PLoS Genet. [JOURNAL]
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200 papers
A tti1 mutation in the Tel2-Tti1-Tti2 complex specifically eliminates the cellular function of Rad3ATR, but not that of other PIKKs in fission yeast.
Bhadra S, Ahamad N, Khan S … +1 more , Xu YJ
PLoS Genet · 2026 Jun · PMID 42275414 · Full text
The Tel2-Tti1-Tti2, or TTT complex, is the co-chaperone for co-translational maturation of all phosphatidylinositol 3-kinase-related kinases (PIKKs). The complex is highly conserved in eukaryotes and controls multiple ce...
The Tel2-Tti1-Tti2, or TTT complex, is the co-chaperone for co-translational maturation of all phosphatidylinositol 3-kinase-related kinases (PIKKs). The complex is highly conserved in eukaryotes and controls multiple cellular processes through PIKKs. Mutations of the TTT complex have recently been linked to disease syndromes and cancer. In Schizosaccharomyces pombe, six PIKKs are expressed: Rad3ATR, Tel1ATM, Tor1 and Tor2 (homologs of mTOR), and Tra1 and Tra2 (homologs of TRRAP). While Rad3ATR and Tel1ATM are the central cellcycle checkpoint kinases in response to DNA damage and replication stress, the other four PIKKs govern cell growth, nutrient sensing, and transcriptional regulation. Here, we report the identification of seven tti1 mutants in fission yeast that are sensitive to genotoxins. Characterization of one of the mutants, tti1-N18, reveals that the mutation selectively eliminates the kinase function of Rad3ATR, but not that of Tel1ATM. Further examination shows that, like Tel1ATM, the functions of the other four PIKKs are also largely uncompromised in the tti1-N18 mutant. These findings suggest a mechanism by which the TTT complex confers functional specificity towards Rad3ATR among the PIKKs. Since human Tel2 has been identified as a target of the antiparasitic drug Ivermectin, further investigation of the substrate specificity of the TTT complex may reveal a therapeutic vulnerability for treatment of cancer or other diseases.
The neuropeptide neuromedin U receptor NMUR-1 buffers insulin receptor signaling in bacteria-dependent C. elegans survival.
Sifoglu D, Pereira B, DeGregory C … +7 more , Shah R, Maier W, Guan J, Clark I, Patel D, Ch'ng Q, Alcedo J
PLoS Genet · 2026 Jun · PMID 42275405 · Full text
Distinct microbial environments exert diverse effects on the physiology and survival of the nematode Caenorhabditis elegans. Here, we show that C. elegans grown on two Escherichia coli strains exhibit different survival...
Distinct microbial environments exert diverse effects on the physiology and survival of the nematode Caenorhabditis elegans. Here, we show that C. elegans grown on two Escherichia coli strains exhibit different survival dynamics. Wild-type C. elegans on the B type OP50 exhibit more early deaths compared to C. elegans on K-12 type CS180. These early deaths on OP50 are characterized by swollen pharynges (P-deaths) due to bacterial accumulation within the tissue. In contrast, animals on CS180 are more resistant to P-deaths. These bacteria-dependent differences in P-deaths depend on bacterial lipopolysaccharide structures and the activities of the C. elegans neuropeptide neuromedin U receptor NMUR-1, which reduces P-deaths on OP50, but not on CS180. Surprisingly, however, NMUR-1 promotes the opposite response when the insulin receptor DAF-2 has reduced function-where NMUR-1 now stimulates P-deaths on OP50, but again with no effect on CS180. We also find that NMUR-1 acts in sensory neurons to promote its bi-directional effects on longevity, which depend on the FOXO transcription factor DAF-16. In addition, NMUR-1 downregulates the expression of the insulin-like peptide daf-28, but only when DAF-2 function is not reduced. This suggests a regulatory mechanism through which NMUR-1 maintains insulin receptor DAF-2 signaling at a suitable level. Thus, our studies reveal that NMUR-1 serves to buffer the dynamic range of DAF-2 receptor signaling, thereby optimizing pharyngeal health and survival in response to specific bacteria.
The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models.
Katow H, Nguyen T, Park SH … +1 more , Ryoo HD
PLoS Genet · 2026 Jun · PMID 42268918 · Full text
The Integrated Stress Response (ISR) mediates cellular adaptation to endoplasmic reticulum (ER) stress, amino acid deprivation, and mitochondrial dysfunction. The ISR regulates gene expression in part by preferentially t...
The Integrated Stress Response (ISR) mediates cellular adaptation to endoplasmic reticulum (ER) stress, amino acid deprivation, and mitochondrial dysfunction. The ISR regulates gene expression in part by preferentially translating the transcription factor ATF4, a process regulated by upstream open reading frames (uORFs) in its 5' leader. In Drosophila, Xrp1 is another transcription factor induced during the ISR, but the precise underlying mechanism remains unclear. Here, we report that Xrp1 induction in response to ER stress is regulated by both its uORFs and the main ORF sequence. Xrp1 has seven splice isoforms, and the two predominant transcripts expressed in eye imaginal discs contain uORFs. Expressing the ER stress-imposing ninaEG69D transgene in this tissue induced Xrp1 expression without significantly changing the Xrp1 splice isoform composition. The uORF-containing 5' leaders, particularly the AUG codon of the second uORF, inhibited DsRed expression when placed upstream of the reporter. Unlike ATF4, the uORF-containing 5' leader alone was insufficient to mediate the main ORF induction, but Xrp1 induction occurred in ninaEG69D-expressing discs when Xrp1's 5' leader and the main ORF sequence were both present. Functionally, Xrp1 was required to maintain the integrity of Drosophila photoreceptors exposed to constant light. In a different disease model, parkin mutants activated Xrp1 target gene expression in specific tissues and Xrp1 loss enhanced the viability of parkin mutant flies during adult eclosion. These results provide molecular and pathological insights into Xrp1 regulation and function in disease models.
The importance of nonsense errors: Estimating the rates and implications of ribosome drop-off during protein synthesis.
Cope AL, Pak D, Gilchrist MA
PLoS Genet · 2026 Jun · PMID 42263105 · Full text
The process of translation is both energetically costly and relatively error-prone compared to transcription and replication. Nonsense errors during translation occur when a ribosome drops off a transcript before reachin...
The process of translation is both energetically costly and relatively error-prone compared to transcription and replication. Nonsense errors during translation occur when a ribosome drops off a transcript before reaching a stop codon, resulting in energetic investment in an incomplete and likely non-functional protein. Nonsense errors impose a potentially significant energy burden on the cell, making it critical to quantify their frequency and energetic cost. Here, we present a model of ribosome movement for estimating protein production, elongation, and nonsense error rates from high-throughput ribosome profiling data. Applying this model to an exemplary ribosome profiling dataset in S. cerevisiae, we find that nonsense error rates vary substantially between codons and that these types of errors place an energetic burden on cells comparable to ribosome pausing. Overall, we present multiple lines of evidence that selection against nonsense errors is a prominent force shaping protein-coding sequence evolution and codon usage bias, in particular.
Rv3839-Rv3840 links the endogenous heme biosynthesis pathway with Mycobacterium tuberculosis adaptation to nitric oxide and iron limitation stress.
Quirk NF, Gregory KN, Morita YS … +1 more , Tan S
PLoS Genet · 2026 Jun · PMID 42258570 · Full text
During infection, Mycobacterium tuberculosis (Mtb) encounters multiple environmental stressors, including nitric oxide (NO) and iron limitation, and an ability to mount an integrated response is essential for the bacteri...
During infection, Mycobacterium tuberculosis (Mtb) encounters multiple environmental stressors, including nitric oxide (NO) and iron limitation, and an ability to mount an integrated response is essential for the bacterium's adaptation and continued survival. Iron-containing prosthetic groups in key enzymes are critical for Mtb sensing and detoxification of NO, and there is significant overlap between NO- and low iron-responsive genes. However, how Mtb adapts to these two stressors concurrently is largely unknown. Here, we find that exposure to NO globally augments expression of low iron-responsive genes and vice versa, with a two gene operon, rv3839-rv3840, among the most highly upregulated. Deletion of rv3839-rv3840 resulted in increased growth under prolonged iron limitation and early exit of Mtb from an adaptive state of growth arrest induced upon exposure to NO/low iron. ∆rv3839-rv3840 Mtb exhibited an elongated cell morphology compared to wild type Mtb in NO/low iron conditions, indicating effects of this operon on cell growth and division under stress conditions, with Rv3839 as the key driver of this phenotype. Coproporphyrin III tetramethyl ester (TMC), a modified precursor molecule in the endogenous Mtb heme biosynthesis pathway, was found to accumulate in ∆rv3839-rv3840 Mtb under iron limiting conditions. Further, intrabacterial heme levels were increased in ∆rv3839-rv3840 Mtb under NO stress and iron limitation. Together, these findings reveal Rv3839-Rv3840 as proteins involved in the downregulation of heme biosynthesis under NO stress and iron limitation, and highlight the link between Mtb growth control in response to NO/low iron and endogenous heme biosynthesis.
RNA Polymerase III subunit Polr3a is required for craniofacial cartilage and bone development in zebrafish.
Lubash BT, Gutierrez R, Hansen NA … +5 more , Fink K, Hopkins CA, Sands LB, Nelson JC, Watt KEN
PLoS Genet · 2026 Jun · PMID 42258504 · Full text
Transcription by RNA Polymerase III (Pol III) is essential for ribosome biogenesis and translation in all cells, but pathogenic variants in genes encoding subunits of Pol III lead to tissue-specific phenotypes including...
Transcription by RNA Polymerase III (Pol III) is essential for ribosome biogenesis and translation in all cells, but pathogenic variants in genes encoding subunits of Pol III lead to tissue-specific phenotypes including craniofacial differences. To understand the function of Pol III in craniofacial development, we examined polr3a mutant zebrafish. These mutants display hypoplasia of the neural crest cell-derived craniofacial cartilage and bone but, surprisingly, no significant changes were observed in neural crest cell proliferation or survival during embryogenesis. At larval stages, increased cell death was observed throughout the head, including in the craniofacial cartilage. These changes coincide with reduced transcription of transfer RNAs and reduced ribosome biogenesis in polr3a mutant zebrafish. To determine tissue-specific transcriptional changes, we performed single-cell RNA-sequencing. Analysis revealed both global and cartilage-specific changes, including upregulation of tp53. However, Tp53 inhibition alone was not sufficient to rescue craniofacial cartilage and bone, indicating that additional factors are important to support cartilage and bone growth in polr3a mutants. Altogether, our study provides new mechanistic insights into the functions of Pol III in craniofacial development.
Tbx16 and mesogenin 1 promote presomitic mesoderm differentiation by repressing the mesodermal progenitor cell state.
Zhu G, Genuth MA, Xiao Y … +3 more , Kindberg AA, Hackett K, Holley SA
PLoS Genet · 2026 Jun · PMID 42258492 · Full text
During zebrafish embryonic body elongation, differentiation of mesodermal progenitors into presomitic mesoderm requires the transcription factors tbx16 and mesogenin 1. Here, by using temporally controlled tbx16 and meso...
During zebrafish embryonic body elongation, differentiation of mesodermal progenitors into presomitic mesoderm requires the transcription factors tbx16 and mesogenin 1. Here, by using temporally controlled tbx16 and mesogenin 1 overexpression and RNAseq to identify immediate downstream changes in gene expression, we elucidate how these genes promote presomitic mesoderm differentiation. Using machine learning and game theory, we integrated differentially expressed genes with wild-type scRNAseq data and identified genes downstream of tbx16 and mesogenin 1 during mesoderm differentiation. This data-driven analysis indicates that mesogenin 1 and tbx16 primarily repress expression of genes as mesodermal progenitors differentiate. Strikingly, the genes that are most important for defining transcriptional cell states during mesoderm differentiation are most strongly repressed by tbx16 and mesogenin 1. Moreover, these downstream effectors are enriched for genes with known roles in mesoderm development and body elongation such as Fgf, Wnt and Bmp pathways and the transcription factors tbxta, eve1, hoxd12a, hoxd13b, lef1, cdx4, tbx16l, ved, vent and vox. Gradients of Fgf and Wnt specify the mesodermal progenitor state in the posterior tailbud and activate many of these transcription factors indicating that tbx16 and mesogenin 1 promote mesoderm differentiation by repressing this progenitor state.
Promotion of shade avoidance by BBX5 involves activation of PIF4 along with auxin biosynthetic and signaling genes.
Zhao F, Yang R, Song Z … +3 more , Bian Y, Xiao Y, Xu D
PLoS Genet · 2026 Jun · PMID 42247454 · Full text
Neighbor proximity triggers changes in light quality that regulate various developmental and physiological processes in plants. phytochrome B (phyB)-PHYTOCHROMEINTERACTING FACTOR 4 (PIF4) module serves as a central regul...
Neighbor proximity triggers changes in light quality that regulate various developmental and physiological processes in plants. phytochrome B (phyB)-PHYTOCHROMEINTERACTING FACTOR 4 (PIF4) module serves as a central regulatory hub enabling plants to accurately perceive and respond to shade cues. Here, we identify B-box PROTEIN 5 (BBX5) as a positive regulator of shade avoidance. phyB interacts with BBX5 and promotes its protein stability. Conversely, the E3 ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENICLY 1 (COP1) associates with and destabilizes BBX5 via the 26S proteasome system in shade. BBX5 binds to the PIF4 promoter to upregulate its expression during the early phase of shade exposure, and directly associates with the promoters of auxin biosynthetic and signaling genes YUCCA8 (YUC8) and INDOLE-3-ACETIC ACID INDUCIBLE 19 (IAA19) to activate their expression in shade. Our study reveals that BBX5 acts as a transcriptional activator of PIF4, YUC8 and IAA19 to promote plant growth and development in response to shade signals.
Chromatin insulators homie and nhomie can interact with distant copies either together or separately, with distinct outcomes for enhancer-promoter interactions.
Fujioka M, Ke W, Schedl P … +1 more , Jaynes JB
PLoS Genet · 2026 Jun · PMID 42247439 · Full text
Chromatin insulators, a.k.a. boundary elements, separate regions of the chromosome with distinct chromatin characteristics, including distinct histone modifications. This activity affects gene expression by allowing chro...
Chromatin insulators, a.k.a. boundary elements, separate regions of the chromosome with distinct chromatin characteristics, including distinct histone modifications. This activity affects gene expression by allowing chromatin domains to be stably regulated and maintained. Insulators also block enhancer-promoter interactions and, somewhat paradoxically, facilitate other interactions, particularly when they stitch together distant regions of the chromosome by pairing with specific partners. Here we explore how long-range interactions facilitated by insulator pairing are affected by the presence of two potentially competing partners. Our results show that when two partners are present, they can reduce each other's effects on distant gene expression, suggesting that enhancer-promoter interactions are best facilitated by pairwise insulator interactions. When a distant copy of an eve insulator (homie or nhomie) is present, it can interact with either or both endogenous insulators. But when one endogenous insulator is removed, the remaining one interacts more strongly with the transgenic copy, biasing the induced enhancer-promoter interactions toward those nearest the remaining endogenous insulator. On the other hand, physical interaction data suggest that strictly pairwise interactions are not the rule, suggesting a more complex model involving tripartite interactions. We further show that removing one or both endogenous eve insulators significantly reduces endogenous eve function at a critical early stage of development, and that the eve Polycomb domain expands in both directions when its insulator boundaries are removed, showing that insulators in their native context are required for each of the main functions that have been ascribed to them based on transgene assays.
The stoichiometry of minor-to-major pilins regulates the dynamic activity of the type IVa competence pilus in Vibrio cholerae.
Christman ND, Dalia TN, Chlebek JL … +1 more , Dalia AB
PLoS Genet · 2026 Jun · PMID 42241457 · Full text
Type IVa pili (T4aP) are bacterial surface appendages that perform various functions including twitching motility, reversible surface attachment, microcolony formation, surface sensing, and DNA uptake for natural transfo...
Type IVa pili (T4aP) are bacterial surface appendages that perform various functions including twitching motility, reversible surface attachment, microcolony formation, surface sensing, and DNA uptake for natural transformation. Pivotal to each of these functions is the ability of T4aP to be dynamically extended and retracted from the cell surface. However, the factors that regulate this dynamic activity remain poorly understood in most systems. To address this question, we employ the competence T4aP from Vibrio cholerae as a model system. T4aP are composed of major and minor pilin subunits, named based on their relative abundance in the pilus filament. Prior work has established that minor pilins form a complex that initiates T4aP assembly. This allows for the subsequent addition of major pilins to the filament, which promotes T4aP extension. Here, we uncover that the stoichiometry of minor-to-major pilins is a crucial determinant of T4aP dynamic activity. Specifically, we show that either 1) overexpressing minor pilins or 2) underexpressing the major pilin results in a dramatic increase in the frequency of T4aP dynamics. These results indicate that the stoichiometry of minor-to-major pilins, not their absolute abundance, is one mechanism that regulates T4aP dynamic activity.
Barrier-to-autointegration factor protects against the cGAS-STING response to chromatin bridges.
Chastant L, Normandin K, El-Mortada F … +2 more , Servant MJ, Archambault V
PLoS Genet · 2026 Jun · PMID 42234713 · Full text
Cellular damage or stress can lead to disorganization, mislocalization or damage to self-DNA that can activate intracellular innate immune response mechanisms. Micronuclei, such as can occur following mitotic defects, ha...
Cellular damage or stress can lead to disorganization, mislocalization or damage to self-DNA that can activate intracellular innate immune response mechanisms. Micronuclei, such as can occur following mitotic defects, have been proposed as a source of DNA capable of activating the cGAS-STING pathway, resulting in IRF3-dependent proinflammatory transcription. However, to what extent micronuclei per se or other concurrent defects contribute to the cGAS-STING response remains unclear. To better understand the ability of post-mitotic defects to induce this response, we compared the effects resulting from inhibition of the Spindle-Assembly Checkpoint (through MPS1 inhibition) or interference with nuclear reassembly (through inactivation of BAF). We found that combining both perturbations synergistically enhances the cGAS-STING response. This effect is not due to an increase in post-mitotic nuclear deformations including micronucleation and lobulation but instead correlates with an increase in destabilized chromatin bridges resulting in structures that potently recruit cGAS. Our results suggest that by stabilizing chromatin bridges, BAF contributes to preventing their degeneration into cGAS-activating chromatin structures. This work helps better understand how the innate immune system detects mitotic defects.
Epistasis among clustered lineage-specific amino acid substitutions in the Drosophila Trio protein.
Borne F, Taverner AM, Andolfatto P
PLoS Genet · 2026 Jun · PMID 42234705 · Full text
Intramolecular epistasis is increasingly recognized as a key factor shaping patterns of evolutionary rate variation among protein sites and constraining adaptive evolution. While genome-wide analyses have revealed that i...
Intramolecular epistasis is increasingly recognized as a key factor shaping patterns of evolutionary rate variation among protein sites and constraining adaptive evolution. While genome-wide analyses have revealed that intramolecular epistatic interactions can drive the spatial clustering of amino acid substitutions, direct empirical evidence for such interactions and their evolutionary consequences remains limited. Using a population genetic screen for spatially-clustered and lineage-specific adaptive amino acid substitutions in Drosophila proteins, we systematically identify experimentally tractable candidates for functional analysis. As proof of concept, we focus on the Trio protein, a Rho guanine nucleotide exchange factor that exhibits three spatially-clustered putatively adaptive amino acid substitutions in the D. melanogaster lineage. By systematically reconstructing evolutionary intermediates in vivo using genome editing, we find that all possible intermediate states exhibit reduced viability and/or locomotor defects, providing strong evidence for epistatic constraints on evolutionary trajectories. Notably, these deleterious effects are recessive, suggesting that intermediate combinations of epistatically interacting amino acid substitutions can accumulate in heterozygotes prior to fixation, thereby circumventing apparent constraints imposed by maladaptive intermediate states. Together, these findings provide a rare empirical view of the fitness landscape shaped by intramolecular epistasis and establish a framework for investigating the constraints on adaptive protein evolution in diploid multicellular organisms.
Dual-function enzyme acts as a global c-di-GMP sink and local anti sigma factor antagonist to drive cellular differentiation.
Cınar Cakmak B, Saric JD, Wrede K … +5 more , Holmes NA, Haist J, Schumacher MA, Buttner MJ, Tschowri N
PLoS Genet · 2026 Jun · PMID 42234673 · Full text
Soil bacteria of the genus Streptomyces are natural producers of over two-thirds of clinically used antibiotics. Their ability to generate these valuable metabolites is tightly linked to a developmental program involving...
Soil bacteria of the genus Streptomyces are natural producers of over two-thirds of clinically used antibiotics. Their ability to generate these valuable metabolites is tightly linked to a developmental program involving the transition from vegetative hyphae to spores. The second messenger cyclic di-GMP (c-di-GMP) stabilizes effector complexes that block sporulation, including the RsiG-σWhiG complex leading to sequestration of the developmental sigma factor by its anti sigma factor. How signal termination and disruption of effector complexes is achieved to allow sporulation, remains poorly understood. Here, we identify the phosphodiesterase RmdB as a dual-function regulator that terminates c-di-GMP signaling both globally and locally. We show that deletion of the rmdB gene leads to increase of the global c-di-GMP pool and delayed development. Using genetic complementation, we demonstrate that both the EAL motif and the GGDEF domain are essential for the physiological function of RmdB. Our co-immunoprecipitation and co-elution assays revealed that RmdB interacts directly with the sigma factor σWhiG via its GGDEF domain, thus preventing binding of the anti sigma factor RsiG to σWhiG and promoting sporulation. Our bacterial two-hybrid analyses identify RmdB as an interaction hub connecting to multiple diguanylate cyclases (DGCs), including CdgE, which also interacts with σWhiG. These findings establish a novel principle of bacterial signaling in which a phosphodiesterase serves as an antagonist of an anti sigma factor, integrating global second messenger degradation with local effector complex formation to control cell fate decisions.
Canalization of neural dynamics by δ-protocadherins in the developing zebrafish optic tectum.
Biswas S, Emond MR, Philip GS … +1 more , Jontes JD
PLoS Genet · 2026 Jun · PMID 42224358 · Full text
Brain dynamics are constrained by the underlying topology of neuronal networks. How genes collaborate to organize these neural networks during development remains an enduring mystery. In humans, large numbers of genes ha...
Brain dynamics are constrained by the underlying topology of neuronal networks. How genes collaborate to organize these neural networks during development remains an enduring mystery. In humans, large numbers of genes have been implicated in neurodevelopmental disorders that are characterized by variable and overlapping phenotypes. The complexity of the brain and the heterogeneity of the disorders makes understanding the relationships between genes, development and neural function challenging. Beginning in the 1940s, Waddington suggested the concept of canalization to describe the role of genes as buffering developmental trajectories against genetic and environmental variation, leading to precise outcomes. Here, we show that members of the δ-protocadherin family of homophilic cell adhesion molecules, Protocadherin-19 and Protocadherin-17, contribute to developmental canalization of neural dynamics in the visual system of larval zebrafish. We provided oriented visual stimuli to zebrafish larvae and performed in vivo 2-photon calcium imaging in the optic tectum. The latent dynamics resulting from the population activity were remarkably conserved among different wild type larvae, allowing quantitative comparisons within and among genotypes. In both Protocadherin-19 and Protocadherin-17 mutants, the latent dynamics diverged stochastically from wild type, suggesting that the loss of these adhesion molecules leads to stochastic phenotypic variability and introduced disruptions of circuit organization that varied among individual mutants. These results are consistent with the developmental canalization of a vertebrate neural circuit, and suggest a framework for understanding the observed variability in complex brain disorders.
Sequence context and methylation interact to shape germline mutation rate variation at CpG sites.
Chandra S, Gao Z
PLoS Genet · 2026 Jun · PMID 42224293 · Full text
A prominent example of sequence context-dependent mutation rate variation is the elevated transition rate at CpG sites, which is largely attributed to cytosine methylation. CpGs with different flanking sequences also exh...
A prominent example of sequence context-dependent mutation rate variation is the elevated transition rate at CpG sites, which is largely attributed to cytosine methylation. CpGs with different flanking sequences also exhibit mutation rate variation, but this variation is only partially correlated with context-specific methylation level. Here, we quantify the CpG mutation rate and mutagenic effect of methylation across sequence contexts. Using a regression framework that accounts for recurrent mutations, we analyze human polymorphisms from the gnomAD dataset to estimate mutation rates of unmethylated and methylated CpGs separately in each unique 4-mer or 6-mer context. We find that CpG mutation rate variation in the human genome is shaped by methylation at the focal cytosine, the flanking nucleotides, and interactions between them, suggesting distinct context-dependent mutation patterns for unmethylated and methylated cytosines. Our analysis further reveals that the context effects are driven by largely independent effects of upstream and downstream sequences. Notably, an upstream adenine markedly increases CpG mutation rates regardless of methylation status or downstream sequences. Furthermore, upstream and downstream sequences have similar effects in chimpanzee and rhesus macaque, indicating that some conserved, intrinsic sequence features shape CpG mutability. On the other hand, some inter-species differences, which are especially pronounced at methylated sites on the chimpanzee lineage, point to recent evolutionary changes, possibly in context-specificity of proteins governing DNA demethylation and repair processes.
Yap1 regulates motility and vertebral development and prevents kyphoscoliosis in zebrafish.
Williams-Ward VC, Wanders K, Hughes SM
PLoS Genet · 2026 May · PMID 42207799 · Full text
Scoliosis affects 2-3% of people, often developing during and after adolescence, and currently has a lifetime chance of surgical intervention of ~0.1% in high income countries. Understanding of causal genetic and environ...
Scoliosis affects 2-3% of people, often developing during and after adolescence, and currently has a lifetime chance of surgical intervention of ~0.1% in high income countries. Understanding of causal genetic and environmental factors is improving, with mechanical feedback interactions between the neuromuscular and skeletal systems thought to be important. While examining mechanosignalling in the zebrafish musculoskeletal system, we observed transient expression of yap1 mRNA in precursor cells of muscle and notochord and wwtr1 mRNA accumulation in differentiated muscle. Yap1 and Wwtr1/Taz are transcriptional coactivators that mediate Hippo pathway signalling, often in response to mechanosignals. Loss of function mutation of either gene alone transiently altered early larval motility and reduced survival to adulthood, but mutation of yap1 specifically diminished overall growth without an obvious histological muscle defect. Yap1 mutants had a temperature-sensitive phenotype of oedema in cardiac and other tissues, which could be rescued by rearing at low temperature. Rescued yap1 mutants showed focal defects in hypochordal col8a1a mRNA expression at 1-2 days post-fertilisation (dpf), an early motility defect at 5 dpf and subsequently developed a fully penetrant vertebral dysmorphology, reflected by a decrease in posterior vertebral height. Thereafter, frank kyphoscoliosis accompanied by additional vertebral defects developed in around a third of the surviving yap1 mutants and was first detected at 11 dpf. Thus, the mild initial vertebral defect can, in a predisposing genetic or environmental background, gradually develop into full kyphoscoliosis through a positive feedback mechanism, analogous to the Hueter-Volkmann 'Law'. Although the cell type/s of cell autonomous yap1 action remain unclear, we hypothesise that Yap1 mechanosensation mediates feedback between bone, muscle and tendon to restrain vertebral overgrowth and protect against the development of kyphoscoliosis.
Species-specific coevolution of RecA-RecN interfaces governs DNA double-strand break repair in Escherichia coli.
Inoue M, Akanuma G, Hayashi M … +1 more , Hishida T
PLoS Genet · 2026 May · PMID 42207797 · Full text
DNA double-strand breaks (DSBs) threaten genome stability and cell survival but can be faithfully repaired through homologous recombination (HR). RecN, a bacterial protein closely related to the structural maintenance of...
DNA double-strand breaks (DSBs) threaten genome stability and cell survival but can be faithfully repaired through homologous recombination (HR). RecN, a bacterial protein closely related to the structural maintenance of chromosomes family, cooperates with RecA in HR-dependent DSB repair, yet the molecular basis and physiological relevance of their interaction remain unclear. Here, we investigated the functional interplay between RecA and RecN during DSB repair by heterologously expressing Pseudomonas aeruginosa RecA (paRecA) and RecN (paRecN) in Escherichia coli. We found that in E. coli ∆recA ∆recN cells, co-expression of paRecA and paRecN fully restored MMC resistance, whereas co-expression of E. coli RecA (ecRecA) with paRecN conferred partial resistance to mitomycin C (MMC), demonstrating species-specific compatibility. Expression analysis revealed that paRecN was poorly expressed in E. coli, but codon optimization significantly enhanced its abundance and repair activity. We further identified gain-of-function paRecN mutants (I73T and R453H) that restored repair without increased expression. These mutants displayed species-specific adaptation, which improved compatibility with ecRecA but reduced functionality with paRecA. Fluorescence microscopy revealed that MMC-induced nucleoid localization was increased in paRecNI73T and paRecNR453H compared with paRecN. Collectively, these findings demonstrate that coevolution optimizes the RecA-RecN interface to ensure efficient DSB repair.
mFABIO: An integrative multi-tissue TWAS fine-mapping approach to prioritize potentially causal genes and tissues underlying binary traits.
Zhang H, He K, Tsoi LC … +1 more , Zhou X
PLoS Genet · 2026 May · PMID 42201988 · Full text
Recent advances in transcriptome-wide association study (TWAS) fine-mapping have enabled the joint modeling of multiple genes to improve causal gene prioritization. However, existing methods have been developed primarily...
Recent advances in transcriptome-wide association study (TWAS) fine-mapping have enabled the joint modeling of multiple genes to improve causal gene prioritization. However, existing methods have been developed primarily for quantitative traits and most of them rely on gene expression data from a single tissue. Here, we present mFABIO, a multi-tissue TWAS fine-mapping method specifically designed for binary traits. mFABIO employs a probit model to directly link genetically regulated expression (GReX) of genes within a locus across multiple tissues to a binary outcome, while accounting for correlations in GReX across genes and tissues. As a result, mFABIO offers substantial power gains for binary traits, while maintaining robust control of false discovery rates (FDR). We evaluated mFABIO through extensive simulations and applied it to an in-depth analysis of six binary disease traits (asthma, breast cancer, gout, hypertension, prostate cancer, and rheumatoid arthritis) in the UK Biobank, using expression data spanning 38 Genotype-Tissue Expression (GTEx) tissues. mFABIO identified an average of 42 likely causal genes and 65 tissue-gene pairs per disease (FDR < 0.05). Notably, 60.9% of the genes and 77.2% of the gene-tissue pairs were supported by existing TWAS or GWAS evidence. This represented at least a 14.9% increase in evidence-supported genes and a 14.8% increase in evidence-supported gene-tissue pairs, compared to existing approaches. Additionally, mFABIO was also able to narrow down the list of potentially causal candidates by at least 51.3% for genes, and 50.8% for gene-tissue pairs, compared to single-tissue approaches. Leveraging its improved power, mFABIO successfully prioritized multiple potentially causal gene-tissue pairs associated with these diseases, with biological support. Notable examples include D2HGDH in lung tissue for asthma, CYBRD1 in breast mammary tissue for breast cancer, and CCR6 in spleen tissue for rheumatoid arthritis. Overall, mFABIO serves as an effective tool for multi-tissue TWAS fine-mapping of binary traits.
Predicting antifolate resistance in the unculturable fungal pathogen Pneumocystis jirovecii.
Rouleau FD, Dubé AK, Pageau A … +3 more , Désautels L, Dufresne PJ, Landry CR
PLoS Genet · 2026 May · PMID 42201980 · Full text
Pneumocystis jirovecii is an opportunistic fungal pathogen responsible for Pneumocystis pneumonia (PCP) in immunocompromised patients. Antifolate drugs targeting the dihydrofolate reductase (DHFR), including trimethoprim...
Pneumocystis jirovecii is an opportunistic fungal pathogen responsible for Pneumocystis pneumonia (PCP) in immunocompromised patients. Antifolate drugs targeting the dihydrofolate reductase (DHFR), including trimethoprim (TMP), remain central to treatment, but studying the effects of mutations in DHFR on resistance to treatment is limited by our inability to culture this organism in vitro or in animal models. We expressed P. jirovecii DHFR (PjDHFR) in Saccharomyces cerevisiae and performed deep mutational scanning (DMS) on this protein to measure the effects of all single amino-acid substitutions on enzyme function and resistance to methotrexate (MTX), a model antifolate which shares structural features with TMP. We integrated experimental results with structural and evolutionary features from multiple biophysical modeling approaches, and by using an interpretable machine-learning framework, we trained a random forest model to classify MTX resistance-conferring mutations in PjDHFR. We then leveraged this framework as a prediction tool to model the effects of mutations on resistance to TMP, which cannot be directly assayed experimentally. Functional measurements from DMS were the strongest contributors to resistance prediction and generally outperformed purely computational features. Resistance-conferring mutations were constrained by function, revealing a functional-resistance trade-off within this essential protein. Feature contribution analyses highlighted key predictors such as distance to ligand, flexibility, stability, and functional trade-off as determinants of resistance. When extrapolated to TMP, the model identified candidate resistance mutations consistent with known biochemical constraints of DHFR. We demonstrate how experimentally measured functional landscapes can be combined with biophysical modeling to help understand and predict antifolate resistance in an unculturable fungal pathogen. Our results provide biological insight into the constraints affecting the evolution of resistance in PjDHFR, and support that resistance arises from mutations altering drug interactions while preserving function. We illustrate how DMS data can enable generalizable, mechanistically interpretable models of drug resistance across structurally related antifolates.
FabF and FadM cooperate to recycle fatty acids and rescue ∆plsX lethality in Staphylococcus aureus.
Wongdontree P, Palmier M, Louche C … +7 more , Leguillier V, Rodrigues CM, Gloux K, Halpern D, Henry C, Anba-Mondoloni J, Gruss A
PLoS Genet · 2026 May · PMID 42201948 · Full text
Phospholipids are essential components of most cell membranes. In Staphylococcus aureus, PlsX acyltransferase is considered indispensable for initiating phospholipid synthesis, unless exogenous fatty acids (FAs) are avai...
Phospholipids are essential components of most cell membranes. In Staphylococcus aureus, PlsX acyltransferase is considered indispensable for initiating phospholipid synthesis, unless exogenous fatty acids (FAs) are available to bypass this requirement. We report that S. aureus can capture internal FA sources to overcome PlsX essentiality in a ∆plsX mutant via point mutations in either of two genes: fabF, which encodes the FA synthesis enzyme 3-oxoacyl-(acyl-carrier-protein) synthase II, or fadM, which encodes an understudied bifunctional acyl-CoA thioesterase and ACP binding protein. Despite growth rescue, both ∆plsX suppressors differ from the parental strain by producing phospholipids with shortened FA lengths, suggesting that both suppressors lead to premature FA release during synthesis. Additionally, both suppressors display increased sensitivity to β-lactam antibiotics. The similar behavior of both suppressors led us to show that fabF suppressors require the presence of fadM, indicative of FabF-FadM cooperation. We propose that reduced processivity of FabF suppressor variants, or greater availability of FadM for ACP binding in FadM variants, facilitates FA release from FabF-acyl-ACP intermediates. A FabF-FadM relay leading to FA release may contribute to homeostasis between FASII and phospholipid synthesis pathways.
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