PLoS Genet. [JOURNAL]
Sun
200 papers
Simplifying causal gene identification in GWAS loci.
Schipper M, Ulirsch J, Posthuma D … +2 more , Ripke S, Heilbron K
PLoS Genet · 2026 Mar · PMID 41843578 · Full text
Genome-wide association studies (GWAS) help to identify disease-linked genetic variants, but pinpointing the most likely causal genes in GWAS loci remains challenging. Existing GWAS gene prioritization tools are powerful...
Genome-wide association studies (GWAS) help to identify disease-linked genetic variants, but pinpointing the most likely causal genes in GWAS loci remains challenging. Existing GWAS gene prioritization tools are powerful but often use complex black box models trained on datasets containing biases. Here, we used a data-driven approach to construct a truth set of causal genes in 200 GWAS loci. We found that a simple logistic regression model performed as well as a more complex XGBoost model, and that many commonly-used gene prioritization features could be removed without meaningfully affecting performance (e.g., expression quantitative trait locus colocalization and Mendelian randomization). We present CALDERA, a gene prioritization tool that uses a logistic regression model and uses just four input features. In independent benchmarking datasets of resolved GWAS loci, CALDERA achieved state-of-the-art performance in comparison with other methods (FLAMES, L2G, and cS2G). CALDERA outputs causal gene probabilities for all genes in a given GWAS locus and we show that these probabilities are well-calibrated. Applying CALDERA to 93 UK Biobank traits, we predicted 11,956 putative causal genes, potentially resolving up to 52% of loci. Overall, CALDERA provides a powerful solution for prioritizing potentially causal genes in GWAS loci that minimizes the data processing required to construct input features and generates an easily-interpretable output score.
Functional interrogation of candidate cis-regulatory elements at the LDLR locus.
Leix K, Serrano-Zayas C, Vyas HS … +2 more , Graham SE, Emmer BT
PLoS Genet · 2026 Mar · PMID 41843552 · Full text
Regulation of LDLR gene expression plays an important role in the development of atherosclerotic diseases including heart attack and stroke. Although LDLR regulation by sterol response elements has been well characterize...
Regulation of LDLR gene expression plays an important role in the development of atherosclerotic diseases including heart attack and stroke. Although LDLR regulation by sterol response elements has been well characterized, the functional significance of other noncoding regions at the LDLR locus remains poorly defined. In this study, we developed and applied a high throughput CRISPR screen to test the functional importance of candidate LDLR cis-regulatory elements (CREs) in their native genomic context. In total, we found 25 discrete regions to exhibit a significant impact on LDLR expression. For one of these regions with particularly strong activity in the first intron, we validated the presence of an enhancer by confirming that its disruption reduced endogenous LDLR expression while its insertion upstream of a minimal promoter augmented reporter gene expression. We then applied a massively parallel reporter assay to fine map enhancer activity within this region to a 129 bp interval that is highly conserved among vertebrates, exhibits biochemical hallmarks of enhancer activity, is enriched for transcription factor binding motifs, and contains a common genetic variant (rs57217136) that has been associated with human LDL cholesterol levels by genome-wide association studies. Overall, these findings demonstrate the power of CRISPR screening to interrogate candidate CREs and clarify the functional landscape of noncoding sequences at the LDLR locus.
Topological stratification of continuous genetic variation in large biobanks.
Diaz-Papkovich A, Zabad S, Snell H … +6 more , Ben-Eghan C, Anderson-Trocmé L, Femerling G, Nathan V, Patel J, Gravel S
PLoS Genet · 2026 Mar · PMID 41838785 · Full text
Biobanks now contain genetic data from millions of individuals. Dimensionality reduction, visualization and clustering are standard when exploring data at these scales; while efficient and tractable methods exist for the...
Biobanks now contain genetic data from millions of individuals. Dimensionality reduction, visualization and clustering are standard when exploring data at these scales; while efficient and tractable methods exist for the first two, clustering remains challenging because of the many ways in which demography and sampling can affect structure. In practice, clustering is commonly performed by drawing shapes around dimensionally reduced data or assuming populations have "type" genomes or allele frequencies that represent a population. We propose to use dimensionality reduction with UMAP followed by clustering with HDBSCAN to identify sets of points forming relatively dense subsets in genotype space. The approach is fast, easy to implement, and integrates with existing pipelines. When applied to simulated data or data from three biobanks, the approach identifies groups of individuals enriched for shared features correlated with ancestry, including country of birth, ethnicity, and sampling location, without requiring strong assumptions about the number or size of clusters, or the sources of population structure. Because it does not rely on proximity to a specific point in genetic space, this topological approach can form clusters that continuously span long distances in genetic space. This can help distinguish admixed populations, which can exhibit wide ancestry variation within populations and overlap of ancestry proportions across populations. Such clusters can highlight and account for interpretable sources of genetic, demographic, or sampling heterogeneity in a dataset that would otherwise have required a range of specialized techniques. We illustrate how topological genetic strata can further help us understand structure within biobanks, evaluate distributions of genotypic and phenotypic data, examine polygenic score transferability, identify potential influential alleles, and perform quality control.
Estimating the distribution of fitness effects of loss of heterozygosity (LOH) events using an engineered library of Saccharomyces cerevisiae.
Ke YH, Orozco-Quime M, Bauman J … +5 more , Carvalho T, Landry GA, Ge S, Kumar A, James TY
PLoS Genet · 2026 Mar · PMID 41838761 · Full text
Loss of heterozygosity (LOH) is a large contributor of genetic variation in natural populations or lab-evolved asexual diploids. However, its contribution to adaptation is uncertain, because the full spectrum of its fitn...
Loss of heterozygosity (LOH) is a large contributor of genetic variation in natural populations or lab-evolved asexual diploids. However, its contribution to adaptation is uncertain, because the full spectrum of its fitness effects remains largely uncharacterized. To systematically investigate the distribution of fitness effects (DFE) of LOH, we engineered a diverse, barcoded library of heterozygous diploid Saccharomyces cerevisiae strains, each containing randomly induced LOH events. By employing competitive fitness assays and barcode sequencing (Bar-seq) across seven distinct environments, including various stressors from chemicals, temperature, and an in vivo host model, we quantified the fitness consequences of LOH events. Our results reveal that the DFE of LOH is predominantly neutral to deleterious, with a general trend of decreasing fitness correlated with larger cumulative lengths of LOH tracts. However, the fitness effects were variable and the fitness landscape was highly environment-dependent. While beneficial LOH events were rare and of small effect in standard rich media, they were common and conferred substantial fitness gains in novel or stressful conditions. A key finding was the prevalence of antagonistic pleiotropy where over 75% of strains exhibited fitness trade-offs, gaining an advantage in one environment at the cost of fitness in others. The magnitude of these trade-offs was also found to correlate with longer LOH tracts. Overall, this work demonstrates that LOH plays a dual role in evolution. While it often imposes a genetic burden, it also provides a powerful mechanism for rapid, environment-specific adaptation, driving specialization by trading general robustness for niche-specific advantages.
Evolutionary turnover of key amino acids explains conservation of function without conservation of sequence in transcriptional activation domains.
LeBlanc CJ, Stefani J, Soriano M … +11 more , Lam AWY, Zintel MA, Kotha SR, Chase EP, Pimentel-Solorio G, Vunnum A, Hu G, Flug KL, Fultineer A, Hummel N, Staller MV
PLoS Genet · 2026 Mar · PMID 41838698 · Full text
In folded protein domains, protein function is frequently more conserved than amino acid sequence because highly diverged sequences can fold into equivalent 3D structures with identical function. During evolution, intrin...
In folded protein domains, protein function is frequently more conserved than amino acid sequence because highly diverged sequences can fold into equivalent 3D structures with identical function. During evolution, intrinsically disordered protein regions (IDRs) often experience rapid amino acid sequence divergence, but because they do not fold into stable 3D structures, it remains largely unknown when and how function is conserved. As a model system for studying the evolution of IDRs, we examined transcriptional activation domains, the regions of transcription factors that bind to coactivator complexes. We systematically identified activation domains on 502 homologs of the transcriptional activator Gcn4 spanning 600 MY of fungal evolution in the Ascomycota. We found that the central activation domain shows strong conservation of function without conservation of sequence. This conservation of function without conservation of sequence arises from evolutionary turnover (gain and loss) at two length scales. Within the central activation domain, we see turnover of acidic and aromatic residues, but primarily loss of short linear motifs. In the full-length transcription factor, we see turnover of entire activation domains. Stabilizing selection and evolutionary turnover at multiple length scales are likely a general mechanism for conservation of function without conservation of sequence in IDRs.
COG5 deficiency disrupts cellular copper homeostasis and underlies the impaired mitochondrial OXPHOS function.
Zhou Y, Li K, Zhu R … +12 more , Ma X, Ye X, Mao M, Li D, Zeng X, Chen Z, Wu J, Jin L, Tang X, Yang Y, Lyu J, Lou X
PLoS Genet · 2026 Mar · PMID 41824529 · Full text
COG5, a subunit of the conserved oligomeric Golgi (COG) complex, plays a critical role in retrograde trafficking within the Golgi apparatus. Dysfunction of COG5 is associated with various human disorders, yet the underly...
COG5, a subunit of the conserved oligomeric Golgi (COG) complex, plays a critical role in retrograde trafficking within the Golgi apparatus. Dysfunction of COG5 is associated with various human disorders, yet the underlying pathogenic mechanisms remain poorly understood. To investigate the mechanisms, we conducted proteomic analyses using COG5-deficient and rescue cell models, which revealed a potential link between COG5 dysfunction and mitochondrial oxidative phosphorylation (OXPHOS) deficiency. Using COG5-deficient cell models and patient-derived cells harboring COG5 variants, we biochemically validated the involvement of COG5 in mitochondrial OXPHOS, particularly in the regulation of complex I content. These models also exhibited elevated cellular copper levels. Notably, the significant reduction in OXPHOS complexes could be rescued by either restoring COG5 expression or administering a copper chelator. We further demonstrated that excessive cellular copper disrupts the function of mitochondrial iron-sulfur clusters, potentially leading to complex I assembly defects. Additionally, we identified a patient with biallelic COG5 variants presenting with a distinct subtype of mitochondrial disease (Leigh syndrome), a phenotype not previously associated with COG5-related disorders. These findings provide novel mechanistic insights into the role of COG5, extending beyond its established function in Golgi-mediated glycosylation modifications. Our results underscore the importance of COG5 in mitochondrial function through a copper-dependent pathway, offering new perspectives on its contribution to cellular homeostasis and disease pathogenesis.
Wanted: A population genetic theory of biological noise regulation.
Weinreich DM, Sgouros T, Raynes Y … +5 more , Burtsev H, Chang E, Rajakumar S, Bravo IG, Petak C
PLoS Genet · 2026 Mar · PMID 41824490 · Full text
Classical population genetics provides a robust, quantitative framework for modeling how natural selection acts on alleles that influence phenotypes with invariant fitness consequences for their carriers, such as running...
Classical population genetics provides a robust, quantitative framework for modeling how natural selection acts on alleles that influence phenotypes with invariant fitness consequences for their carriers, such as running speed or drug resistance. By contrast, modifier theory considers the evolution of alleles that influence population genetic parameter values in their carriers, such as mutation or recombination rates. This is a more complicated problem. First, the fitness effects of modifier alleles reflect independently realized stochastic phenotype perturbations they induce in their carriers. And second, the association between modifier alleles and their induced phenotypes can decay over generations. Consequently, general results in modifier theory have been few. Here, we propose recasting modifier theory as exploring the evolution of alleles that influence the amount of stochasticity in inheritance, be it genetic, epigenetic, cytoplasmic or somatic transmission. We then present a toy model that predicts the existence of a selectively optimal amount of such "reproductive noise," which depends on the rate of environment change, the timescale of association between noise allele and induced phenotype, and population size. Next, we suggest that the same framework can be applied to the evolution of alleles that influence "developmental noise," i.e., the amount of stochastic phenotypic variation among genetically identical organisms reared in identical environments. This theoretical connection is timely, because high throughput assays are now demonstrating widespread heritability in the amount of developmental noise. Our approach also resolves the long-standing teleological criticism of the hypothesis that evolvability can evolve by natural selection. Taken together, this work demonstrates the opportunities for a robust, quantitative population genetic theory of alleles that influence the amount of biological noise.
Nucleosome positioning shapes cryptic antisense transcription.
Kok JY, Harvey ZH, Axelsson E … +1 more , Berger F
PLoS Genet · 2026 Mar · PMID 41824417 · Full text
Maintaining transcriptional fidelity is essential for precise gene regulation and genome stability. Despite this, cryptic antisense transcription, occurring opposite to canonical coding sequences, is a pervasive feature...
Maintaining transcriptional fidelity is essential for precise gene regulation and genome stability. Despite this, cryptic antisense transcription, occurring opposite to canonical coding sequences, is a pervasive feature across all domains of life. How such potentially harmful cryptic sites are regulated remains incompletely understood. Here, we show that nucleosome arrays within gene bodies play a key role in suppressing cryptic transcription. Using the fission yeast Schizosaccharomyces pombe as a model, we demonstrate that the CHD-family chromatin remodeler Hrp3 coordinates with the transcription elongation machinery, via the transcriptional regulator Prf1/RTF1, to position nucleosomes at sites of cryptic transcription initiation within gene bodies. In the absence of Hrp3, AT-rich sequences within gene bodies lose nucleosome occupancy, exposing promoter-like sequences that drive cryptic initiation. While cryptic transcription is generally detrimental, we identify a subset of antisense transcripts that encode critical meiotic genes, suggesting that cryptic transcription can also serve as a source of regulatory innovation. These findings define an elongation‑coupled chromatin pathway that preserves transcriptional fidelity and reveal how nucleosome remodeling shapes antisense transcription, cellular homeostasis, and adaptive potential.
Unraveling the genetic links between stature and disease in East Asians: A multi-biobank genetic correlation and risk prediction study.
Lin YJ, Liu TY, Yang JS … +13 more , Li JP, Chiou JS, Lu HF, Ariyoshi K, Hikino K, Terao C, Chou CH, Liang WM, Chou IC, Lin TH, Liao CC, Huang SM, Tsai FJ
PLoS Genet · 2026 Mar · PMID 41824406 · Full text
Both genetic and environmental factors affect human stature, including overall height and familial short stature (FSS), and it is associated with various health outcomes. However, the study of genetic connections between...
Both genetic and environmental factors affect human stature, including overall height and familial short stature (FSS), and it is associated with various health outcomes. However, the study of genetic connections between stature and health conditions remains lacking in East Asian populations. Hence, we conducted parallel genome-wide association studies (GWAS) of body height and FSS in the Han Taiwanese population, aiming to elucidate the genetic influences of stature on health and facilitate the formulation of precision-health strategies. We analyzed large-scale GWAS data on adult height (120,301 Han Taiwanese) and FSS (FSS; 2,050 cases, 27,966 controls) to examine cross-trait genetic correlations across five East Asian biobanks, and applied phenome-wide association studies (PheWAS) and polygenic risk score (PRS) analyses to assess clinical outcomes using Cox proportional hazard models and Kaplan-Meier analyses. We identified 293 loci for height and five for FSS, with cross-biobank genetic correlations linking stature to body size, lung function, and cardiovascular/reproductive traits (atrial flutter/fibrillation [AF], menarche, and endometriosis). PheWAS showed that height PRS increased risks of AF and endometriosis, while FSS PRS had a protective effect against endometriosis. MR analyses showed that taller stature increased AF risk independently and endometriosis risk through menarche/weight, while shorter stature had a weak protective effect against endometriosis. Survival analyses showed the association of higher height PRS with greater AF risk and an earlier divergence of cumulative incidence curves. These time-to-event patterns were consistently replicated using meta-analysis-derived PRSs. The findings highlight stature-related genetic determinants, associated health outcomes, and polygenic risk scores as effective tools for early risk prediction and precision health strategies in East Asian populations.
Homeodomain protein Sxi1α independently controls cell-cell fusion and gene expression during sexual reproduction in Cryptococcus deneoformans.
Huang J, Lehmann AE, Peterson PP … +4 more , Xu Z, Xiong L, Sun S, Heitman J
PLoS Genet · 2026 Mar · PMID 41818280 · Full text
Sex-specific homeodomain (HD) proteins are key regulators of cell identity and sexual development in fungi, typically functioning as heterodimers to govern transcription. In the human fungal pathogens Cryptococcus neofor...
Sex-specific homeodomain (HD) proteins are key regulators of cell identity and sexual development in fungi, typically functioning as heterodimers to govern transcription. In the human fungal pathogens Cryptococcus neoformans and Cryptococcus deneoformans, the HD proteins Sxi1α and Sxi2a (Sex-inducer 1α and 2a) have been characterized as interacting components that play critical roles in sexual development during α x a sexual reproduction. α cells are the predominant mating type in natural populations of Cryptococcus, and unisexual (same-sex) mating can also occur in certain genetic backgrounds. The roles of Sxi1α and Sxi2a in unisexual reproduction are not fully understood. To elucidate the functions of Sxi1α and Sxi2a, we first applied AlphaFold3 prediction, which identified potential heterodimeric and homodimeric complexes. Formation of a Sxi2a homodimer was then experimentally validated through yeast two-hybrid assays. We subsequently deleted SXI1α and SXI2a in the hyper-filamentous self-fertile C. deneoformans strains XL280α and XL280a. Disruption of these genes did not result in noticeable defects in vegetative growth, virulence-associated traits, colony morphology, sporulation, or competitive fitness during unisexual crosses. Interestingly, both bilateral (mutant x mutant) and unilateral (mutant x wild type) crosses involving the sxi1αΔ mutant showed significantly increased α-α cell fusion efficiency, suggesting a previously unrecognized inhibitory role for Sxi1α in regulating same-sex cell fusion. Consistently, genes encoding mating pheromones and the α-pheromone receptor Ste3 were upregulated in the sxi1αΔ fusion assays. Transcriptomic analysis of sxi1αΔ and sxi2aΔ mutants led to the identification of unique subsets of genes negatively regulated by each transcription factor during unisexual reproduction. Additionally, α x a crosses between sxi1αΔ and sxi2aΔ mutants revealed differential regulation of mating-type (MAT) loci genes dependent only on Sxi1α or Sxi2a. Together, our findings reveal a novel role for Sxi1α in governing cell fusion and demonstrate that Sxi1α and Sxi2a have distinct transcriptional control during unisexual and α x a sexual reproduction, potentially exerting opposing regulation of sex-specific MAT genes.
The genetic basis of mimicry in the snowy bumble bee (Bombus niveatus) in Anatolia with insights from a color polymorphic gynandromorph.
Dabak T, Özenirler Ç, Kamalak E … +4 more , Smith C, Aytekin S, Aytekin AM, Hines HM
PLoS Genet · 2026 Mar · PMID 41811856 · Full text
Bumble bees (Bombus spp.) display remarkable color pattern diversity and convergence driven largely by Müllerian mimicry. In Anatolia, bumble bees mimic each other by converting ancestral yellow anterior setal body color...
Bumble bees (Bombus spp.) display remarkable color pattern diversity and convergence driven largely by Müllerian mimicry. In Anatolia, bumble bees mimic each other by converting ancestral yellow anterior setal body color to white in multiple independent lineages. Here, we investigate the genetic basis of white-yellow mimetic color dimorphism in the snowy bumble bee Bombus niveatus, separated into two subspecies based on coloration: the white Bombus niveatus niveatus and the yellow Bombus niveatus vorticosus. Using a genome-wide association study (GWAS) of males sampled across dimorphic populations, we identify a strong association peak linked to white-yellow variation in the cis-regulatory region of the homeobox gene BarH, a gene previously implicated in driving spatial patterning of epidermal projections and pigmentation. This locus, coined the snowy locus, involves a derived tandem duplication unique to the white form that likely increases the number of transcription factor binding sites. Comparative sequencing of snowy indicates co-mimicking species use different variants for their white-yellow convergent transitions. Additionally, we describe and genetically analyze a largely bilateral mosaic gynandromorph of B. niveatus with a mix of both color forms across its body. This was determined to be generated by a mosaic of at least two separate haploid sources with different snowy alleles, and diploid tissue heterozygous for the color locus. This supports the genetic basis for the color polymorphism and reinforces the conspecific status of the two forms. Together, these findings expand our understanding of the genetic basis of mimetic color pattern convergence in this phenotypic radiation.
Alanine-scanning mutagenesis library of MreB reveals distinct roles for regulating cell shape and viability.
Maharjan S, Sloan R, Lusk J … +3 more , Bevienguevarr R, Surber J, Morgenstein RM
PLoS Genet · 2026 Mar · PMID 41802002 · Full text
The bacterial actin-homolog MreB is a crucial component of the Rod-system (elongasome) that maintains rod shape in many bacteria. It is localized beneath the cytoplasmic membrane, where it organizes the elongasome comple...
The bacterial actin-homolog MreB is a crucial component of the Rod-system (elongasome) that maintains rod shape in many bacteria. It is localized beneath the cytoplasmic membrane, where it organizes the elongasome complex. Depletion or deletion of mreB results in loss of rod shape and cell death; however, the mechanism of how MreB operates is not known. Past studies have reported that mutations in mreB cause varying degrees of cell shape and size alterations based on the type and position of the substitution. To better understand the role of MreB in rod shape formation we have taken the first truly systematic approach by replacing the native copy of mreB with an alanine-scanning mutagenesis library. Surprisingly, we observed stably growing spherical mutants that have lost MreB's function(s) for shape regulation without losing viability. Hence, MreB has vital functions related to growth in addition to shape maintenance that can be separated. In support of this, rod shape suppressor analysis of these spherical mutants only revealed reversions or intragenic mreB mutations, suggesting that MreB is indispensable for rod shape. Additionally, our results imply the elongasome is no longer active in these strains, suggesting a novel way for rod shaped bacteria to synthesize cell wall.
The effect of long-range linkage disequilibrium on allele-frequency dynamics under stabilizing selection.
Negm S, Veller C
PLoS Genet · 2026 Mar · PMID 41801963 · Full text
Stabilizing selection on a polygenic trait reduces the trait's genetic variance by (i) generating correlations (linkage disequilibria) between opposite-effect alleles throughout the genome, and (ii) selecting against rar...
Stabilizing selection on a polygenic trait reduces the trait's genetic variance by (i) generating correlations (linkage disequilibria) between opposite-effect alleles throughout the genome, and (ii) selecting against rare alleles at loci that affect the trait, eroding heterozygosity at these loci. Here, we show that the linkage disequilibria, which stabilizing selection generates on a rapid timescale, slow down the subsequent allele-frequency dynamics at individual loci, which proceed on a much longer timescale. Exploiting this separation of timescales, we obtain expressions for the expected per-generation change in minor-allele frequency at individual loci, as functions of the effect sizes at these loci, the strength of selection on the trait, its variance and heritability, and the linkage relations among loci. Using whole-genome simulations, we show that our expressions predict allele-frequency dynamics under stabilizing selection more accurately than the formulae that have previously been used for this purpose. Our results have implications for understanding the genetic architecture of complex traits.
Polygenic risk scores and Parkinson's disease in South Africa advancing ancestry informed disease prediction.
Step K, Ndong Sima CAA, Grant S … +5 more , Kim JJ, Waldo E, Bardien S, Mata IF, Global Parkinson’s Genetics Program (GP2)
PLoS Genet · 2026 Mar · PMID 41801886 · Full text
Parkinson's disease (PD) is a complex neurodegenerative disorder with environmental and genetic influences. Using genotyping array data of 661 South African PD cases and 737 controls, we conduct a polygenic risk score (P...
Parkinson's disease (PD) is a complex neurodegenerative disorder with environmental and genetic influences. Using genotyping array data of 661 South African PD cases and 737 controls, we conduct a polygenic risk score (PRS) analysis using PRSice-2. Summary statistics from two PD association studies have been used as base datasets. We split the target dataset into training (70%; n = 979) and validation (30%; n = 419) cohorts. We test various clumping window sizes, linkage disequilibrium thresholds, and p-value thresholds to determine the optimal combination for risk prediction. Additionally, we investigate the variance explained by different combinations of covariates. Overall, we observe modest predictive performance (AUC: 0.5847-0.6183). Age at recruitment emerges as the strongest individual predictor, while sex contributes the least. These findings provide the first evaluation of PRS performance for PD in a highly admixed South African cohort, underscoring the importance of including underrepresented populations in genetic risk prediction. By systematically assessing predictive performance across two base datasets, we highlight how ancestry composition and study design affect risk estimation in diverse populations. This work lays a foundation for refining genomic prediction in admixed populations and contributes to ongoing efforts to ensure that advances in precision medicine are globally relevant.
Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling.
Botero V, Barrios J, Knauss A … +4 more , Dahlen G, Rosendahl E, Colodner KJ, Tomchik SM
PLoS Genet · 2026 Mar · PMID 41785270 · Full text
Neurofibromatosis type 1 results from mutations in the NF1 gene and its encoded neurofibromin protein. This condition produces multiple symptoms, including tumors, behavioral alterations, and metabolic changes. Molecular...
Neurofibromatosis type 1 results from mutations in the NF1 gene and its encoded neurofibromin protein. This condition produces multiple symptoms, including tumors, behavioral alterations, and metabolic changes. Molecularly, neurofibromin mutations affect Ras activity, influencing multiple downstream signaling pathways, including MAPK (Raf/MEK/ERK) and PI3K/Akt/mTOR signaling. This pleiotropy raises the question of which pathways could be targeted to treat the disease symptoms, and whether different phenotypes driven by neurofibromin mutations exhibit similar or diverging dependence on the signaling pathways downstream of Ras. To test this, we examined metabolic and behavioral alterations in the genetically tractable Drosophila neurofibromatosis type 1 model. In vivo genetic analysis revealed that behavioral effects of neurofibromin were mediated by MEK signaling, with no necessity for Akt. In contrast, metabolic effects of neurofibromin were mediated by coordinated actions MEK/ERK and Akt/mTOR/S6K/4E-BP signaling. At the systemic level, loss of neurofibromin dysregulated metabolism via molecular effects in interneurons and muscle. These changes were accompanied by altered muscle mitochondria morphology, with no concomitant changes in neuronal ultrastructure or neuronal mitochondria. Overall, this suggests that neurofibromin mutations affect multiple signaling cascades downstream of Ras, which differentially affect metabolic and behavioral neurofibromatosis type 1 phenotypes.
PARP-2 catalytic activity drives replication-ICL repair in an allele-specific manner during germline development.
Ren X, Hu A, Liu Z … +2 more , Kim S, Kim HM
PLoS Genet · 2026 Mar · PMID 41785248 · Full text
Maintaining genome integrity in the germline is critical for fertility and organismal survival. Here, we identify C. elegans PARP-2 as an essential and non-redundant regulator of replication-coupled DNA repair. PARP-2 lo...
Maintaining genome integrity in the germline is critical for fertility and organismal survival. Here, we identify C. elegans PARP-2 as an essential and non-redundant regulator of replication-coupled DNA repair. PARP-2 localizes to chromatin during germline development and is also present in the nucleolus; replication stress is associated with changes in its nucleolar distribution, linking fork perturbation to nucleolar signaling and ribosomal homeostasis. Loss of PARP-2 leads to embryonic lethality, larval arrest, and hypersensitivity to replication-blocking and crosslinking agents, accompanied by accumulation of recombination intermediates. Strikingly, a catalytic-dead mutant (E509K) causes even more severe defects than the null allele, including hyperactivation of DNA damage pathways and elevated apoptosis, revealing that PARP-2 enzymatic activity not only executes repair but also restrains excessive stress responses. Chromatin profiling further shows enrichment of PARP-2 at promoter-proximal, fragile loci, suggesting a constitutive surveillance role. Together, these findings establish PARP-2 as a multifunctional genome guardian that integrates catalytic and structural roles to maintain genome stability and nucleolar function, with implications for understanding PARP-associated disease mutations.
Transcriptional repression of reaper by Stand still ensures female germline development in Drosophila.
Matsui M, Kawaguchi S, Kai T
PLoS Genet · 2026 Mar · PMID 41785206 · Full text
Apoptosis plays a central role in shaping tissues and preserving cellular integrity across developmental stages. In the germline, its precise regulation is critical to ensure both the elimination of aberrant cells and th...
Apoptosis plays a central role in shaping tissues and preserving cellular integrity across developmental stages. In the germline, its precise regulation is critical to ensure both the elimination of aberrant cells and the maintenance of reproductive capacity. However, the molecular mechanisms that control apoptotic susceptibility in germline cells remain poorly defined. Here, we identify stand still (stil) as a female germline-specific regulator of apoptosis in Drosophila. Loss of stil leads to near-complete depletion of germline cells at the time of eclosion, associated with upregulation of the pro-apoptotic gene reaper (rpr) and activation of caspase-dependent cell death. Reporter assays in S2 cells show that Stil directly represses rpr transcription through its N-terminal BED-type zinc finger domain. The Dietera-restricted conservation of stil and rpr is consistent with a functional association. Despite the absence of stil, undifferentiated germline cells remain resistant to apoptosis. Analysis of publicly available chromatin data reveals that the rpr locus in these cells resides in a closed, H3K9me3-enriched chromatin state, suggesting a Stil-independent mode of transcriptional silencing. Together, our findings uncover two distinct mechanisms that protects the female germline from rpr-dependent apoptosis: Stil-mediated transcriptional repression that operates in both undifferentiated and differentiated germline cells, and an additional chromatin-based silencing mechanism that functions specifically in undifferentiated cells. This work provides new insights into the interplay between transcriptional and chromatin-based regulations that maintain germline cell identity and survival.
Genetic correlation-guided mega-analysis of DO mice provides mechanistic insight and candidate genes for age-related pathologies.
Mullis MN, Lefebvre AEYT, Sivasubramanian K … +10 more , Luo A, Schmid F, Sooknah M, Wright KM, Raj A, Zavala-Solorio J, Zhang C, Riegler J, Gillich A, Ruby JG
PLoS Genet · 2026 Feb · PMID 41758904 · Full text
Diversity Outbred (DO) mice are a powerful model system for mapping complex traits due to their high genetic diversity and mapping resolution. However, while there are extensive tools available for standard genetic analy...
Diversity Outbred (DO) mice are a powerful model system for mapping complex traits due to their high genetic diversity and mapping resolution. However, while there are extensive tools available for standard genetic analysis in DO mice, fewer techniques have been implemented to facilitate integrated, cross-study analysis. Here, we implement Haseman-Elston regression to estimate genetic correlations among 7,233 phenotypes measured across eleven independent DO mouse studies. We used this network of genetic correlations to cluster phenotypes according to shared genetics, which enhanced the power to detect quantitative trait loci (QTL). This approach empowered the detection of 884 QTL for 383 meta-phenotypes, explaining an average of 40.36% of the total genetic variance per mega-analysis. We leveraged this network for insights into specific areas of biology, including lifespan, frailty, immune composition, histological and functional lung phenotypes, and histological phenotypes of the aorta. We found the genetics of lifespan to share limited correlation with the genetics of frailty but stronger correlation with the genetics of immune cell composition. Additionally, mega-analyses driven by genetic correlations identified candidate genes (e.g., Cdkn2b) associated with degraded extracellular matrix in the aorta. Finally, an ensemble of genetic analyses implicated pulmonary neuroendocrine cell signaling and/or differentiation as a key driver of multiple lung pathophenotypes.
Aneuploidy alleviates the cell proliferation defect caused by mutations affecting origin licensing in Saccharomyces cerevisiae.
de La Roche Saint-André C
PLoS Genet · 2026 Feb · PMID 41758868 · Full text
Although aneuploidy is generally detrimental to the survival and growth of normal cells, it can be beneficial under certain stress conditions, such as those caused by harmful mutations. In Saccharomyces cerevisiae, we fi...
Although aneuploidy is generally detrimental to the survival and growth of normal cells, it can be beneficial under certain stress conditions, such as those caused by harmful mutations. In Saccharomyces cerevisiae, we find that duplication of chromosome III accelerates cell proliferation in the orc5-1 mutant. Enhanced proliferation is also observed when a fragment from a different chromosome is introduced, demonstrating that the benefit is not simply due to extra copies of specific genes. A comparable growth-enhancing effect of an extra chromosome is observed for mutations affecting other proteins involved in DNA replication licensing. The suppression of orc5-1 growth defect is also observed in the absence of the G1 cyclin Cln3, which lengthens the G1 phase, while overexpressing CLN3, which shortens G1, has the opposite effect. Additionally, Cln3 loss mirrors the effect of an extra chromosome for other mutations. These findings indicate that the severity of mutations impacting origin licensing hinges on the length of the G1 phase. Thus, we propose that the fitness-enhancing effect of an extra chromosome in DNA replication licensing mutants largely stems from its ability to extend G1, compensating for inefficient origin licensing.
Expanding the fly eye gene regulatory network: From Drosophila to the hoverfly Episyrphus balteatus.
Navarro T, Torres J, Sáez-Moreno R … +7 more , Guerrero G, Almudí I, Iannini A, Figueras J, Wotton K, Aerts S, Casares F
PLoS Genet · 2026 Feb · PMID 41746980 · Full text
Comparing organ-specific gene regulatory networks (GRNs) across large evolutionary distances remains a major challenge, particularly when the species under study differ in data resolution. This applies to the GRN control...
Comparing organ-specific gene regulatory networks (GRNs) across large evolutionary distances remains a major challenge, particularly when the species under study differ in data resolution. This applies to the GRN controlling compound eye development in insects, which is well characterized in Drosophila melanogaster but less well understood in other lineages. Here, we introduce the marmalade fly Episyrphus balteatus (Syrphidae), which diverged from Drosophila approximately 90 million years ago, as a comparative model to study eye development in Diptera. Using RNA-seq and ATAC-seq datasets, we reconstruct the first eye GRN in Episyrphus. Many genes involved in early Drosophila eye specification and differentiation are also active in Episyrphus. Among these, both species share a set of 22 transcription factors (TFs). The GRN built from these TFs and their DNA-binding motifs displays a high degree of internal connectivity. Link conservation analysis, followed by experimental testing in Drosophila, further identifies the AML1/Runx transcription factor lozenge (lz) as a negative regulator of the retinal determination gene dachshund (dac). Within the eye GRN, the degree of regulatory link conservation varies among genes, and both the number and position of regulatory regions often differ across orthologous loci. These results expand the eye GRN of Diptera and suggest extensive network rewiring over the evolutionary span separating Episyrphus and Drosophila.
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