PLoS Genetics最新文献

{"title":"The nuclear poly(A)-binding protein Pab2/PABPN1 promotes heterochromatin assembly through the formation of Pab2 nuclear condensates.","authors":"Ziyue Liu, Xiuyi Song, Gobi Thillainadesan, Tomoyasu Sugiyama","doi":"10.1371/journal.pgen.1011647","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011647","url":null,"abstract":"<p><p>The assembly of constitutive heterochromatin is a prerequisite for maintaining genome stability. However, the mechanism of heterochromatin formation has yet to be completely understood. Here, we demonstrate a crucial role of the nuclear poly(A)-binding protein (PABP) Pab2/PABPN1 in promoting constitutive heterochromatin formation in the fission yeast Schizosaccharomyces japonicus. Histone H3 Lys 9 di- and tri-methylation, hallmarks of heterochromatin, are significantly reduced at centromeres in the absence of Pab2. Pab2 forms nuclear condensates through its RNA-recognition motif (RRM) and the intrinsically disordered domain (IDR), both of which bind to centromeric non-coding RNAs. Intriguingly, two key heterochromatin factors, the histone H3 Lys9 methyltransferase Clr4 and the Mi2-type chromatin remodeler Mit1, associate with centromeres in a Pab2-dependent manner. Pab2 interacts with two putative RNA-binding proteins, the ZC3H3 ortholog Red5 and the RBM26·27 ortholog Rmn1, both essential for heterochromatin formation. Deletion of the Pab2 N-terminal region, which disrupts this interaction, largely abolishes Pab2 function, underscoring the importance of this complex. Pab2 also associates and colocalizes with Ppn1 (a PPP1R10 ortholog), a component of the cleavage and polyadenylation specificity factor (CPSF) complex, and ppn1 mutations disrupt constitutive heterochromatin. Notably, both Ppn1 and Rmn1 are able to interact with Clr4. Our findings reveal that Pab2 plays a pivotal role in heterochromatin assembly by forming nuclear condensates through its RRM/IDR, and Pab2 condensates facilitate the recruitment of Clr4 and Mit1 to centromeres, potentially through its binding proteins, Ppn1 and Rmn1. This study provides new insights into the mechanisms underlying heterochromatin formation and highlights the importance of RNA-binding proteins and phase separation in this process.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011647"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755438","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":"Doxifluridine promotes host longevity through bacterial metabolism.","authors":"Rui Wei, Yuling Peng, Yamei Luo, Xinyuan Wang, Zhenzhong Pan, Ran Zhou, Huan Yang, Zongyao Huang, Yaojia Liu, Lunzhi Dai, Yuan Wang, Yan Zhang","doi":"10.1371/journal.pgen.1011648","DOIUrl":"10.1371/journal.pgen.1011648","url":null,"abstract":"<p><p>Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drug(s) can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative, rescues age-associated AS defects and extends lifespan. Combining bacterial DNA sequencing, proteomics, metabolomics and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate drug's functions through complex interplay among drug, bacteria and host.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011648"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755288","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":"Gene expression in soft-shell clam (Mya arenaria) transmissible cancer reveals survival mechanisms during host infection and seawater transfer.","authors":"Samuel F M Hart, Fiona E S Garrett, Jesse S Kerr, Michael J Metzger","doi":"10.1371/journal.pgen.1011629","DOIUrl":"10.1371/journal.pgen.1011629","url":null,"abstract":"<p><p>Transmissible cancers are unique instances in which cancer cells escape their original host and spread through a population as a clonal lineage, documented in Tasmanian devils, dogs, and ten bivalve species. For a cancer to repeatedly transmit to new hosts, these lineages must evade strong barriers to transmission, notably the metastasis-like physical transfer to a new host body and rejection by that host's immune system. We quantified gene expression in a transmissible cancer lineage that has spread through the soft-shell clam (Mya arenaria) population to investigate potential drivers of its success as a transmissible cancer lineage, observing extensive differential expression of genes and gene pathways. We observed upregulation of genes involved with genotoxic stress response, ribosome biogenesis and RNA processing, and downregulation of genes involved in tumor suppression, cell adhesion, and immune response. We also observe evidence that widespread genome instability affects the cancer transcriptome via gene fusions, copy number variation, and transposable element insertions. Finally, we incubated cancer cells in seawater, the presumed host-to-host transmission vector, and observed conserved responses to halt metabolism, avoid apoptosis and survive the low-nutrient environment. Interestingly, many of these responses are also present in healthy clam cells, suggesting that bivalve hemocytes may have inherent seawater survival responses that may partially explain why transmissible cancers are so common in bivalves. Overall, this study reveals multiple mechanisms this lineage may have evolved to successfully spread through the soft-shell clam population as a contagious cancer, utilizing pathways known to be conserved in human cancers as well as pathways unique to long-lived transmissible cancers.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011629"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755293","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":"Archaic introgression and the distribution of shared variation under stabilizing selection.","authors":"Aaron P Ragsdale","doi":"10.1371/journal.pgen.1011623","DOIUrl":"10.1371/journal.pgen.1011623","url":null,"abstract":"<p><p>Many phenotypic traits are under stabilizing selection, which maintains a population's mean phenotypic value near some optimum. The dynamics of traits and trait architectures under stabilizing selection have been extensively studied for single populations at steady state. However, natural populations are seldom at steady state and are often structured in some way. Admixture and introgression events may be common, including over human evolutionary history. Because stabilizing selection results in selection against the minor allele at a trait-affecting locus, alleles from the minor parental ancestry will be selected against after admixture. We show that the site-frequency spectrum can be used to model the genetic architecture of such traits, allowing for the study of trait architecture dynamics in complex multi-population settings. We use a simple deterministic two-locus model to predict the reduction of introgressed ancestry around trait-contributing loci. From this and individual-based simulations, we show that introgressed-ancestry is depleted around such loci. When introgression between two diverged populations occurs in both directions, as has been inferred between humans and Neanderthals, the locations of such regions with depleted introgressed ancestry will tend to be shared across populations. We argue that stabilizing selection for shared phenotypic optima may explain recent observations in which regions of depleted human-introgressed ancestry in the Neanderthal genome overlap with Neanderthal-ancestry deserts in humans.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011623"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755099","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":"Significant roles in RNA-binding for the amino-terminal regions of Drosophila Pumilio and Nanos.","authors":"Tammy H Wharton, Mohammad Marhabaie, Robin P Wharton","doi":"10.1371/journal.pgen.1011616","DOIUrl":"10.1371/journal.pgen.1011616","url":null,"abstract":"<p><p>The Drosophila Pumilio (Pum) and Nanos (Nos) RNA-binding proteins govern abdominal segmentation in the early embryo, as well as a variety of other events during development. They bind together to a compound Nanos Response Element (NRE) present in thousands of maternal mRNAs in the ovary and embryo, including hunchback (hb) mRNA, thereby regulating poly-adenylation, translation, and stability. Many studies support a model in which mRNA recognition and effector recruitment are carried out by distinct regions of each protein. The well-ordered Pum and Nos RNA-binding domains (RBDs) are sufficient to specifically recognize NREs; the larger intrinsically disordered N-terminal regions (NTRs) of each protein have been thought to act by recruiting mRNA regulators. Here we use yeast interaction assays and experiments testing the regulation of hb mRNA in vivo to show that the NTRs play a significant role in recognition of the NRE, acting via two mechanisms. First, the Pum and Nos NTRs interact in trans to promote assembly of the Pum/Nos/NRE ternary complex. Second, the Pum NTR acts via an unknown mechanism in cis, modifying NRE recognition by its RBD. The ability of the NTR to alter binding to the NRE is conserved in human Pum2.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011616"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755437","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":"RatXcan: A framework for cross-species integration of genome-wide association and gene expression data.","authors":"Natasha Santhanam, Sandra Sanchez-Roige, Sabrina Mi, Yanyu Liang, Apurva S Chitre, Daniel Munro, Denghui Chen, Jianjun Gao, Angel Garcia-Martinez, Anthony M George, Alexander F Gileta, Wenyan Han, Katie Holl, Alesa Hughson, Christopher P King, Alexander C Lamparelli, Connor D Martin, Festus Nyasimi, Celine L St Pierre, Sarah Sumner, Jordan Tripi, Tengfei Wang, Hao Chen, Shelly Flagel, Keita Ishiwari, Paul Meyer, Oksana Polesskaya, Laura Saba, Leah C Solberg Woods, Abraham A Palmer, Hae Kyung Im","doi":"10.1371/journal.pgen.1011583","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011583","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) have implicated specific alleles and genes as risk factors for numerous complex traits. However, translating GWAS results into biologically and therapeutically meaningful discoveries remains extremely challenging. Most GWAS results identify noncoding regions of the genome, suggesting that differences in gene regulation are the major driver of trait variability. To better integrate GWAS results with gene regulatory polymorphisms, we previously developed PrediXcan (also known as \"transcriptome-wide association studies\" or TWAS), which maps SNPs to predicted gene expression using GWAS data. In this study, we developed RatXcan, a framework that extends this methodology to outbred heterogeneous stock (HS) rats. RatXcan accounts for the close familial relationships among HS rats by modeling the relatedness with a random effect that encodes the genetic relatedness. RatXcan also corrects for polygenic-driven inflation because of the equivalence between a relatedness random effect and the infinitesimal polygenic model. To develop RatXcan, we trained transcript predictors for 8,934 genes using reference genotype and expression data from five rat brain regions. We found that the cis genetic architecture of gene expression in both rats and humans was sparse and similar across brain tissues. We tested the association between predicted expression in rats and two example traits (body length and BMI) using phenotype and genotype data from 5,401 densely genotyped HS rats and identified a significant enrichment between the genes associated with rat and human body length and BMI. Thus, RatXcan represents a valuable tool for identifying the relationship between gene expression and phenotypes across species and paves the way to explore shared biological mechanisms of complex traits.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011583"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755436","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":"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":"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":"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975134/pdf/","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":"OA","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":"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}