Genetics最新文献

{"title":"Two eIF4E paralogs occupy separate germ granule mRNPs that mediate mRNA repression and translational activation.","authors":"Gita Gajjar, Hayden P Huggins, Eun Suk Kim, Weihua Huang, Frederic X Bonnet, Dustin L Updike, Brett D Keiper","doi":"10.1093/genetics/iyaf053","DOIUrl":"https://doi.org/10.1093/genetics/iyaf053","url":null,"abstract":"<p><p>We studied translation factor eIF4E paralogs that regulate germline mRNAs. Translational control of mRNAs is essential for germ cell differentiation and embryogenesis. Messenger ribonucleoprotein (mRNP) complexes assemble on mRNAs in the nucleus, as they exit via perinuclear germ granules, and in the cytoplasm. Bound mRNP proteins including eIF4Es exert both positive and negative post-transcriptional regulation. In C. elegans, germ granules are surprisingly dynamic mRNP condensates that remodel during development. Two eIF4E paralogs (IFE-1 and IFE-3), their cognate eIF4E-Interacting Proteins (4EIPs), and polyadenylated mRNAs are present in germ granules. Affinity purification of IFE-1 and IFE-3 mRNPs allowed mass spectrometry and mRNA-Seq to identify other proteins and the mRNAs that populate stable eIF4E complexes. We find translationally repressed mRNAs (e.g. pos-1, mex-3, spn-4, etc.) enriched with IFE-3, but excluded from IFE-1. Identified mRNAs overlap substantially with mRNAs previously described to be IFE-1-dependent for translation. The findings suggest that oocytes and embryos utilize the two eIF4Es for opposite purposes on critically regulated germline mRNAs. Sublocalization within adult perinuclear germ granules suggests an architecture in which Vasa/GLH-1, PGL-1 and the IFEs are stratified, which may facilitate sequential remodeling of mRNPs leaving the nucleus. Biochemical composition of isolated mRNPs indicates opposing yet cooperative roles for the two eIF4Es. We propose that the IFEs accompany controlled mRNAs in the repressed or activated state during transit to the cytoplasm. Copurification of IFE-1 with IFE-3 suggests they may interact to move repressed mRNAs to ribosomes.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mediator-29 Limits Caenorhabditis elegans Fecundity.","authors":"Qi Fan, Christopher Tran, Wei Cao, Roger Pocock","doi":"10.1093/genetics/iyaf051","DOIUrl":"https://doi.org/10.1093/genetics/iyaf051","url":null,"abstract":"<p><p>Mediator is an evolutionarily conserved multiprotein complex that acts as a critical coregulator of RNA polymerase II-mediated transcription. While core Mediator components are broadly required for transcription, others govern specific regulatory modules and signalling pathways. Here, we investigated the function of MDT-29/MED29 in the Caenorhabditis elegans germ line. We found that endogenously-tagged MDT-29 is ubiquitously expressed and concentrated in discrete foci within germ cell nuclei. Functionally, depleting MDT-29 in the germ line during larval development boosted fecundity. We determined that the increase in progeny production was likely caused by a combination of an expanded germline stem cell pool and decreased germ cell apoptosis. Thus, MDT-29 may act to optimize specific gene expression programs to control distinct germ cell behaviors, providing flexibility to progeny production in certain environments.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fork-barrier-independent roles of topoisomerase I in the ribosomal DNA.","authors":"Temistocles Molinar, Daniel Sultanov, Hannah Klein, Andreas Hochwagen","doi":"10.1093/genetics/iyaf052","DOIUrl":"10.1093/genetics/iyaf052","url":null,"abstract":"<p><p>Topoisomerase I, a nickase that allows swiveling of the DNA substrate, is highly enriched in the ribosomal DNA (rDNA) from yeast to humans, but its function at this locus remains poorly understood. S. cerevisiae mutants lacking topoisomerase I (top1) exhibit pronounced rDNA instability and accumulate bubbles of single-stranded DNA (ssDNA) on 35S ribosomal RNA genes, suggesting a role in relieving transcription-associated topological stress. However, Top1-cleavage complexes are most highly enriched in the rDNA-encoded replication-fork barrier, a genetically encoded source of rDNA instability, and only weakly in the 35S promoter, leading to the proposal that top1-associated rDNA instability may be linked to the fork barrier. Here, we show that the rDNA instability phenotypes of top1 mutants, including increased formation of extrachromosomal rDNA circles, elevated genetic marker loss, and instability of critically short rDNA arrays, are independent of the replication fork barrier. In addition, we link Top1 binding at the 35S promoter to the formation of a DNA species with a long ssDNA tail, which originates in the 35S promoter region and is undetectable in top1 mutants. This DNA species is abundant in wild-type cells, occurs independently of S phase, and may be the resolution product of the ssDNA bubbles seen in top1 mutants. Whether formation of this DNA species is important for rDNA stability remains unclear, but our findings link Top1 to highly active DNA metabolism in the 35S promoter.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New perspectives on Drosophila melanogaster de novo gene origination revealed by investigation of ancient African genetic variation.","authors":"Julie M Cridland, Elizabeth S Polston, David J Begun","doi":"10.1093/genetics/iyaf044","DOIUrl":"https://doi.org/10.1093/genetics/iyaf044","url":null,"abstract":"<p><p>De novo genes can be defined as sequences producing evolutionarily derived transcripts that are not homologous to transcripts produced in an ancestor. While they appear to be taxonomically widespread, there is little agreement regarding their abundance, their persistence times in genomes, the population genetic processes responsible for their spread or loss, or their possible functions. In Drosophila melanogaster, two approaches have been used to discover these genes and investigate their properties. One uses traditional comparative approaches and existing genomic resources and annotations. A second approach uses raw transcriptome data to discover unannotated genes for which there is no evidence of presence in related species. Investigations using the second approach have focused on D. melanogaster genotypes from recently established cosmopolitan populations. However, most of the genetic variation in the species is found in African populations, suggesting the possibility that fuller understanding of genetic novelties in the species may follow from studies of these populations. Here we investigate de novo gene candidates expressed in testis and accessory glands in a sample of flies from Zambia and compare them to candidate de novo genes expressed in North American populations. We report a large number of previously undiscovered de novo gene candidates, most of which are expressed polymorphically. Many are predicted to code for secreted proteins. In spite of much different levels of genomic variation in Zambian and North American populations, they express similar numbers of candidate de novo genes. We find evidence from genetic analysis of Raleigh inbred lines that a fraction of rarely expressed gene candidates in this population represent deleterious transcription promoted by inbreeding depression. Many de novo gene candidates are expressed in multiple tissues and both sexes, raising questions about how they may interact with natural selection. The relative importance of positive and negative selection, however, remains unclear.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic regulation of murine RNA Polymerase III transcription during heat shock stress.","authors":"Thomas F Nguyen, James Z J Kwan, Jennifer E Mitchell, Jieying H Cui, Sheila S Teves","doi":"10.1093/genetics/iyaf042","DOIUrl":"https://doi.org/10.1093/genetics/iyaf042","url":null,"abstract":"<p><p>Cells respond to many different types of stresses by overhauling gene expression patterns, both at the transcriptional and translational level. Under heat stress, global transcription and translation are inhibited, while the expression of chaperone proteins are preferentially favored. As the direct link between mRNA transcription and protein translation, tRNA expression is intricately regulated during the stress response. Despite extensive research into the heat shock response (HSR), the regulation of tRNA expression by RNA Polymerase III (Pol III) transcription has yet to be fully elucidated in mammalian cells. Here, we examine the regulation of Pol III transcription during different stages of heat shock stress in mouse embryonic stem cells (mESCs). We observe that Pol III transcription is downregulated after 30 minutes of heat shock, followed by an overall increase in transcription after 60 minutes of heat shock. This effect is more evident in tRNAs, though other Pol III gene targets are also similarly affected. Notably, we show that the downregulation at 30 minutes of heat shock is independent of HSF1, the master transcription factor of the HSR, but that the subsequent increase in expression at 60 minutes requires HSF1. Taken together, these results demonstrate an adaptive RNA Pol III response to heat stress, and an intricate relationship between the canonical HSR and tRNA expression.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Theory of Heterosis.","authors":"Zhao-Bang Zeng, Gabriel De Siqueira Gesteira, Lujia Mo, Yingjie Xiao, Jianbing Yan","doi":"10.1093/genetics/iyaf045","DOIUrl":"https://doi.org/10.1093/genetics/iyaf045","url":null,"abstract":"<p><p>Heterosis refers to the superior performance of a hybrid over its parents. It is the basis for hybrid breeding particularly for maize and rice. Genetically it is due to interactions between alleles of quantitative trait loci (QTL) (dominance and epistasis). Despite enormous interest and efforts to study the genetic basis of heterosis, the relative contribution of dominance vs. epistasis to heterosis is still not clear. This is because most published studies estimate QTL effects in pieces, not able to put them together to assess the overall pattern adequately. We propose a theoretical framework that focuses on the inference of the relationship between genome and traits that includes the identification of multiple QTL and estimation of the whole set of QTL (additive, dominant, and epistatic) effects. Used for heterosis, it gives a clear genetic definition and interpretation of heterosis. We applied the theory and methods to a large maize dataset with a factorial design of many male and female inbred lines and their hybrid crosses. Heterosis of ear weight in maize is primarily due to QTL dominant effects, many are over-dominant. The contribution to heterosis due to epistasis is small and diffused. For comparison, we also analyzed a rice dataset that is an F2-type population derived from a cross between two inbred lines. The result indicates that dominance is still the main contributor to heterosis, and epistasis contribution is small.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human MeCP2 binds to promoters and inhibits transcription in an unmethylated yeast genome.","authors":"Joshua A R Brown, Maggie Y M Ling, Juan Ausió, LeAnn J Howe","doi":"10.1093/genetics/iyaf043","DOIUrl":"https://doi.org/10.1093/genetics/iyaf043","url":null,"abstract":"<p><p>MeCP2 is a DNA-binding transcriptional regulator that is present at near-histone levels in mammalian cortical neurons. Originally identified as a DNA methylation reader, MeCP2 has been proposed to repress transcription by recruiting corepressors to methylated DNA. While some genome-wide occupancy studies support a preference for methylated DNA, others suggest that MeCP2 binding is more influenced by DNA sequence and accessibility than methylation status. Moreover, multiple studies also suggest a role for MeCP2 in gene activation. To clarify its function, we expressed MeCP2 in Saccharomyces cerevisiae, which lacks DNA methylation and known MeCP2 corepressors. We find that MeCP2 is toxic to yeast and globally inhibits transcription, indicating that MeCP2 can have significant functional impacts without DNA methylation or mammalian corepressors. A subset of MeCP2 mutations that cause the neurodevelopmental disorder Rett syndrome, particularly those that map to the DNA binding domain, alleviate the toxicity of MeCP2 in yeast. Consistent with the importance of DNA binding for growth inhibition, we show that MeCP2 binds to the yeast genome, with increased occupancy at GC-rich, nucleosome-depleted sequences. These findings present yeast as a useful tool for analyzing MeCP2 and reveal MeCP2 properties that are not strictly dependent on DNA methylation or mammalian corepressors.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CelEst: a unified gene regulatory network for estimating transcription factor activities in C. elegans.","authors":"Marcos Francisco Perez","doi":"10.1093/genetics/iyae189","DOIUrl":"10.1093/genetics/iyae189","url":null,"abstract":"<p><p>Transcription factors (TFs) play a pivotal role in orchestrating critical intricate patterns of gene regulation. Although gene expression is complex, differential expression of hundreds of genes is often due to regulation by just a handful of TFs. Despite extensive efforts to elucidate TF-target regulatory relationships in Caenorhabditis elegans, existing experimental datasets cover distinct subsets of TFs and leave data integration challenging. Here, I introduce CelEst, a unified gene regulatory network designed to estimate the activity of 487 distinct C. elegans TFs-∼58% of the total-from gene expression data. To integrate data from ChIP-seq, DNA-binding motifs, and eY1H screens, optimal processing of each data type was benchmarked against a set of TF perturbation RNA-seq experiments. Moreover, I showcase how leveraging TF motif conservation in target promoters across genomes of related species can distinguish highly informative interactions, a strategy which can be applied to many model organisms. Integrated analyses of data from commonly studied conditions including heat shock, bacterial infection, and sex differences validates CelEst's performance and highlights overlooked TFs that likely play major roles in coordinating the transcriptional response to these conditions. CelEst can infer TF activity on a standard laptop computer within minutes. Furthermore, an R Shiny app with a step-by-step guide is provided for the community to perform rapid analysis with minimal coding required. I anticipate that widespread adoption of CelEsT will significantly enhance the interpretive power of transcriptomic experiments, both present and retrospective, thereby advancing our understanding of gene regulation in C. elegans and beyond.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wolbachia pipientis modulates germline stem cells and gene expression associated with ubiquitination and histone lysine trimethylation to rescue fertility defects in Drosophila.","authors":"Catherine H Kagemann, Jaclyn E Bubnell, Gabriela M Colocho, Daniela C Arana, Charles F Aquadro","doi":"10.1093/genetics/iyae220","DOIUrl":"10.1093/genetics/iyae220","url":null,"abstract":"<p><p>Wolbachia pipientis are maternally transmitted endosymbiotic bacteria commonly found in arthropods and nematodes. These bacteria manipulate reproduction of the host to increase their transmission using mechanisms, such as cytoplasmic incompatibility, that favor infected female offspring. The underlying mechanisms of reproductive manipulation by W. pipientis remain unresolved. Interestingly, W. pipientis infection partially rescues female fertility in flies containing hypomorphic mutations of bag of marbles (bam) in Drosophila melanogaster, which plays a key role in germline stem cell daughter differentiation. Using RNA-seq, we find that W. pipientis infection in bam hypomorphic females results in differential expression of many of bam's genetic and physical interactors and enrichment of ubiquitination and histone lysine methylation genes. We find that W. pipientis also rescues the fertility and germline stem cell functions of a subset of these genes when knocked down with RNAi in a wild-type bam genotype. Our results show that W. pipientis interacts with ubiquitination and histone lysine methylation genes which could be integral to the mechanism by which W. pipientis modulates germline stem cell gene function.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trait genetic architecture and population structure determine model selection for genomic prediction in natural Arabidopsis thaliana populations.","authors":"Patrick M Gibbs, Jefferson F Paril, Alexandre Fournier-Level","doi":"10.1093/genetics/iyaf003","DOIUrl":"10.1093/genetics/iyaf003","url":null,"abstract":"<p><p>Genomic prediction applies to any agro- or ecologically relevant traits, with distinct ontologies and genetic architectures. Selecting the most appropriate model for the distribution of genetic effects and their associated allele frequencies in the training population is crucial. Linear regression models are often preferred for genomic prediction. However, linear models may not suit all genetic architectures and training populations. Machine learning approaches have been proposed to improve genomic prediction owing to their capacity to capture complex biology including epistasis. However, the applicability of different genomic prediction models, including non-linear, non-parametric approaches, has not been rigorously assessed across a wide variety of plant traits in natural outbreeding populations. This study evaluates genomic prediction sensitivity to trait ontology and the impact of population structure on model selection and prediction accuracy. Examining 36 quantitative traits in 1,000+ natural genotypes of the model plant Arabidopsis thaliana, we assessed the performance of penalized regression, random forest, and multilayer perceptron at producing genomic predictions. Regression models were generally the most accurate, except for biochemical traits where random forest performed best. We link this result to the genetic architecture of each trait-notably that biochemical traits have simpler genetic architecture than macroscopic traits. Moreover, complex macroscopic traits, particularly those related to flowering time and yield, were strongly correlated to population structure, while molecular traits were better predicted by fewer, independent markers. This study highlights the relevance of machine learning approaches for simple molecular traits and underscores the need to consider ancestral population history when designing training samples.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}