PLoS Genet. [JOURNAL]
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200 papers
Rare heterozygous missense variants in VSX2 are associated with retinal detachment.
Brock DC, Dhindsa JS, Chen Y … +13 more , Ravanmehr V, Mitchell J, Hu F, Li X, Nandigam L, Wang Q, Wu K, Butts JC, Dhindsa HS, Frankfort BJ, Tran NM, Petrovski S, Dhindsa RS
PLoS Genet · 2026 Feb · PMID 41632798 · Full text
Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architectu...
Retinal detachment (RD) is a sight-threatening emergency requiring urgent intervention to prevent permanent vision loss. While both environmental and genetic risk factors contribute to RD, its complete genetic architecture remains unknown. Here, we performed the largest whole genome sequencing-based case-control study in RD to date, including data from 7,276 RD cases and 236,741 controls in the UK Biobank. Through variant- and gene-level association analyses, we identified VSX2 as a genetic determinant of RD risk while confirming established associations including FAT3, RDH5, and COL2A1. Gene-level collapsing analysis revealed that rare heterozygous missense variants in VSX2 confer a 2.8-fold increased risk of RD (p = 2.4x10-10; odds ratio (OR) = 2.8; 95% confidence interval (CI): [2.1, 3.7]). One missense variant in this gene, p.Glu218Asp, demonstrated a particularly strong effect size (p = 9.3x10-10; OR = 5.9; 95% CI: [3.7, 9.4]). Replication analyses in two additional cohorts, totaling 1,331 cases and 52,355 controls strengthened both the gene- and variant-level associations even further (p = 1.4x10-10 and 1.1x10-11, respectively). Other contributory heterozygous variants included previously reported pathogenic homozygous variants for anophthalmia and microphthalmia. These findings thus reveal a previously unknown gene dosage curve for VSX2, where homozygous mutations cause severe developmental eye disorders and heterozygous mutations cause adult-onset retinal detachment. Extending this observation, we found a significant enrichment for other known recessive Mendelian eye disease genes among nominally significant (p < 0.05) genes associated with RD in the collapsing analysis. This work provides a compelling example of how heterozygous variants in recessive disease genes can be associated with less severe clinical phenotypes.
Using TraDIS as a complementary approach to long term evolution for mapping adaptive mutations in Escherichia coli.
Milner MT, Sen H, Banzhaf M … +1 more , Lund PA
PLoS Genet · 2026 Feb · PMID 41628264 · Full text
Long term laboratory-based evolution experiments are a powerful tool that are increasingly being used to study fundamental aspects of evolution and to identify genes that contribute to overall fitness under different con...
Long term laboratory-based evolution experiments are a powerful tool that are increasingly being used to study fundamental aspects of evolution and to identify genes that contribute to overall fitness under different conditions. However, even with automation, the time that they take to execute limits the extent to which evolution experiments can be used as part of a high throughput approach to understand the links between genotype and phenotype. Mutations that lead to genetic loss of function (LoF) are frequently selected for in evolution experiments. Thus, in principle these experiments could be done more rapidly by starting not with clonal isolates but with dense transposon libraries that will contain loss of function mutations in all non-essential genes. Here, we test this hypothesis by comparing the results of long term (5 month) evolution experiment, in which E. coli was grown with daily transfers in unbuffered LB starting at pH 4.5, with short term (5 and 10 day) experiments on a high-density transposon library in the same strain and under the same conditions. We show that there is a overlap in the genes and pathways identified using the two methods, as well as identifying other gene of interest whose LoF contributes to fitness. This approach has the potential to complement laboratory-based evolution, enabling rapid, higher throughput, testing of a wide range of parameters that may have an influence on evolutionary trajectories.
The regenerative period of somatosensory nerves is closed by a DCC signaling axis.
Hammer J, Smith CJ
PLoS Genet · 2026 Feb · PMID 41628252 · Full text
Tissues and organs have periods of plasticity that close with age. While period closures can lock in tissue architecture and prevent aberrant cellular interactions, they also limit regenerative capacity. These regenerati...
Tissues and organs have periods of plasticity that close with age. While period closures can lock in tissue architecture and prevent aberrant cellular interactions, they also limit regenerative capacity. These regenerative periods - a timeframe with regeneration capacity - are defined, but the underlying genetic mechanisms that close specific regenerative periods remains critical knowledge that needs expanding. Here, we established zebrafish larvae as a model to study the genetic basis of regenerative period closure. We demonstrated that laser axotomy of the centrally-projecting axons of dorsal root ganglia (DRG) neurons exhibit a robust regenerative period that is closed by 3 days post fertilization (dpf). The closure of the regenerative period corresponds with the rearrangement of glia that express netrin, introducing the idea that changes in the DCC-mediated signaling axis could be a genetic and molecular basis closing the regenerative period. To test this hypothesis, we manipulated dcc, cAMP, and Rac1 in transgenic animals that label axons and the actin cytoskeleton. Combined with genetic epistasis analysis, we show that altering DCC signaling can re-open the regenerative period, allowing severed axons to regrow into the spinal cord. We show that this increased capacity to reinvade the spinal cord is mediated by growth cone invadopodia. Using calcium reporters and behavioral analysis, we demonstrate that re-opening the regenerative period by manipulating the DCC signaling axis restores the sensory circuit and sensory-specific behaviors. By introducing this genetic basis for regenerative period closure, these results reveal an active suppression process that keeps regenerative periods closed and establishes a new model for future dissection of such periods.
Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics.
Mezzell AT, Zhang Y, Perez AM … +1 more , Vest KE
PLoS Genet · 2026 Jan · PMID 41587185 · Full text
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disease caused by modest alanine expansion at the amino terminus of the nuclear polyadenosine RNA binding protein PABPN1. PABPN1 is expressed ubiquitously and is...
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disease caused by modest alanine expansion at the amino terminus of the nuclear polyadenosine RNA binding protein PABPN1. PABPN1 is expressed ubiquitously and is involved in multiple steps in RNA processing including optimal cleavage and polyadenylation, polyadenylation signal selection, and export of polyadenylated RNAs from the nucleus. Expanded PABPN1 forms aggregates in a subset of muscle nuclei, but PABPN1 levels are paradoxically low in muscle compared to other tissues. Despite several studies in model systems and patient tissues, it remains unclear whether alanine expansion directly impairs PABPN1 function. The molecular mechanisms leading to OPMD pathology are poorly understood. Here we used a proximity labeling approach to better understand the effect of alanine expansion on PABPN1 function in a cell culture model of skeletal muscle. To avoid the confounding factor of overexpression, PABPN1 constructs containing a carboxy-terminal TurboID tag were expressed in skeletal myotubes at near native levels using an inducible promoter. Although non-expanded PABPN1-TurboID was able to complement RNA export and myoblast differentiation defects caused by deficiency of endogenous PABPN1, alanine expanded PABPN1-TurboID was not. Comparative proteomics revealed increased interaction between expanded PABPN1 and RNA splicing and polyadenylation machinery and follow-up studies identified a dominant negative effect of expanded PABPN1 on RNA export in differentiated myotubes. These data indicate that alanine expansion can impair PABPN1 function regardless of the presence of wild type PABPN1 and support a model wherein both loss function and dominant negative effects of expanded PABPN1 contribute to OPMD pathology.
Joint modeling of effect sizes for two correlated traits: Characterizing trait properties to enhance polygenic risk prediction.
Zhang C, Zhou G, Chen T … +1 more , Zhao H
PLoS Genet · 2026 Jan · PMID 41587179 · Full text
Recent years have witnessed a surge in the development of innovative polygenic score (PGS) methods, driving their extensive application in disease prevention, monitoring, and treatment. However, the accuracy of genetic r...
Recent years have witnessed a surge in the development of innovative polygenic score (PGS) methods, driving their extensive application in disease prevention, monitoring, and treatment. However, the accuracy of genetic risk prediction remains moderate for most traits. Currently, most PGSs were built based on the summary statistics from the target trait, while many traits exhibit varied degrees of shared genetic architecture or pleiotropy. Appropriate leveraging of pleiotropy from correlated traits can potentially improve the performance of PGS of the target trait. In this study, we present PleioSDPR, a novel method that jointly models the genetic effects of complex traits and identifies conditions under which leveraging pleiotropy can improve polygenic risk prediction. PleioSDPR models the joint distribution of effect sizes across traits, allowing SNPs to be null for both traits, causal for only one trait, or causal for both traits, and it flexibly captures region-specific genetic correlations and unequal heritability across traits. Through extensive simulations and real data applications, we demonstrate that PleioSDPR improves prediction performance compared with several univariate and multivariate PGS methods, especially when there is no validation dataset. For example, by incorporating information from schizophrenia or leg fat-free mass, PleioSDPR effectively improves the prediction accuracy of bipolar disorder (14.5% accuracy gain) and hip circumference (14.6% accuracy gain), respectively. Moreover, our results indicate that traits with stronger genetic correlations to the target trait, greater heritability, and limited sample overlap contribute more substantially to enhancing prediction accuracy for the target trait. Overall, our study highlights the potential of PleioSDPR to enhance the accuracy of genetic risk prediction by effectively leveraging pleiotropy across traits and diseases. These findings contribute to a broader understanding of polygenic risk prediction and underscore the importance of incorporating pleiotropic information to improve the use of these predictions in disease prevention and treatment strategies.
Shared latent genetic liability across fibromyalgia and psychiatric traits: Novel insights from genomic structural equation modeling.
Lin L, Li Y, Ji F … +6 more , Lin J, Zhu M, Liang D, Cao M, Fu G, Fu Y
PLoS Genet · 2026 Jan · PMID 41576141 · Full text
BACKGROUND: Fibromyalgia, insomnia, depression, and anxiety share common clinical comorbidities, but their underlying genetic architecture and mechanism remain unclear. METHODS: We conducted phenotype-specific Genome-wid...
BACKGROUND: Fibromyalgia, insomnia, depression, and anxiety share common clinical comorbidities, but their underlying genetic architecture and mechanism remain unclear. METHODS: We conducted phenotype-specific Genome-wide association study (GWAS) meta-analyses for fibromyalgia, insomnia, depression, and anxiety, respectively. Genomic structural equation modeling was employed to identify a shared genetic factor (mvFibroPsych). Lead SNPs and associated genes were annotated using Functional Mapping and Annotation (FUMA), followed by gene-set and tissue enrichment analyses. The Latent Causal Variable (LCV) method was utilized to identify modifiable risk factors and phenotypes influenced by mvFibroPsych. Additionally, brain-wide and proteome-wide Mendelian randomization (MR) analyses were applied to explore brain regions and biomarkers associated with mvFibroPsych. Multi-layer molecular quantitative trait locus (QTL) analyses were conducted for mechanistic insights into mvFibroPsych. RESULTS: Strong genetic correlations were observed among the four phenotypes (rg = 0.55-0.84), with excellent model fit for the common factor [comparative fit index (CFI) = 0.999, standardized root mean square residual (SRMR) = 0.015]. The mvFibroPsych GWAS identified 49 lead SNPs across 43 loci, including 32 novel loci. Gene prioritization revealed 342 protein-coding genes, and pathway analysis indicated enrichment in synaptic function pathway. LCV identified 133 phenotypes causally linked to mvFibroPsych. Brain-wide MR found fractional anisotropy in the splenium of the corpus callosum to be inversely associated with mvFibroPsych. Proteome-wide MR identified five proteins significantly associated with mvFibroPsych, while multi-layer brain QTL analysis prioritized CD40 as a potential target. CONCLUSIONS: This study provides strong evidence for a shared genetic factor underlying fibromyalgia, insomnia, depression, and anxiety, linked to synaptic function, brain structure integrity, and neuroinflammatory pathways.
An ArfGAP-dependent signaling modulates synaptic plasticity via IP3-regulated calcium release from the endoplasmic reticulum.
Mallik B, Kushwaha S, Bisht A … +3 more , Mj H, Frank CA, Kumar V
PLoS Genet · 2026 Jan · PMID 41576032 · Full text
Calcium release from intracellular stores influences synaptic response timing and magnitude. Despite the critical role of inositol trisphosphate (IP3)- and ryanodine receptor (RyR)-dependent calcium release in regulating...
Calcium release from intracellular stores influences synaptic response timing and magnitude. Despite the critical role of inositol trisphosphate (IP3)- and ryanodine receptor (RyR)-dependent calcium release in regulating synaptic strength, the upstream signaling mechanisms that govern IP3 receptor or RyR activity remain elusive. Here, we provide evidence that the ArfGAP-containing protein Asap modulates NMJ morphogenesis and synaptic calcium homeostasis by activating IP3-mediated calcium release from the endoplasmic reticulum (ER) via the phospholipase C-beta (PLCβ) signaling pathway. Using CRISPR/Cas9-engineered Asap mutants and genetically encoded calcium sensors, we demonstrate that loss of Asap leads to elevated resting synaptic calcium, resulting in increased evoked amplitude, elevated spontaneous miniature frequency, and reduced synaptic failures under low extracellular calcium conditions. Additional pharmacological and genetic manipulations of calcium regulatory pathways further support the role of increased resting intracellular calcium in driving enhanced neurotransmission in Asap-deficient synapses. Consistent with the role of Asap's ArfGAP domain in NMJ morphogenesis and intracellular calcium regulation, expressing a GDP-locked form of Arf6 (Arf6DN) or knocking down Arf6 in Asap mutants not only rescues Asap-associated synaptic defects but also normalizes synaptic calcium levels. Furthermore, epistatic analysis revealed that attenuation of IP3-signaling components in animals constitutively expressing Arf6CA normalized the NMJ morphological defects and synaptic functions. Together, these findings provide novel insights into the role of Asap-Arf6-PLCβ signaling in IP3-regulated calcium dynamics, sustaining both structural and functional synaptic plasticity.
Transcription factor ZEB2 is essential for ureteral smooth muscle cell differentiation.
Kumar S, Fan X, Pattam H … +10 more , Yan K, Liaw EJ, Ji J, Zaltz E, Song P, Jiang Y, Nishizaki Y, Higashi Y, Cai CL, Lu W
PLoS Genet · 2026 Jan · PMID 41576029 · Full text
Mowat-Wilson Syndrome (MWS) is an autosomal dominant genetic disorder caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 (ZEB2) gene. Congenital anomalies of the kidney and urinary...
Mowat-Wilson Syndrome (MWS) is an autosomal dominant genetic disorder caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 (ZEB2) gene. Congenital anomalies of the kidney and urinary tract (CAKUT), including hydroureter and hydronephrosis, have been reported in patients with MWS. However, the role of the ZEB2 gene in urinary tract development and the cellular and molecular mechanisms underlying the CAKUT phenotypes in MWS remain unknown. In this study, we examined ZEB2 expression in the developing mouse ureter and generated Zeb2 ureteral mesenchyme-specific conditional knockout mice (Zeb2 cKO) by crossing Zeb2 floxed mice with Tbx18Cre+ mice. The urinary tract of Zeb2 cKO mice and their wild-type littermates was analyzed for morphological and histological changes. Our results show that ZEB2 is expressed in TBX18+ ureteral mesenchymal cells during mouse ureter development. Deleting Zeb2 in these cells caused hydroureter and hydronephrosis, indicating obstructive uropathy. Cellular and molecular marker analysis revealed that the TAGLN+ACTA2+ ureteral smooth muscle cell (SMC) layer was absent in Zeb2 cKO mice. In contrast, the tunica adventitia cell layer was significantly expanded compared to controls. At the molecular level, Zeb2 cKO mice had significantly decreased TBX18 expression but increased SOX9 expression in the developing ureter compared to wild-type controls. Our findings demonstrate that ZEB2 is crucial for normal ureteral SMC differentiation during ureter development. Additionally, our study suggests that MWS patients may have abnormal ureteral SMC development, which contributes to the abnormalities of the urinary tract.
A C. elegans model of copper deficiency: Dietary interventions rescue CTR1/CHCA-1 copper transporter mutant phenotype.
Fu Y, Bai X, Chun L … +2 more , Xu XZS, Liu J
PLoS Genet · 2026 Jan · PMID 41575937 · Full text
Copper is an essential micronutrient for all living organisms. Mutations in the copper-importing transporter CTR1/CHCA-1 are associated with a severe copper deficiency disorder in humans, for which no effective cures are...
Copper is an essential micronutrient for all living organisms. Mutations in the copper-importing transporter CTR1/CHCA-1 are associated with a severe copper deficiency disorder in humans, for which no effective cures are currently available. Here, we develop C. elegans as a model for copper deficiency. We show that chca-1 mutant worms fed HT115 bacterial diet exhibited a severe developmental phenotype resulting from copper deficiency, reminiscent of the symptoms observed in human patients. Remarkably, this phenotype can be rescued by switching to OP50 bacterial diet or by supplementing HT115 bacterial diet with glutathione disulfide (GSSG), a metabolite enriched in OP50. Such dietary interventions remodeled the transcriptome of chca-1 mutants towards that of wild-type worms and upregulated the expression of CTR1/CHCA-1-like copper transporters, thereby ameliorating the mutant phenotype. Our findings establish C. elegans as a model for copper deficiency caused by CTR1/CHCA-1, suggesting that dietary interventions may offer a potential therapeutic approach for this severe disease.
Chromatin state architecture governs transcription factor accessibility across plant genomes.
Shukla V, Axelsson E, Hisanaga T … +3 more , Haseloff J, Berger F, Romani F
PLoS Genet · 2026 Jan · PMID 41570051 · Full text
The complexity of varied modifications of chromatin composition is integrated in archetypal combinations called chromatin states that predict the local potential for transcription. The degree of conservation of chromatin...
The complexity of varied modifications of chromatin composition is integrated in archetypal combinations called chromatin states that predict the local potential for transcription. The degree of conservation of chromatin states has not been established amongst plants, and how they interact with transcription factors is unknown. Here we identify and characterize chromatin states in the flowering plant Arabidopsis thaliana and the bryophyte Marchantia polymorpha, showing a large degree of functional conservation over more than 450 million years of land plant evolution. We used this new resource of conserved plant chromatin states to understand the influence of chromatin states on gene regulation. We established the preferential association of chromatin states with binding sites and activity of transcription factors. These associations define three main groups of transcription factors that bind upstream of the transcription start site, at the + 1 nucleosome or further downstream of the transcription start site and broadly associate with distinct biological functions including a list of potential candidate pioneer factors we know little about in plants, compared to their important roles in animal stem cells and early development.
Molecular evolution of CO2-sensing ab1C neurons underlies divergent sensory responses in the Drosophila suzukii species group.
Gadau A, Mills S, Zhu Jiang XY … +6 more , Li C, Svetec N, Xu Z, Li W, Nagel KI, Zhao L
PLoS Genet · 2026 Jan · PMID 41570048 · Full text
Organisms evolve behavioral and morphological traits to adapt to their ecological niches, yet the genetic basis of adaptation remains largely unknown. Drosophila suzukii has evolved a distinctive oviposition preference f...
Organisms evolve behavioral and morphological traits to adapt to their ecological niches, yet the genetic basis of adaptation remains largely unknown. Drosophila suzukii has evolved a distinctive oviposition preference for ripe fruit, unlike most Drosophila species such as D. melanogaster, which prefer overripe fruit. Carbon dioxide (CO2), a metabolic volatile that increases as fruit ripens and decays, may act as a critical ecological cue shaping these preferences. Here, we focus on D. suzukii and its sister species D. subpulchrella, which shows an intermediate preference, to investigate the genetic basis of CO2 responses. We report a previously unrecognized shift in CO2-guided oviposition: D. suzukii and D. subpulchrella readily lay eggs on CO2-enriched substrates, unlike the strong aversion displayed by D. melanogaster. Electrophysiological recordings revealed a species-specific sensory tuning, characterized by an early spike in CO2-evoked neuronal firing in D. suzukii and D. subpulchrella-a temporal response feature absent in D. melanogaster. To dissect the genetic basis of this shift, we generated transgenic D. melanogaster expressing either the D. suzukii Gr63a coding sequence or the D. subpulchrella Gr63a cis-regulatory element. Remarkably, both manipulations reproduced the early-onset firing pattern of CO2 sensitivity, demonstrating that either receptor function or expression can independently drive this sensitivity adaptation. Our findings reveal that evolution can shape ecological adaptation through distinct genetic mechanisms, leading to convergent physiological traits among closely related species.
20-hydroxyecdysone promotes brain development via upregulating MMP2 expression during metamorphosis in Helicoverpa armigera.
Tian C, Feng PY, Wang L … +3 more , Liu TW, Li YX, Zhao XF
PLoS Genet · 2026 Jan · PMID 41570035 · Full text
Matrix metalloproteinases (MMPs) play crucial roles in both physiological and pathological conditions by degrading the extracellular matrix; however, the roles and regulatory mechanisms of MMPs in brain development remai...
Matrix metalloproteinases (MMPs) play crucial roles in both physiological and pathological conditions by degrading the extracellular matrix; however, the roles and regulatory mechanisms of MMPs in brain development remain insufficiently understood. In this study, using the lepidopteran insect Helicoverpa armigera, the cotton bollworm, a serious agricultural pest, as an experimental model, we revealed that MMP2 is an important factor in insect brain development during metamorphosis under steroid hormone 20-hydroxyecdysone (20E) regulation. MMP2 is highly expressed in the brain during metamorphosis. MMP2 is localized in some surface and internal cells in the brain during metamorphosis. The knockdown of Mmp2 by RNA interference in larvae repressed brain development, accompanied by an increase in autophagy and a decrease in cell proliferation. In addition, the nutrient levels of glucose and glutamate decreased in the brain, and the expression of glucose transporters and glutamate transporters decreased after Mmp2 was knocked down. The transcription of Mmp2 was upregulated by 20E via the transcription factor forkhead box O (FOXO) in a time- and concentration-dependent manner. These data suggest that MMP2 facilitates neural cell proliferation and nutrient supply, and ultimately regulates brain development during insect metamorphosis.
Correction: The C-terminal of CASY-1/Calsyntenin regulates GABAergic synaptic transmission at the Caenorhabditis elegans neuromuscular junction.
Thapliyal S, Vasudevan A, Dong Y … +3 more , Bai J, Koushika SP, Babu K
PLoS Genet · 2026 Jan · PMID 41557638 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1007263.].
[This corrects the article DOI: 10.1371/journal.pgen.1007263.].
Retraction: Genome-wide identification of RETINOBLASTOMA RELATED 1 binding sites in Arabidopsis reveals novel DNA damage regulators.
PLOS Genetics Editors
PLoS Genet · 2026 Jan · PMID 41557589 · Full text
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Genetic variation shapes the chromatin accessibility landscape and transcriptional responses in mouse adipose tissue.
Mononen J, Taipale M, Malinen M … +4 more , Levonen AL, Ruotsalainen AK, Norton L, Heikkinen S
PLoS Genet · 2026 Jan · PMID 41544130 · Full text
Most of the disease associated genetic variants identified in genome wide association studies have been mapped to the non-coding regions of the genome. One of the leading mechanisms by which these variants are thought to...
Most of the disease associated genetic variants identified in genome wide association studies have been mapped to the non-coding regions of the genome. One of the leading mechanisms by which these variants are thought to affect disease susceptibility is by altering transcription factor (TF) binding. Even though inbred mouse strains have been commonly used to investigate polygenic diseases, less is known on how their genetic differences translate to the level of gene regulation and chromatin landscape. Here, we investigated how genetic variation affects chromatin accessibility in the epididymal white adipose tissue (eWAT) of C57BL/6J and 129S1/SvImJ mice, which are commonly used to study diet-induced obesity, fed either chow or high-fat diet. We show that differences in chromatin accessibility are almost exclusively strain-specific and driven by genetic variation. In addition, we integrate ATAC-seq (chromatin accessibility) and H3K27ac ChIP-seq (active regulatory regions) data to show that tissue-specific TF binding sites are commonly found in the active regulatory regions hosting TF motif altering variants in eWAT. Using footprint analysis, we also show that TF occupancy is consistent with TF binding motif scores at the genetically altered loci. In addition, we validate these findings by extending the analysis to ATAC-seq and H3K27ac ChIP-seq data obtained from the liver. We employ RNA-seq to show that differentially expressed genes are co-located with differentially accessible regions hosting genetic variants. Overall, our findings highlight the connection between differential chromatin accessibility and genetic variation across metabolically central tissues of a mouse model for polygenic obesity.
Temperature and genetic background drive mobilization of diverse transposable elements in a global human fungal pathogen.
Mackey AI, Fraunfelter V, Shaltz S … +6 more , McCormick J, Schroeder C, Perfect JR, Feschotte C, Magwene PM, Gusa A
PLoS Genet · 2026 Jan · PMID 41544091 · Full text
Transposable elements (TEs) are key agents of genome evolution across all domains of life. These mobile genetic elements can cause mutations through transposition or by promoting structural rearrangements. Stress conditi...
Transposable elements (TEs) are key agents of genome evolution across all domains of life. These mobile genetic elements can cause mutations through transposition or by promoting structural rearrangements. Stress conditions can amplify TE mobility, either by impairing TE suppression mechanisms or through stress-induced interactions between transcription factors and TE sequences, offering a route for rapid genetic change. As such, TEs represent an important source of adaptability within populations. To investigate the interplay between environmental stress and eukaryotic TE dynamics relevant to infectious disease, we examined how heat stress and host-mimicking medium (RPMI) affect TE mobility in the global human fungal pathogen Cryptococcus neoformans, using a collection of clinical and environmental isolates. Using a selection-based screen, we captured the mobilization of seven distinct mobile element families, encompassing diverse retrotransposons and DNA transposons, whose insertions conferred antifungal resistance. This includes a novel element, CNEST, which belongs to the CACTA, Mirage, Chapaev (CMC) supergroup. Heat stress at human body temperature (37°C) significantly increased the mobilization of a subset of these TEs, leading to higher rates of acquired antifungal resistance. Whole-genome assemblies revealed that, compared to retrotransposons, DNA transposons were hypomethylated and approximately uniformly distributed throughout the genome, features that may contribute to their frequent mobilization. We further assessed TE-driven genomic changes within hosts using serial isolates from patients with recurrent cryptococcal infections and from isolates passaged through mice. While we observed evidence of TE copy number changes near chromosome ends, we found no indication of TE-mediated alterations near gene-coding regions across any of the serial isolates. Finally, TE mobility was isolate- and strain-dependent, with significant variation even among clonally related strains collected from the same patient, emphasizing the role of genetic background in shaping TE activity. Together, these findings reveal a complex and dynamic relationship between environmental stress, genetic background, TE type-specific epigenetic regulation, and TE mobility, with important implications for adaptation and acquired antifungal resistance in C. neoformans.
Correction: Genomic regions of current low hybridisation mark long-term barriers to gene flow in scarce swallowtail butterflies.
PLOS Genetics Staff
PLoS Genet · 2026 Jan · PMID 41544033 · Full text
[This corrects the article DOI: 10.1371/journal.pgen.1011655.].
[This corrects the article DOI: 10.1371/journal.pgen.1011655.].
Impact of maternal compensation on developmental phenotypes in a zebrafish model of severe congenital muscular dystrophy.
Flannery KP, Mowla S, Battula N … +9 more , Clark LR, Oliveira CD, Simhon LM, Liu D, Venkatesan C, Karas BF, Terez KR, Burbano D, Manzini MC
PLoS Genet · 2026 Jan · PMID 41533692 · Full text
Genetic compensation is a common phenomenon in zebrafish in response to genetic alterations. Differences between genetic and morpholino-mediated zebrafish models of human diseases have led to significant difficulties in...
Genetic compensation is a common phenomenon in zebrafish in response to genetic alterations. Differences between genetic and morpholino-mediated zebrafish models of human diseases have led to significant difficulties in phenotypic interpretation and translatability. One form of compensation is the maternal deposit of mRNAs and proteins to the oocyte that supports developmental processes before zygotic genome activation. In this study, we generated a zebrafish model of severe congenital muscular dystrophy (CMD) by targeting protein O-mannose N-Acetylglucosaminyltransferase 2 (pomgnt2), a maternally provided gene that maintains cell-extracellular matrix interactions through glycosylation and leads to congenital muscular dystrophy when mutated. Zygotic knockouts (ZKOs) retain protein function in the first week post fertilization and survive to adulthood, only developing muscle disease later in life. In contrast, maternal-zygotic KOs (MZKOs) generated from ZKO females develop early-onset muscle disease, reduced motor function, neuronal axon guidance deficits, and retinal synapse disruptions recapitulating features of the human presentation. While assessing transcriptional changes linked to disease progression, the availability of embryos obtained from different breeding strategies also allowed for a direct comparison of ZKOs and MZKOs to define the impact of having a KO mother. We found that offspring from a ZKO mother, independently of genotype, show distinct expression patterns from animals obtained from heterozygous breedings. Some of these changes reflect changes in metabolic function, possibly stemming from maternal metabolic disruption. These findings will not only be applicable for other CMD models targeting maternally provided genes, but also provide new insight into modeling disease using maternal-zygotic mutants.
Sleep rescues age-associated loss of glial engulfment.
Zhang J, Brown EB, Lloyd E … +3 more , Yeragi E, Farhy-Tselnicker I, Keene AC
PLoS Genet · 2026 Jan · PMID 41529082 · Full text
Neuronal injury due to trauma or neurodegeneration is a common feature of aging. The clearance of damaged neurons by glia is thought to be critical for maintenance of proper brain function. Sleep loss has been shown to i...
Neuronal injury due to trauma or neurodegeneration is a common feature of aging. The clearance of damaged neurons by glia is thought to be critical for maintenance of proper brain function. Sleep loss has been shown to inhibit the motility and function of glia that clear damaged axons while enhancement of sleep promotes clearance of damaged axons. Despite the potential role of glia in maintenance of brain function and protection against neurodegenerative disease, surprisingly little is known about how sleep loss impacts glial function in aged animals. Axotomy of the Drosophila antennae triggers Wallerian degeneration, where specialized olfactory ensheathing glia engulf damaged neurites. This glial response provides a robust model system to investigate the molecular basis for glial engulfment and neuron-glia communication. Glial engulfment is impaired in aged and sleep-deprived animals, raising the possibility that age-related sleep loss underlies deficits in glial function. To define the relationship between sleep- and age-dependent reductions in glial function, we used two complementary approaches to enhance sleep in aged animals and examined the effects on glial clearance of damaged axons. Both pharmacological and genetic induction of sleep restores clearance of damaged neurons in aged flies. Further analysis revealed that sleep restored post-injury induction of the phagocytic protein Draper to aged flies, fortifying the notion that loss of sleep contributes to reduced glial-mediated debris clearance in aged animals. To identify age-related changes in the transcriptional response to neuronal injury, we used single-nucleus RNA-seq (snRNA-seq) of the central brains from axotomized young and old flies. We identified broad transcriptional changes within the ensheathing glia of young flies, and the loss of transcriptional induction of autophagy-associated genes. We also identify age-dependent loss of transcriptional induction of 18 transcripts encoding for small and large ribosomal protein subunits following injury in old flies, suggesting dysregulation of ribosomal biogenesis contributes to loss of glial function. Together, these findings provide further support for a functional link between sleep loss, aging and Wallerian degeneration.
Local mitochondrial physiology defined by mtDNA quality guides purifying selection.
Thoma F, Hagen J, Rathberger R … +4 more , Padovani F, Hörl D, Schmoller KM, Osman C
PLoS Genet · 2026 Jan · PMID 41512010 · Full text
The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain and ATP synthase. Mutations in these genes impair oxidative phosphorylation, compromise mitochondrial ATP production and cellula...
The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain and ATP synthase. Mutations in these genes impair oxidative phosphorylation, compromise mitochondrial ATP production and cellular energy supply, and can cause mitochondrial diseases. These consequences highlight the importance of mtDNA quality control (mtDNA-QC), the process by which cells selectively maintain intact mtDNA to preserve respiratory function. Here, we developed a high-throughput flow cytometry assay for Saccharomyces cerevisiae to track mtDNA segregation in cell populations derived from heteroplasmic zygotes, in which wild-type (WT) mtDNA is fluorescently labeled and mutant mtDNA remains unlabeled. Using this approach, we observe purifying selection against mtDNA lacking subunits of complex III (COB), complex IV (COX2) or the ATP synthase (ATP6), under fermentative conditions that do not require respiratory activity. By integrating cytometric data with growth assays, qPCR-based mtDNA copy-number measurements, and simulations, we find that the decline of mtDNAΔatp6 in populations derived from heteroplasmic zygotes is largely explained by the combination of its reduced mtDNA copy number-biasing zygotes toward higher contributions of intact mtDNA-and the proliferative disadvantage of cells carrying this variant. In contrast, the loss of mtDNAΔcob and mtDNAΔcox2 cannot be explained by growth defects and copy-number asymmetries alone, indicating an additional intracellular selection against these mutant genomes when intact mtDNA is present. In heteroplasmic cells containing both intact and mutant mtDNA, fluorescent reporters revealed local reductions in ATP levels and membrane potential ([Formula: see text]) near mutant genomes, indicating spatial heterogeneity in mitochondrial physiology that reflects local mtDNA quality. Disruption of the respiratory chain by deletion of nuclear-encoded subunits (RIP1, COX4) abolished these physiological gradients and impaired mtDNA-QC, suggesting that local bioenergetic differences are required for selective recognition. Together, our findings support a model in which yeast cells assess local respiratory function as a proxy for mtDNA integrity, enabling intracellular selection for functional mitochondrial genomes.
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