PLoS Genetics最新文献

{"title":"Design and interpretation of eQTL-GWAS colocalisation studies: Lessons from a large-scale evaluation.","authors":"Guillermo Reales, Jeffrey M Pullin, Ichcha Manipur, Elena Vigorito, Chris Wallace","doi":"10.1371/journal.pgen.1012141","DOIUrl":"https://doi.org/10.1371/journal.pgen.1012141","url":null,"abstract":"<p><p>Colocalisation analysis integrates GWAS and molecular QTL datasets to identify candidate effector genes. Even with a wide range of molecular QTLs, 40% or more of GWAS loci remain unexplained, leaving a \"colocalisation gap\". We systematically characterised two large-scale eQTL colocalisation studies, to describe the determinants of this gap and ultimately inform the selection and design of eQTL studies to close the gap. We analyse over 1.3 million colocalisation tests from Open Targets Genetics (OTG) and perform and analyse colocalisations from 14 immune-mediated disease (IMD) GWAS and 12 diverse immune cell eQTL studies, selected to cover a range of cellular granularities and sample sizes. We find that 50% of GWAS peaks in OTG and 34% in IMDs colocalised and were more likely to colocalise if they were located nearer to genes and had a more common lead variant. Colocalisation was also more likely to occur in disease relevant tissues. The lowest granularity immune cell eQTL studies had the largest sample sizes, the greatest eQTL discovery and produced the largest number of colocalisations, particularly for lower-frequency variants. However, while higher resolution eQTL studies detected fewer eQTLs, each of those eQTLs was more likely to colocalise with a GWAS peak, emphasising the importance of cell specific eQTLs. Indeed, over 50% of colocalisations were found in only one cell type. Overall, our results suggest that a diverse set of cells in different contexts, and large, high granularity studies will be needed to identify remaining colocalisations. In addition, we observed that 47% of GWAS peaks colocalised with multiple genes in OTG and 37% in IMDs. Through simulations, sensitivity analyses, and integration of enhancer-promoter capture data we find that multiple colocalisations likely represent coregulation. While disentangling causality from horizontal pleiotropy will ultimately require experimental perturbation, triangulation using different sources of observational data is likely to be necessary for gene prioritisation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 5","pages":"e1012141"},"PeriodicalIF":3.7,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856691","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":"Simulated sample splitting approach to address biases due to instrument selection and participant overlap in two-sample Mendelian Randomization studies.","authors":"Amanda Forde, Gibran Hemani, John Ferguson","doi":"10.1371/journal.pgen.1011949","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011949","url":null,"abstract":"<p><p>Mendelian randomization (MR) is a popular statistical technique that uses genetic variants to explore causal relationships in observational epidemiology. Summary-level MR, the most common form, relies on published GWAS summary statistics to estimate causal effects between exposures and outcomes. However, empirical analyses tend to ignore issues relating to Winner's Curse of instrument effects, weak instrument bias and sample overlap. Our simulations and empirical analyses using the UK Biobank indicate that such mechanisms can induce substantial bias in routine MR approaches. We propose MR Simulated Sample Splitting (MR-SimSS), a novel method that corrects this bias requiring no additional data beyond GWAS summary statistics for the exposure and outcome of interest. It operates by simulating statistically independent sets of summary statistics, analogous to what would be produced by splitting the individual-level data into independent subsets, which can then be plugged into existing two-sample MR methods. With sufficient instrument variants, MR-SimSS is robust to a range of sample overlap scenarios, providing a practical and modular solution to Winner's Curse and weak instrument bias.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 5","pages":"e1011949"},"PeriodicalIF":3.7,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856964","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":"Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterations.","authors":"Chang Liu, Sofya Golenkina, Natasha Fahey, Priya Kumar, Louise Y Cheng","doi":"10.1371/journal.pgen.1012150","DOIUrl":"https://doi.org/10.1371/journal.pgen.1012150","url":null,"abstract":"<p><p>Cancer cachexia is a multifactorial syndrome characterized by systemic metabolic dysfunction, including liver steatosis. In this study, we examined the role of larval oenocytes - hepatocyte-like cells, in a Drosophila model of cancer cachexia. We found that oenocytes in tumour-bearing larvae accumulate lipid droplets in response to tumour-secreted signals, Gbb and ImpL2. This lipid accumulation reflects systemic changes in lipid metabolism, responding to lipid metabolism manipulations in either the fat body or the muscle. Disrupting lipid synthesis/breakdown (via FASN1 and Bmm), storage (via Lsd2), or trafficking (via apolipoproteins) in these tissues significantly modulated lipid droplet accumulation in oenocytes. Moreover, oenocyte-specific knockdown of FASN1 reduced their lipid content and non-autonomously affected lipid droplet size in the fat body, suggesting cross-regulatory interactions between these tissues. Cachectic oenocytes also exhibited altered signaling profiles, characterized by reduced PI3K signalling. Enhancing PI3K signalling through Akt overexpression restored oenocyte size and reduced lipid levels; however, these changes did not significantly improve muscle integrity. Together, our data suggests that dynamic exchange of lipids occur between the fat body, oenocytes and the muscle during cancer cachexia. While the fat body and muscle lipid pools are key regulators of muscle integrity, oenocytes - despite their metabolic responsiveness, do not appear to play an active role in preserving muscle function during cachexia.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 5","pages":"e1012150"},"PeriodicalIF":3.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845035","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":"Tissue-specific transfer learning improves functional variant and therapeutic target discoveries in breast and prostate cancer.","authors":"Qing Li, Dinghao Wang, Zilong Zhang, Deshan Perera, Zhishan Chen, Wanqing Wen, M Ethan MacDonald, Weijia Cai, Jun Yan, Xiao-Ou Shu, Wei Zheng, Xingyi Guo, Quan Long","doi":"10.1371/journal.pgen.1012145","DOIUrl":"https://doi.org/10.1371/journal.pgen.1012145","url":null,"abstract":"<p><p>DNA foundation models trained on large-scale genomic and epigenomic datasets have shown promise for regulatory variant interpretation, yet their application to tissue-specific contexts remain limited. Here, we present a transfer learning (TL) framework to adapt Enformer, a deep neural network trained on 5,313 multi-omics tracks, to breast and prostate cancer using 275 and 357 tissue-specific transcription factor (TF) ChIP-seq tracks, respectively. We computed tissue-specific cis-regulatory activity (tCRA) scores for millions of single-nucleotide variants (SNVs) in genome-wide association study (GWAS) datasets and prioritized high-impact SNV subsets (1M, 1.5M, and 2M). These TL-prioritized variants demonstrated consistently greater enrichment in tissue-specific enhancers, cancer GWAS risk variants, and ClinVar pathogenic variants compared to the original Enformer model. Transcriptome-wide association studies (TWAS) using TL-based SNVs identified more cancer-relevant genes, many of which exhibited functional essentiality (DepMap), therapeutic tractability (drug databases), and disease relevance (DisGeNET). Notably, TL models outperformed the base model in identifying genes enriched for drug targets and clinically relevant disease associations. Our results show that TL-derived tCRA scores enhance regulatory variant prioritization and improve susceptibility gene discovery in a tissue-specific manner. Our study provides a generalizable framework for tailoring foundation models to disease-relevant contexts, with implications for variant interpretation, therapeutic target discovery, and precision medicine.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 5","pages":"e1012145"},"PeriodicalIF":3.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844970","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":"Correction: The foraging gene coordinates brain and heart networks to modulate socially cued interval timing in Drosophila.","authors":"Hongyu Miao, Wenjing Li, Yongwen Huang, Woo Jae Kim","doi":"10.1371/journal.pgen.1012140","DOIUrl":"https://doi.org/10.1371/journal.pgen.1012140","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1371/journal.pgen.1011752.].</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 5","pages":"e1012140"},"PeriodicalIF":3.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844963","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":"KAT6A is essential for developmental control gene expression in neural stem and progenitor cells.","authors":"Anne K Voss, Samantha Eccles, Johannes Wichmann, Waruni Abeysekera, Maria I Bergamasco, Alexandra L Garnham, Nishika Ranathunga, Yuqing Yang, Rory Bowden, Gordon K Smyth, Tim Thomas","doi":"10.1371/journal.pgen.1012133","DOIUrl":"https://doi.org/10.1371/journal.pgen.1012133","url":null,"abstract":"<p><p>Heterozygous variants in the KAT6A gene encoding the histone lysine acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome, a cognitive impairment syndrome. Histone acetylation is generally associated with active gene transcription. Genetic deletion of both alleles of the Kat6a gene in mice causes developmental defects including anterior homeotic transformation, cleft palate, interrupted aortic arch and cardiac septal defects. Loss of KAT6A impairs expression of HOX, DLX and TBX genes, which are essential for body segment identity specification, palate, heart and aortic arch development. However, the effects of loss of KAT6A on chromatin modifications and gene expression in neural cells, which are relevant to normal brain development and function, is still poorly understood. In this study, we used an automated high-throughput chromatin profiling method and RNA sequencing in mouse neural system and progenitor cells to assess the effects of loss of one or two alleles of Kat6a on gene expression, histone acetylation and methylation. We also assessed occupancy by a trithorax group protein and RNA polymerase II. Our data suggests two modes of action for KAT6A: (1) acetylation of histone H3 on lysine 23 at promoters and enhancers and (2) recruitment of the trithorax group protein MLL1 (KMT2A) to promote the expression of developmental genes, including SOX and homeodomain genes. Together, these two functions appear to be required for normal gene expression in neural progenitors and essential for proliferation and neuronal differentiation.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 5","pages":"e1012133"},"PeriodicalIF":3.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel role of tRNA-derived fragments in porcine granulosa-oocyte cell communication and cuproptosis.","authors":"Linyuan Shen, Xue Zhao, Shuang Wu, Yuhang Lei, Shuang Liang, Saihao Wang, Haodong Dai, Yan Wang, Lei Chen, Ye Zhao, Mailin Gan, Shijun Xiao, Guangbin Zhou, Li Zhu","doi":"10.1371/journal.pgen.1012119","DOIUrl":"https://doi.org/10.1371/journal.pgen.1012119","url":null,"abstract":"<p><p>Copper is essential for reproductive function, yet its accumulation can lead to cytotoxicity and cuproptosis. However, the specific molecular mechanisms underlying granulosa cell cuproptosis and follicular atresia remain unclear. Particularly, the molecular pathway by which tRNA-derived fragments (tRFs), recognized as crucial epigenetic regulators, are involved in the regulation of granulosa cell cuproptosis requires further elucidation. In this study, we indicated that copper accumulation disrupted mitochondrial respiration and protein lipoylation, resulting in impaired mitochondrial TCA cycling and subsequent cellular metabolic imbalance. Furthermore, a direct correlation was identified between tRFs and copper homeostasis. Functional analysis demonstrated that tRF-Gly-M3, produced by angiopoietin (ANG) splicing, was significantly upregulated in granulosa cells cuproptosis, and impaired mitochondrial function to induce cuproptosis by silencing the expression of GLS mRNA. tRF-Gly-M3 in exosomes secreted by cuproptosis-induced granulosa cells was high expression, and these exosomes could be delivered into oocytes. tRF-Gly-M3 also impaired oocytes mitochondrial metabolic function, inhibited oocytes maturation, first polar body extrusion and parthenogenesis via silencing GLS mRNA. Overall, our findings indicated that tRFs from granulosa cells could be intercellularly delivered to oocytes, effectively regulating oocyte development.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 4","pages":"e1012119"},"PeriodicalIF":3.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13132174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147822703","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":"The RCAR12-CAP1-OST1 module controls ABA-mediated stomatal closure in Arabidopsis.","authors":"Xiaoyi Li, Qian Zhang, Jiangjie Kang, Lianxin Jiang, Yihan Feng, Juan Du, Chaowen Xiao, Jianglan Wei, Qirong Wen, Ying Wang, Jianmei Wang, Yi Yang","doi":"10.1371/journal.pgen.1012092","DOIUrl":"https://doi.org/10.1371/journal.pgen.1012092","url":null,"abstract":"<p><p>Phytohormone abscisic acid (ABA) induces the stomatal closure in plants under drought stress, a process requiring actin reorganization. Yet how ABA perception couples with cytoskeletal dynamics in stomatal closure remains unclear. In this study, we report that Arabidopsis cyclase-associated protein 1 (CAP1) functions as a negative regulator of ABA-induced drought responses through modulating actin network organization in Arabidopsis. Further analyses demonstrate that CAP1 interacts with RCAR12 suppresses actin filaments (F-actin) disassembly, whereas ABA disrupts the CAP1-RCAR12 interaction, thus recovering CAP1's depolymerization activity. Further, ABA-activated OST1 (OPEN STOMATA 1) phosphorylates CAP1 in Arabidopsis. OST1-mediated phosphorylation of CAP1 attenuates CAP1 binding to ADF4 and inhibits the ADF4-CAP1 complex. This inhibition leads to F-actin stabilization, which in turn maintains stomata in a closed state. This study demonstrates that CAP1 orchestrates ABA-induced stomatal closure under drought stress in Arabidopsis. Specifically, CAP1 acts by coupling ABA signaling to dynamic reorganization of actin cytoskeleton.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 4","pages":"e1012092"},"PeriodicalIF":3.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786737","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 positive feedback loop between sensory and octopaminergic neurons underlies nociceptive plasticity in Drosophila larvae.","authors":"Jean-Christophe Boivin, Yi Q Zhao, Jiayi Zhu, Jared T Dakin, Jing Ning, Tomoko Ohyama","doi":"10.1371/journal.pgen.1012122","DOIUrl":"10.1371/journal.pgen.1012122","url":null,"abstract":"<p><p>Adaptive modulation of nociceptive behaviour based on prior experience is essential for responding effectively to environmental threats. In Drosophila larvae, nociceptive escape behaviours are robust and stereotyped, yet emerging evidence suggests this can be modulated by experience and internal state. Here, we demonstrate that repeated activation of nociceptive sensory neurons enhances both the likelihood and intensity of nocifensive rolling, reflecting a form of behavioural sensitization. This heightened responsiveness is accompanied by a sustained increase in activity within nociceptive sensory neurons, suggesting that plasticity arises, at least in part, within the sensory compartment. We identified the neuromodulator octopamine as a critical regulator of the sensitization: signalling through the octopamine receptor OAMB is required to sustain elevated nociceptive gain, and feedback from one of octopaminergic neurons class, the ventral unpaired median (VUM) neurons, amplifies sensory neuron output. Together, these findings reveal an experience-dependent positive feedback loop in the nociceptive system, where neuromodulatory circuits tune behavioural output.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 4","pages":"e1012122"},"PeriodicalIF":3.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13152156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786705","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":"INS-17 acts as a nutrient deprivation signal to mediate adult IIS-regulated associative behaviors in C. elegans.","authors":"Emily J Leptich, Priyadharshini Vijayakumar, Edward W Pietryk, Meredith I Williams, Rachana Rajupalem, Rachel N Arey","doi":"10.1371/journal.pgen.1012130","DOIUrl":"10.1371/journal.pgen.1012130","url":null,"abstract":"<p><p>Insulin/Insulin-like growth factor 1 (IGF-1) signaling (IIS) is a pleiotropic signaling pathway that functions across tissues to coordinate phenotypic changes in response to nutrient status. Thus, the ubiquity of the IIS pathway hinders efforts to elucidate the mechanisms driving specific IIS-related phenotypes. Previous research in the nematode worm C. elegans has demonstrated that loss of function of the IIS transmembrane receptor (IR) ortholog, DAF-2, results in a doubled lifespan and enhanced learning and memory behaviors in young and aged animals. However, these findings are the result of reducing DAF-2 receptor function rather than modulating ligand-receptor interactions. In the current study, we aimed to dissect ligand-receptor interactions that may regulate associative behaviors apart from canonical IIS lifespan phenotypes in C. elegans. To this end, we performed targeted genetic screening of Insulin-like Peptides (ILPs) previously identified as DAF-2 antagonists to test their role in learning and memory phenotypes. We discovered that only a single uncharacterized ILP, INS-17, is required for learning and memory. We also demonstrate that INS-17 is sufficient to confer extended memory ability and can promote the maintenance of learning and memory with age. Additionally, we observe that INS-17 regulates associative behaviors independent of lifespan, uncoupling some IIS-mutant phenotypes. We find that regulation of the ins-17 genetic locus explains its unique requirement among ILPs for learning and memory behaviors. Finally, we found that INS-17 acts to signal a state of nutrient deprivation. This activity is required to properly process stimulus valence to promote advantageous behaviors. Our findings deepen the understanding of how IIS can regulate specific phenotypic outputs in response to changes in internal metabolic states.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"22 4","pages":"e1012130"},"PeriodicalIF":3.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786664","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}