PLoS Genetics最新文献

{"title":"Glycolytic disruption restricts Drosophila melanogaster larval growth via the cytokine Upd3.","authors":"Madhulika Rai, Hongde Li, Robert A Policastro, Robert Pepin, Gabriel E Zentner, Travis Nemkov, Angelo D'Alessandro, Jason M Tennessen","doi":"10.1371/journal.pgen.1011690","DOIUrl":"10.1371/journal.pgen.1011690","url":null,"abstract":"<p><p>Drosophila larval growth requires efficient conversion of dietary nutrients into biomass. Lactate dehydrogenase (Ldh) and glycerol-3-phosphate dehydrogenase (Gpdh1) support this larval metabolic program by cooperatively promoting glycolytic flux. Consistent with their cooperative functions, the loss of both enzymes, but not either single enzyme alone, induces a developmental arrest. However, Ldh and Gpdh1 exhibit complex and often mutually exclusive expression patterns, suggesting that the lethal phenotypes exhibited by Gpdh1; Ldh double mutants could be mediated non-autonomously. Supporting this possibility, we find that the developmental arrest displayed by double mutants extends beyond simple metabolic disruption and instead stems, in part, from changes in systemic growth factor signaling. Specifically, we demonstrate that the simultaneous loss of Gpdh1 and Ldh results in elevated expression of Upd3, a cytokine involved in Jak/Stat signaling. Furthermore, we show that upd3 loss-of-function mutations suppress the Gpdh1; Ldh larval arrest phenotype, indicating that Upd3 signaling restricts larval development in response to decreased glycolytic flux. Together, our findings reveal a mechanism by which metabolic disruptions can modulate systemic growth factor signaling.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 5","pages":"e1011690"},"PeriodicalIF":4.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035946","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":"Heat inducible nuclear translocation of Kdm6bb drives temperature dependent sex reversal in Nile tilapia.","authors":"Jigang Lu, Siqi Huang, Shicen Wei, Jiangbo Cheng, Wei Li, Yueyue Fei, Jihui Yang, Ruiqin Hu, Songqian Huang, Wanying Zhai, Zhichao Wu, Mingli Liu, Qianghua Xu, Peng Hu, Liangbiao Chen","doi":"10.1371/journal.pgen.1011664","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011664","url":null,"abstract":"<p><p>Understanding the primary molecular events driving temperature-dependent sex reversal (TSR) has proven challenging, particularly in distinguishing these from secondary effects of sexual differentiation. The mechanisms translating temperature into a sex-determining signal in fish are still largely unknown. Through combined transcriptomic and genome-wide histone methylation analyses of gonads in Nile tilapia (Oreochromis niloticus) exposed to normal and elevated temperatures, we observed significant upregulation of male-promoting genes (amh, dmrt1, gsdf) and suppression of female-promoting genes (wt1a and foxl3) at high temperature. These changes were correlated with methylation changes in H3K27 and H3K4 in the promoter regions of these genes. Among the histone methylation enzymes induced by high temperature, we identified the H3K27 demethylase Kdm6bb to be a key factor. Gene deletion and biochemical studies confirmed that Kdm6bb significantly impacts the H3K27 methylation level, that influences sex determination. Crucially, we discovered that the TSR function of Kdm6bb is mediated by the alternative inclusion of a previously unrecognized intron, enabling nuclear translocation of the demethylase to perform its function. Our findings refute the previously proposed \"translation deficiency\" mechanism of kdm6bb, and highlight the critical role of mRNA alternative splicing and subcellular localization of the demethylase in temperature-induced sex reversal.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011664"},"PeriodicalIF":4.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051560","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":"Probing the limits of cis-acting gene regulation using a model of allelic imbalance quantitative trait loci.","authors":"Cathal Seoighe, Seán Connaire, Mehak Chopra","doi":"10.1371/journal.pgen.1011446","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011446","url":null,"abstract":"<p><p>Imbalance in gene expression between alleles is a hallmark of cis-acting expression quantitative trait loci (eQTLs) and several methods have been developed to exploit allelic imbalance to support the identification of eQTLs. Allelic imbalance is also of scientific and, potentially, clinical interest as it can erode the degree to which the effects of deleterious variants are buffered in a diploid organism and has been reported to be associated with the penetrance of pathological genomic variants. Here, we develop and apply a statistical model that is designed to evaluate whether the genotype of a locus is associated with the degree of allelic imbalance of a gene and refer to such loci as allelic imbalance quantitative trait loci (aiQTLs). An advantage of our approach is that it does not depend on linkage disequilibrium between the aiQTL and the associated gene and is, therefore, suited to the identification of eQTLs that act in cis over very large distances. We applied our model to data from the GTEx consortium and examined the relationship between the distance of an eQTL from the TSS of the associated gene and the evidence that the eQTL acts in cis. Previous studies have used a distance of 1Mb from the target gene as an indication that an eQTL acts in cis; however, our results suggest that the majority of eQTLs at distances more than 500 kb from the TSS of the target gene are likely to act in trans (and thus to affect both gene copies). The model used here is also well suited to comparing the overall extent of allelic imbalance between samples. We show that in some tissues allelic imbalance is correlated with age; however, this correlation may be due to changes in the abundance of immune cell populations with age, as we found strong correlations between sample-level allelic imbalance and the inferred abundance of multiple immune cell types across whole blood samples.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011446"},"PeriodicalIF":4.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027480","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":"In vivo AGO-APP identifies a module of microRNAs cooperatively preserving neural progenitors.","authors":"Karine Narbonne-Reveau, Andrea Erni, Norbert Eichner, Shobana Sankar, Surbhi Kapoor, Gunter Meister, Harold Cremer, Cédric Maurange, Christophe Beclin","doi":"10.1371/journal.pgen.1011680","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011680","url":null,"abstract":"<p><p>MicroRNAs are essential regulators of gene expression. Their function is particularly important during neurogenesis, when the production of large numbers of neurons from a limited number of neural stem cells depends on the precise control of determination, proliferation and differentiation. However, microRNAs can target many mRNAs and vice-versa, raising the question of how specificity is achieved to elicit a precise regulatory response. Here we introduce in vivo AGO-APP, a novel approach to purify Argonaute-bound, and therefore active microRNAs from specific cell types. Using AGO-APP in the larval Drosophila central nervous system, we identify a module of microRNAs predicted to redundantly target all iconic genes known to control the transition from neuroblasts to neurons. While microRNA overexpression generally validated predictions, knockdown of individual microRNAs did not induce detectable phenotypes. In contrast, neuroblasts were induced to differentiate precociously when several microRNAs were knocked down simultaneously. Our data supports the concept that at physiological expression levels, the cooperative action of miRNAs allows efficient targeting of entire gene networks.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011680"},"PeriodicalIF":4.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021208","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":"Disentangling the mutational effects on protein stability and interaction of human MLH1.","authors":"Sven Larsen-Ledet, Aleksandra Panfilova, Amelie Stein","doi":"10.1371/journal.pgen.1011681","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011681","url":null,"abstract":"<p><p>Missense mutations can have diverse effects on proteins, depending on their location within the protein and the specific amino acid substitution. Mutations in the DNA mismatch repair gene MLH1 are associated with Lynch syndrome, yet the underlying mechanism of most disease-causing mutations remains elusive. To address this gap, we aim to disentangle the mutational effects on two essential properties for MLH1 function: protein stability and protein-protein interaction. We systematically examine the cellular abundance and interaction with PMS2 of 4839 (94%) MLH1 variants in the C-terminal domain. Our combined data shows that most MLH1 variants lose interaction with PMS2 due to reduced cellular abundance. However, substitutions to charged residues in the canonical interface lead to reduced interaction with PMS2. Unexpectedly, we also identify a distal region in the C-terminal domain of MLH1 where substitutions cause both decreased and increased binding with PMS2, and propose a region in PMS2 as the binding site. Our data correlate with clinical classifications of benign and pathogenic MLH1 variants and align with thermodynamic stability predictions and evolutionary conservation. This work provides mechanistic insights into variant consequences and may help interpret MLH1 variants.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011681"},"PeriodicalIF":4.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044073","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":"Meiotic divisions and round spermatid formation do not require centriole duplication in mice.","authors":"Marnie W Skinner, Paula B Nhan, Carter J Simington, Philip W Jordan","doi":"10.1371/journal.pgen.1011698","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011698","url":null,"abstract":"<p><p>Centrosomes, composed of centrioles and pericentriolar matrix proteins, are traditionally viewed as essential microtubule-organizing centers (MTOCs) that facilitate bipolar spindle formation and chromosome segregation during spermatogenesis. In this study, we investigated the role of centrioles in male germ cell development by using a murine conditional knockout (cKO) of Sas4, a critical component of centriole biogenesis. We found that while centriole duplication was impaired in Sas4 cKO spermatocytes, these cells were still capable of progressing through meiosis I and II. Chromosome segregation was able to proceed through the formation of a non-centrosomal MTOC, indicating that centrioles are not required for meiotic divisions. However, spermatids that inherited fewer than two centrioles exhibited severe defects in spermiogenesis, including improper manchette formation, constricted perinuclear rings, disrupted acrosome morphology, and failure to form flagella. Consequently, Sas4 cKO males were infertile due to the absence of functional spermatozoa. Our findings demonstrate that while centrioles are dispensable for meiosis in male germ cells, they are essential for spermiogenesis and sperm maturation. This work provides key insights into the role of centrosomes in male fertility and may have implications for understanding certain conditions of male infertility associated with centriole defects.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011698"},"PeriodicalIF":4.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018274","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":"Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.","authors":"Xiaomeng Yang, Ruichen Wei, Fanfan Meng, Dianchen Liu, Xuan Gong, Gary Ruvkun, Wei Wei","doi":"10.1371/journal.pgen.1011678","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011678","url":null,"abstract":"<p><p>Mitochondrial fission and fusion are tightly regulated to specify mitochondrial abundance, localization, and arrangement during cell division as well as in the diverse differentiated cell types and physiological states. However, the regulatory pathways for such mitochondrial dynamics are less explored than the mitochondrial fission and fusion components. Here we report a large-scale screen for genes that regulate mitochondrial fission. Mitochondrial fission defects cause a characteristic uneven fluorescent pattern in embryos carrying mitochondrial stress reporter genes. Using this uneven activation, we performed RNAi screens that identified 3 kinase genes from a ~ 500-kinase library and another 11 genes from 3,300 random genes that function in mitochondrial fission. Many of these identified genes play roles in chromosome segregation. We found that chromosome missegregation and genome instability lead to dysregulation of mitochondrial fission, possibly independent of DRP-1. ATL-1, the C. elegans ATR orthologue, plays a potentially protective role in alleviating the mitochondrial fission defect caused by chromosome missegregation. This establishes a screening paradigm for identifying mitochondrial fission regulators, which reveals the potential role of ATR in surveilling mitochondrial fission to mitigate dysregulation caused by improper chromosome segregation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011678"},"PeriodicalIF":4.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021791","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":"Isolating selective from non-selective forces using site frequency ratios.","authors":"Jody Hey, Vitor A C Pavinato","doi":"10.1371/journal.pgen.1011427","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011427","url":null,"abstract":"<p><p>A new method is introduced for estimating the distribution of mutation fitness effects using site frequency spectra. Unlike previous methods, which make assumptions about non-selective factors, or that try to incorporate such factors into the underlying model, this new method mostly avoids non-selective effects by working with the ratios of counts of selected sites to neutral sites. An expression for the likelihood of a set of selected/neutral ratios is found by treating the ratio of two Poisson random variables as the ratio of two gaussian random variables. This approach also avoids the need to estimate the relative mutation rates of selected and neutral sites. Simulations over a wide range of demographic models, with linked selection effects show that the new SFRatios method performs well for statistical tests of selection, and it performs well for estimating the distribution of selection effects. Performance was better with weak selection models and for expansion and structured demographic models than for bottleneck models. Applications to two populations of Drosophila melanogaster reveal clear but very weak selection on synonymous sites. For nonsynonymous sites, selection was found to be consistent with previous estimates and stronger for an African population than for one from North Carolina.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011427"},"PeriodicalIF":4.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027314","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":"Mammary gland multi-omics data reveals new genetic insights into milk production traits in dairy cattle.","authors":"Wentao Cai, John B Cole, Michael E Goddard, Junya Li, Shengli Zhang, Jiuzhou Song","doi":"10.1371/journal.pgen.1011675","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011675","url":null,"abstract":"<p><p>Although many sequence variants have been discovered in cattle, deciphering the relationship between genome and phenome remains a significant challenge. In this study, we identified functional classes, including mammary-specific genes, lactation-associated genes, novel long non-coding RNAs, miRNAs, RNA editing sites, DNA methylation, histone modifications, and expression quantitative trait loci. We estimated their contributions to genetic variance for milk production traits using 3 million variants in 23,566 Holstein bulls. Sequence variants in the 5'-UTR, synonymous, and splicing regions disproportionately contributed to genetic variance of milk production traits compared to other genomic regions. Genes specifically expressed in the mammary gland, particularly those active in lactating tissue (e.g., GLYCAM1, DGAT1), account for significantly more genetic variance of milk production traits than specific genes from non-mammary tissues. We identified 8,560 differentially expressed genes (DEGs) between lactating and non-lactating tissues. Among these, both up-regulated and small-fold changes of down-regulated DEGs exhibited greater genetic variance enrichment of milk production traits than other genes. Mammary enhancers (e.g., H3K27ac, H3K4Me1) explained more variance than repressive elements, while small changes in DNA methylation level (≤0.2) contributed more variance than that with larger changes (> 0.2). Notably, lactation-associated RNA editing sites in mammary explained more variance for milk production traits than expected by chance. We proposed a novel miRNA prioritization strategy for selecting candidate miRNAs related to milk production traits, based on the overlaps between significant enrichment tests of miRNA target correlations and the relatively large variance explained by these targets. Additionally, we integrated these nine functional classes into the variance component analysis simultaneously, revealing that sQTLs, histone modification and DEGs showed the highest per-SNP variance enrichment. Finally, we constructed a new 624K SNP panel, which improved the reliabilities of genomic predictions by 0.22%. Dividing routine SNPs into two groups based on functional classes improved the reliabilities by 0.21%, particularly for milk protein percentage (0.68% improvement). Overall, incorporating prior biological knowledge of the mammary gland directly enhances our understanding of milk production's genetic architecture and improves the reliability of genomic predictions for milk production traits. This integrative approach establishes a paradigm for translating biological knowledge into agricultural genomics applications.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011675"},"PeriodicalIF":4.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035945","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":"Myelin regulatory factor (MYRF) is a critical early regulator of retinal pigment epithelial development.","authors":"Michelle L Brinkmeier, Su Qing Wang, Hannah A Pittman, Leonard Y Cheung, Lev Prasov","doi":"10.1371/journal.pgen.1011670","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011670","url":null,"abstract":"<p><p>Myelin regulatory factor (Myrf) is a critical transcription factor in early retinal and retinal pigment epithelial development, and human variants in MYRF are a cause for nanophthalmos. Single cell RNA sequencing (scRNAseq) was performed on Myrf conditional knockout mice (Rx > Cre Myrffl/fl) at 3 developmental timepoints. Myrf was expressed specifically in the RPE, and expression was abrogated in Rx > Cre Myrffl/fl eyes. scRNAseq analysis revealed a loss of RPE cells at all timepoints resulting from cell death. GO-term analysis in the RPE revealed downregulation of melanogenesis and anatomic structure morphogenesis pathways, which were supported by electron microscopy and histologic analysis. Novel structural target genes including Ermn and Upk3b, along with macular degeneration and inherited retinal disease genes were identified as downregulated, and a strong upregulation of TGFß/BMP signaling and effectors was observed. Regulon analysis placed Myrf downstream or parallel to Pax6 and Mitf and upstream of Sox10 in RPE differentiation. Together, these results suggest a strong role for MYRF in the RPE maturation by regulating melanogenesis, cell survival, and cell structure, in part acting through suppression of TGFß signaling and activation of Sox10.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011670"},"PeriodicalIF":4.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027315","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}