null,"abstract":"<p><p>Eukaryotic chromosome segregation relies on the assembly of a bipolar machinery based on microtubules (MTs), named the mitotic spindle. Formation of the mitotic spindle follows a force balance mechanism that ensures the proper capture and separation of sister chromatids. Many proteins have been involved in the establishment of this force balance, although kinesin 5 is well recognized as the major outward pushing force generator, since its inactivation results in monopolar, non-functional spindles. In order to find additional players in the force balance mechanism, we have performed a suppressor screen using a conditional allele of the fission yeast kinesin 5 ortholog Cut7. This screen identified that the lack of the PP6 phosphatase partially suppresses cut7 phenotypes, at least by defective translation of MT regulators, such as the minus end-directed kinesin Klp2, the MT stabilizer Alp7 and the MT bundler Ase1, impacting on the force balance mechanism. Additionally, our data show that the Elongator complex, a target activated by PP6 for efficient tRNA modification, also contributes to the force balance, albeit to a lesser extent. Importantly, this complex has recently been implicated in direct MT polymerization in metazoans, a role not shared by its fission yeast counterpart.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011596"},"PeriodicalIF":3.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245536","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}

{"title":"A high-resolution crossover landscape in Drosophila santomea reveals rapid and concerted evolution of multiple properties of crossing over control.","authors":"Ana Llopart, Nikale Pettie, Abigail Ryon, Josep M Comeron","doi":"10.1371/journal.pgen.1011885","DOIUrl":"10.1371/journal.pgen.1011885","url":null,"abstract":"<p><p>Crossing over is a fundamental process in sexually reproducing species, ensuring proper chromosome segregation during gamete formation and generating new allelic combinations that enhance adaptation. Despite its essential role, genes involved in crossing over evolve rapidly and there is extensive variation in the rate and genomic distribution of crossovers across species. Considering this rapid evolution, identifying differences between very closely related species is crucial for understanding the molecular basis of natural variation in crossing over control. Here, we present a genome-wide, high-resolution crossover map for Drosophila santomea and compare it with those of its sister species D. yakuba and the more distantly related D. melanogaster. Upon examining 784 individual meiotic products based on an experimental design that captures intraspecific variation in crossing over control, we identified 2,288 crossovers genome-wide. Our analyses reveal striking differences in crossover patterns between D. santomea and D. yakuba despite their recent split only 400,000 years ago and sharing a significant amount of ancestral polymorphism. The D. santomea X chromosome shows a major reduction in genetic length compared to D. yakuba (62.7 cM vs. 93.8 cM), while autosomes show a slight increase (262.6 vs. 245.6 cM), resulting in overall genetic maps of 324.2 cM for D. santomea and 339.3 cM for D. yakuba. All D. santomea autosomal arms show a significant reduction of the centromere effect relative to D. yakuba, more closely resembling D. melanogaster autosomes. At the same time, estimates of crossover interference indicate weaker intensity across all autosomal arms in D. santomea compared to D. yakuba, while the X chromosome exhibits considerably stronger interference. These findings suggest a link between the intensity of crossover interference and the centromere effect. We propose that stronger crossover interference is associated with a smaller crossover-competent region-determined by the combined centromere and telomere effects-to prevent the deleterious consequences of multiple crossovers occurring too close together. Finally, we examined whether the D. santomea X chromosome exhibits the crossover-associated meiotic drive mechanism (MDCO) reported in D. yakuba, in which chromatids with crossovers are preferentially included in oocytes. Tetrad analysis of the D. santomea X chromosome revealed no evidence of an active MDCO, potentially explaining the reduced crossover rates observed on this chromosome relative to D. yakuba even though the numbers of meiosis I crossovers may be similar in both species.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011885"},"PeriodicalIF":3.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards a transcriptomic biomarker for the classification of melanocytic neoplasms.","authors":"Elizabeth S Borden, Colin T Hastings, Nithish Prakash, Tyler Kuo, Edgar Tapia, Michael Yozwiak, Paul Sagerman, Danielle Vargas de Stefano, Kenneth H Buetow, Melissa A Wilson, Clara Curiel-Lewandrowski, Hsiao-Hui Sherry Chow, Bonnie J LaFleur, Karen Taraszka Hastings","doi":"10.1371/journal.pgen.1011869","DOIUrl":"10.1371/journal.pgen.1011869","url":null,"abstract":"<p><p>Histopathologic diagnosis of thin, invasive cutaneous melanoma (CM) is only 34-62% accurate. Therefore, we sought to develop a transcriptomic biomarker to distinguish benign from malignant melanocytic neoplasms. We generated a targeted RNA-Sequencing dataset (TempO-Seq) of benign nevi (BN; n = 50) and CM (Breslow depth ≤ 1.0 mm; n = 51) and demonstrated enrichment of immune-related pathways among the 450 differentially expressed genes. Next, we trained a putative transcriptomic biomarker in two datasets, including BN and CM, and one dataset with CM in association with a nevus, macrodissected into CM and nevus regions. We refer to the nevus portion of CM in association with a nevus as progressing nevi (PN), since these nevi progressed to CM. Principal component analysis showed that PN samples clustered in a component intermediate to BN and CM. Ordinal regularized regression selected PYGL, AP000845.1, PHYHIP, WSCD1, FBXO7, TRPM1, SLC4A4, NALCN, FRMD4B, HHATL, COL1A1, CRYM, EPOP, RGS1, KRT6C, IGHG1, CNTN1, MMP11, GZMM, AP001880.1, TTYH3, TMEM132A, and PRAME; these genes were consistently selected in 1000 models using data from bootstrap resamples and had a single model predictive accuracy of at least 0.90 (area under the receiver operator characteristics curve). Linear regression models fit with these 23 genes in the TempO-Seq data, and publicly available microarray datasets from BN, dysplastic nevi, and CM, showed high consistency in the magnitude and directionality of gene expression differences between nevi and CM. Furthermore, immunohistochemical staining showed consistent protein-level changes in MMP11 and PYGL. These results illuminate the potential for a transcriptomic biomarker to differentiate benign from malignant melanocytic neoplasms and improve the accuracy of melanoma diagnosis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 10","pages":"e1011869"},"PeriodicalIF":3.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12507199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-evolutionary exome analysis identifies novel type 2 diabetes mellitus genes in the UK Biobank and all of us.","authors":"Kevin Wilhelm, Jennifer Asmussen, Kwanghyuk Lee, Maryam Samieinasab, Emmanuel Asante, Marek Kimmel, Olivier Lichtarge","doi":"10.1371/journal.pgen.1011889","DOIUrl":"10.1371/journal.pgen.1011889","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) risk is heavily influenced by genetics, yet current association tests have explained only parts of its heritability. We developed MEVA (Meta-Evolutionary Action), a meta-analytic framework that integrates three complementary methods-EAML, Sigma-Diff, and GeneEMBED-to assess the functional burden of protein-coding variants using evolutionary data. MEVA was applied to exome data from 28,115 T2DM cases and 28,115 controls in the UK Biobank (UKB), identifying 101 genes (p < 1e-5). MEVA outperformed its component methods, each of which substantially outperformed a conventional burden test (MAGMA), in recovering known T2DM genes (AUROC = 0.925) and maintaining robustness in progressively smaller cohorts (AUROC = 0.917). MEVA showed significant enrichment for T2DM-related loci (p = 6.8e-10, p = 2.0e-34), protein interactions (z = 4.6, z = 4.2), pathways (p = 1.3e-6, z = 2.0), phenotypes (p = 1.3e-21, z = 9.1), and literature mentions (z = 7.2). Replication in 16,915 T2DM cases and 16,915 controls from All of Us (AoU) yielded 99 genes (p < 1e-5), 23 of which were also recovered in the UKB cohort - far exceeding random chance. These included established genes (SLC30A8, WFS1, HNF1A) and less-characterized candidates (NRIP1, ADAM30, CALCOCO2, TUBB1, ZFP36L2, WDR90). Notably, NRIP1 loss-of-function variants were associated with increased T2DM risk in both the UKB (OR = 1.09, FDR = 5.4e-4) and AoU (OR = 1.09, FDR = 0.046), and TUBB1 and CALCOCO2 gain-of-function variants showed consistent risk effects (FDR < 0.05). Pathway analyses revealed convergence on endoplasmic reticulum chaperone complexes (FDR = 0.02) and Hippo signaling (FDR = 8.5e-4). Finally, all 177 candidate genes were functionally prioritized using ten orthogonal criteria to guide experimental follow-up. These results demonstrate that combining complementary, impact-aware association tests increases sensitivity, improves replication, and expands the catalog of genetic risk factors for T2DM.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011889"},"PeriodicalIF":3.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}