PLoS Genetics最新文献

{"title":"Fluctuating reproductive isolation and stable ancestry structure in a fine-scaled mosaic of hybridizing Mimulus monkeyflowers.","authors":"Matthew C Farnitano, Keith Karoly, Andrea L Sweigart","doi":"10.1371/journal.pgen.1011624","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011624","url":null,"abstract":"<p><p>Hybridization among taxa impacts a variety of evolutionary processes from adaptation to extinction. We seek to understand both patterns of hybridization across taxa and the evolutionary and ecological forces driving those patterns. To this end, we use whole-genome low-coverage sequencing of 458 wild-grown and 1565 offspring individuals to characterize the structure, stability, and mating dynamics of admixed populations of Mimulus guttatus and Mimulus nasutus across a decade of sampling. In three streams, admixed genomes are common and a M. nasutus organellar haplotype is fixed in M. guttatus, but new hybridization events are rare. Admixture is strongly unidirectional, but each stream has a unique distribution of ancestry proportions. In one stream, three distinct cohorts of admixed ancestry are spatially structured at ~20-50m resolution and stable across years. Mating system provides almost complete isolation of M. nasutus from both M. guttatus and admixed cohorts, and is a partial barrier between admixed and M. guttatus cohorts. Isolation due to phenology is near-complete between M. guttatus and M. nasutus. Phenological isolation is a strong barrier in some years between admixed and M. guttatus cohorts, but a much weaker barrier in other years, providing a potential bridge for gene flow. These fluctuations are associated with differences in water availability across years, supporting a role for climate in mediating the strength of reproductive isolation. Together, mating system and phenology accurately predict fluctuations in assortative mating across years, which we estimate directly using paired maternal and offspring genotypes. Climate-driven fluctuations in reproductive isolation may promote the longer-term stability of a complex mosaic of hybrid ancestry, preventing either complete isolation or complete collapse of species barriers.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011624"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755290","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":"Human genetic evidence enriched for side effects of approved drugs.","authors":"Eric Vallabh Minikel, Matthew R Nelson","doi":"10.1371/journal.pgen.1011638","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011638","url":null,"abstract":"<p><p>Safety failures are an important factor in low drug development success rates. Human genetic evidence can select drug targets causal in disease and enrich for successful programs. Here, we sought to determine whether human genetic evidence can also enrich for labeled side effects (SEs) of approved drugs. We combined the SIDER database of SEs with human genetic evidence from genome-wide association studies, Mendelian disease, and somatic mutations. SEs were 2.0 times more likely to occur for drugs whose target possessed human genetic evidence for a trait similar to the SE. Enrichment was highest when the trait and SE were most similar to each other, and was robust to removing drugs where the approved indication was also similar to the SE. The enrichment of genetic evidence was greatest for SEs that were more drug specific, affected more people, and were more severe. There was significant heterogeneity among disease areas the SEs mapped to, with the highest positive predictive value for cardiovascular SEs. This supports the integration of human genetic evidence early in the drug discovery process to identify potential SE risks to be monitored or mitigated in the course of drug development.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011638"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755314","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":"Quantitative analysis of relationship between mutation rate and speed of adaptation under antibiotic exposure in Escherichia coli.","authors":"Atsushi Shibai, Minako Izutsu, Hazuki Kotani, Chikara Furusawa","doi":"10.1371/journal.pgen.1011627","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011627","url":null,"abstract":"<p><p>Mutations are the ultimate source of biological evolution that creates genetic variation in populations. Mutations can create new advantageous traits but can also potentially interfere with pre-existing organismal functions. Therefore, organisms may have evolved mutation rates to appropriate levels to maintain or improve their fitness. In this study, we aimed to experimentally quantify the relationship between the mutation rate and evolution of antibiotic resistance. We conducted an evolution experiment using 12 Escherichia coli mutator strains with increased mutation rates and five antibiotics. Our results demonstrated that the rate of adaptation generally increased with higher mutation rates, except in a single mutator strain with the highest mutation rate, which exhibited a significant decline in evolutionary speed. To further elucidate these findings, we developed a simple population dynamics model that successfully recapitulated the observed dependence of adaptation speed on mutation rate. These findings provide important insights into the evolution of mutation rate accompanied by the evolution.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011627"},"PeriodicalIF":4.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736165","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":"Alternative promoter usage during organ development.","authors":"Jiang Tan, Yidan Sun","doi":"10.1371/journal.pgen.1011635","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011635","url":null,"abstract":"<p><p>Dynamic gene expression is crucial for mammalian organ development, influencing organ-specific functions and responses. A significant number of mammalian protein-coding genes are regulated by multiple distinct promoters, suggesting that the choice of promoter is as critical as its transcriptional output. However, the role of alternative promoters in organ development remains largely unexplored. In this study, we utilized RNA-seq data from 313 mouse samples across various developmental stages in seven major organs to identify active promoters. Our analyses revealed between 967 and 3,237 developmentally dynamic promoters (DDPs) in each organ. These DDPs encompass not only major promoters with the highest activity within a gene but also alternative promoters with lower activity, which are often overlooked in traditional gene-level analyses. Notably, we found that alternative DDPs can be independently regulated compared to their major counterparts, suggesting the involvement of unique transcriptional regulatory mechanisms. Furthermore, we observed that increased alternative promoter usage plays a pivotal role in driving organ-specific functions and gene expression alterations. Our findings underscore the importance of alternative promoter usage in shaping organ identity and function, providing new insights into the regulatory complexity of organogenesis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011635"},"PeriodicalIF":4.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736154","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":"Chemical genomics informs antibiotic and essential gene function in Acinetobacter baumannii.","authors":"Jennifer Suzanne Tran, Ryan David Ward, Rubén Iruegas-López, Ingo Ebersberger, Jason Matthew Peters","doi":"10.1371/journal.pgen.1011642","DOIUrl":"10.1371/journal.pgen.1011642","url":null,"abstract":"<p><p>The Gram-negative pathogen, Acinetobacter baumannii, poses a serious threat to human health due to its role in nosocomial infections that are resistant to treatment with current antibiotics. Despite this, our understanding of fundamental A. baumannii biology remains limited, as many essential genes have not been experimentally characterized. These essential genes are critical for bacterial survival and, thus, represent promising targets for drug discovery. Here, we systematically probe the function of essential genes by screening a CRISPR interference knockdown library against a diverse panel of chemical inhibitors, including antibiotics. We find that most essential genes show chemical-gene interactions, allowing insights into both inhibitor and gene function. For instance, knockdown of lipooligosaccharide (LOS) transport genes increased sensitivity to a broad range of chemicals. Cells with defective LOS transport showed cell envelope hyper-permeability that was dependent on continued LOS synthesis. Using phenotypes across our chemical-gene interaction dataset, we constructed an essential gene network linking poorly understood genes to well-characterized genes in cell division and other processes. Finally, our phenotype-structure analysis identified structurally related antibiotics with distinct cellular impacts and suggested potential targets for underexplored inhibitors. This study advances our understanding of essential gene and inhibitor function, providing a valuable resource for mechanistic studies, therapeutic strategies, and future key targets for antibiotic development.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011642"},"PeriodicalIF":4.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736159","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":"Valve cells are crucial for efficient cardiac performance in Drosophila.","authors":"Christian Meyer, Achim Paululat","doi":"10.1371/journal.pgen.1011613","DOIUrl":"10.1371/journal.pgen.1011613","url":null,"abstract":"<p><p>Blood flow in metazoans is regulated by the activity of the heart. The open circulatory system of insects consists of relatively few structural elements that determine cardiac performance via their coordinated interplay. One of these elements is the intracardiac valve between the aorta and the ventricle. In Drosophila, it is built by only two cells, whose unique histology represents an evolutionary novelty. While the development and differentiation of these highly specialised cells have been elucidated previously, their physiological impact on heart performance is still unsolved. The present study investigated the physiological consequences of cardiac valve malformation in Drosophila. We show that cardiac performance is reduced if valves are malformed or damaged. Less blood is transported through the heart proper, resulting in a decreased overall transport capacity. A reduced luminal opening was identified as a main reason for the decreased heart performance in the absence of functional valves. Intracardiac hemolymph flow was visualised at the valve region by microparticle injection and revealed characteristic similarities to valve blood flow in vertebrates. Based on our data, we propose a model on how the Drosophila intracardiac valves support proper hemolymph flow and distribution, thereby optimising general heart performance.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011613"},"PeriodicalIF":4.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671662","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":"A defining member of the new cysteine-cradle family is an aECM protein signalling skin damage in C. elegans.","authors":"Thomas Sonntag, Shizue Omi, Antonina Andreeva, Claire Valotteau, Jeanne Eichelbrenner, Andrew D Chisholm, Jordan D Ward, Nathalie Pujol","doi":"10.1371/journal.pgen.1011593","DOIUrl":"10.1371/journal.pgen.1011593","url":null,"abstract":"<p><p>Apical extracellular matrices (aECMs) act as crucial barriers, and communicate with the epidermis to trigger protective responses following injury or infection. In Caenorhabditis elegans, the skin aECM, the cuticle, is produced by the epidermis and is decorated with periodic circumferential furrows. We previously showed that mutants lacking cuticle furrows exhibit persistent immune activation (PIA), providing a valuable model to study the link between cuticle damage and immune response. In a genetic suppressor screen, we identified spia-1 as a key gene downstream of furrow collagens and upstream of immune signalling. spia-1 expression oscillates during larval development, peaking between each moult together with patterning cuticular components. It encodes a secreted protein that localises to furrows. SPIA-1 shares a novel cysteine-cradle domain with other aECM proteins. SPIA-1 mediates immune activation in response to furrow loss and is proposed to act as an extracellular signal activator of cuticle damage. This research provides a molecular insight into intricate interplay between cuticle integrity and epidermal immune activation in C. elegans.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011593"},"PeriodicalIF":4.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671659","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":"Mouse-Geneformer: A deep learning model for mouse single-cell transcriptome and its cross-species utility.","authors":"Keita Ito, Tsubasa Hirakawa, Shuji Shigenobu, Hironobu Fujiyoshi, Takayoshi Yamashita","doi":"10.1371/journal.pgen.1011420","DOIUrl":"10.1371/journal.pgen.1011420","url":null,"abstract":"<p><p>Deep learning techniques are increasingly utilized to analyze large-scale single-cell RNA sequencing (scRNA-seq) data, offering valuable insights from complex transcriptome datasets. Geneformer, a pre-trained model using a Transformer Encoder architecture and human scRNA-seq datasets, has demonstrated remarkable success in human transcriptome analysis. However, given the prominence of the mouse, Mus musculus, as a primary mammalian model in biological and medical research, there is an acute need for a mouse-specific version of Geneformer. In this study, we developed a mouse-specific Geneformer (mouse-Geneformer) by constructing a large transcriptome dataset consisting of 21 million mouse scRNA-seq profiles and pre-training Geneformer on this dataset. The mouse-Geneformer effectively models the mouse transcriptome and, upon fine-tuning for downstream tasks, enhances the accuracy of cell type classification. In silico perturbation experiments using mouse-Geneformer successfully identified disease-causing genes that have been validated in in vivo experiments. These results demonstrate the feasibility of analyzing mouse data with mouse-Geneformer and highlight the robustness of the Geneformer architecture, applicable to any species with large-scale transcriptome data available. Furthermore, we found that mouse-Geneformer can analyze human transcriptome data in a cross-species manner. After the ortholog-based gene name conversion, the analysis of human scRNA-seq data using mouse-Geneformer, followed by fine-tuning with human data, achieved cell type classification accuracy comparable to that obtained using the original human Geneformer. In in silico simulation experiments using human disease models, we obtained results similar to human-Geneformer for the myocardial infarction model but only partially consistent results for the COVID-19 model, a trait unique to humans (laboratory mice are not susceptible to SARS-CoV-2). These findings suggest the potential for cross-species application of the Geneformer model while emphasizing the importance of species-specific models for capturing the full complexity of disease mechanisms. Despite the existence of the original Geneformer tailored for humans, human research could benefit from mouse-Geneformer due to its inclusion of samples that are ethically or technically inaccessible for humans, such as embryonic tissues and certain disease models. Additionally, this cross-species approach indicates potential use for non-model organisms, where obtaining large-scale single-cell transcriptome data is challenging.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011420"},"PeriodicalIF":4.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665105","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":"Evolution of canonical circadian clock genes underlies unique sleep strategies of marine mammals for secondary aquatic adaptation.","authors":"Daiqing Yin, Zhaomin Zhong, Fan Zeng, Zhikang Xu, Jing Li, Wenhua Ren, Guang Yang, Han Wang, Shixia Xu","doi":"10.1371/journal.pgen.1011598","DOIUrl":"10.1371/journal.pgen.1011598","url":null,"abstract":"<p><p>To satisfy the needs of sleeping underwater, marine mammals, including cetaceans, sirenians, and pinnipeds, have evolved an unusual form of sleep, known as unihemispheric slow-wave sleep (USWS), in which one brain hemisphere is asleep while the other is awake. All aquatic cetaceans have only evolved USWS without rapid eye movement (REM) sleep, whereas aquatic sirenians and amphibious pinnipeds display both bihemispheric slow-wave sleep (BSWS) and USWS, as well as REM sleep. However, the molecular genetic changes underlying USWS remain unknown. The present study investigated the evolution of eight canonical circadian genes and found that positive selection occurred mainly within cetacean lineages. Furthermore, convergent evolution was observed in lineages with USWS at three circadian clock genes. Remarkably, in vitro assays showed that cetacean-specific mutations increased the nuclear localization of zebrafish clocka, and enhanced the transcriptional activation activity of Clocka and Bmal1a. In vivo, transcriptome analysis showed that the overexpression of the cetacean-specific mutant clocka (clocka-mut) caused the upregulation of the wakefulness-promoting glutamatergic genes and the differential expression of multiple genes associated with sleep regulation. In contrast, the GABAergic and cholinergic pathways, which play important roles in promoting sleep, were downregulated in the bmal1a-mut-overexpressing zebrafish. Concordantly, sleep time of zebrafish overexpressing clocka-mut and bmal1a-mut were significantly less than the zebrafish overexpressing the wild-type genes, respectively. These findings support our hypothesis that canonical circadian clock genes may have evolved adaptively to enhance circadian regulation ability relating to sleep in cetaceans and, in turn, contribute to the formation of USWS.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011598"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659445","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":"MEOX1-mediated transcriptional regulation of circABHD3 exacerbates hepatic fibrosis through promoting m6A/YTHDF2-dependent YPEL3 mRNA decay to activate β-catenin signaling.","authors":"Limin Chen, Hui Yang, Juan Wang, Haoye Zhang, Kangkang Fu, Yu Yan, Zhenguo Liu","doi":"10.1371/journal.pgen.1011622","DOIUrl":"10.1371/journal.pgen.1011622","url":null,"abstract":"<p><strong>Background: </strong>Hepatic fibrosis may progress to liver cirrhosis and eventually cause death. Epithelial-mesenchymal transition (EMT) of hepatocytes plays critical roles in hepatic fibrosis. Exploring the mechanisms underlying EMT is crucial for a better understanding of hepatic fibrosis pathogenesis.</p><p><strong>Methods: </strong>Hepatocyte EMT wad induced with TGF-β1 and evaluated by Western blotting and immunofluorescence staining. Methylated RNA immunoprecipitation (MeRIP) was applied to assess N6-methyladenosine (m6A) modification. RIP and RNA pull-down assays were performed to analyze the interaction between circABHD3, YTHDF2 and YPEL3 mRNA. MEOX1-mediated transcription of ABHD3 was examined by luciferase and chromatin immunoprecipitation (ChIP). Mice were intraperitoneally injected with CCl4 or treated with bile duct ligation (BDL) surgery for hepatic fibrosis induction. Liver injury and collagen deposition were examined with hematoxylin and eosin (HE), Masson, and Sirius Red staining. Alanine transaminase (ALT), aspartate transaminase (AST) and hydroxyproline (HYP) were examined using ELISA.</p><p><strong>Results: </strong>CircABHD3 was upregulated in in vitro and in vivo models of hepatic fibrosis and patients. Knockdown of circABHD3 inhibited TGF-β1-induced expression of fibrosis markers, EMT and mitochondrial impairment in hepatocytes. MEOX1 could directly bind to the promoter of ABHD3 to facilitate its transcription and subsequent circABHD3 generation. Knockdown of MEOX1 suppressed TGF-β1-induced EMT and mitochondrial impairment through suppression of circABHD3. CircABHD3 destabilized YPEL3 mRNA via promoting YTHDF2-dependent recognition of m6A-modified YPEL3 mRNA to trigger β-catenin signaling activation. Furthermore, circABHD3 silencing-mediated inhibition of EMT and mitochondrial impairment was counteracted by YPEL3 knockdown and activation of β-catenin signaling. Depletion of circABHD3 significantly reduced EMT, mitochondrial impairment and hepatic fibrosis via promoting YPEL3 expression and suppressing β-catenin signaling in vivo.</p><p><strong>Conclusion: </strong>MEOX1-mediated generation of circABHD3 promotes EMT and mitochondrial impairment by enhancing YTHDF2-mediated degradation of YPEL3 mRNA and activating downstream β-catenin signaling, thus exacerbating hepatic fibrosis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011622"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659468","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}