PLOS Genetics: New Articles

METTL1-mediated m⁷G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis

2026-09-22T14:00:00Z

by Xinyan Gan, Qiwen Li, Qiuchan Xiong, Denghao Huang, Zizheng Liu, Qi Yin, Shuang Jiang, Takuma Matsubara, Shoichiro Kokabu, Wei Yan, Quan Yuan

Rapid hair follicle cycling requires precise fate commitment and differentiation of hair follicle stem cells. While the essential role of transcription factors in establishing cell identity is well recognized, how cells control its protein synthesis to achieve tissue specificity remains unknown. RNA modifications constitute a pivotal layer of post-transcriptional regulation for protein synthesis. Among them, the N⁷-methylguanosine (m⁷G) modification has recently emerged as a critical regulator with diverse functional impacts. Here, we reveal a pivotal role of METTL1, the key enzyme for RNA m⁷G modification, in hair follicle cycle. Conditional knockout of Mettl1 in keratinocytes leads to severe hair follicle developmental dysplasia, impaired regeneration, and disrupted keratinocyte adhesion. Complementarily, keratinocyte-specific knock-in of Mettl1 accelerates hair regeneration. Mechanistically, beyond its effects on tRNAs, METTL1 deficiency destabilizes HOXC13 mRNA through internal m⁷G modification, which in turn downregulates the HOXC13/FOXN1/DSG4 signaling axis. Our findings establish METTL1-mediated internal mRNA m⁷G methylation as one of the essential regulatory layers of RNA modification in hair follicle morphogenesis and cycling, operating through the precise post-transcriptional control of a key transcriptional circuit to ensure structural integrity and timely regeneration.

Bacterial chromosomal gene positioning is likely shaped by selection on both mean and growth-dependent expression

2026-09-21T14:00:00Z

by Ruiqi Yuan, Jianzhi Zhang

In bacteria with circular chromosomes, genes near the replication origin (oriC) are replicated earlier and consequently attain higher copy numbers than genes near the terminus (ter), particularly during rapid growth. Hence, mutations altering a gene’s chromosomal position can affect its expression level and be subject to selection. Two non–mutually exclusive hypotheses regarding the target of this selection have been proposed. The mean expression hypothesis (MEH) posits that the target is a gene’s average expression across environments, whereas the growth-dependent expression hypothesis (GEH) proposes that the target is the growth dependence of gene expression, quantified by the expression slope—the change in expression level per unit change in growth rate. To test these hypotheses and assess their relative support, we analyze eight multi-environment protein expression datasets from three bacterial species, as well as Escherichia coli promoter strengths measured in two environments. Consistent with both MEH and GEH, we observe a significant decrease in both mean expression and expression slope from oriC to ter in six and four of the eight datasets, respectively. In regression models predicting gene position, the relative contributions of the two hypotheses differ across species. However, even when combined, the two hypotheses explain only a small fraction of chromosomal gene positioning, in part because the replication-dose effect is incompletely offset by compensatory evolution of individual promoter strengths. The positional gradients in mean and growth-dependent expression are disproportionately contributed by genes involved in translation and transcription. We conclude that patterns of bacterial chromosomal gene positioning are consistent with moderate effects of selection on both mean and growth-dependent expression.

Genetic analysis of epistasis between nucleotide excision repair and homologous recombination in the recovery of persisters after fluoroquinolone treatment

2026-09-21T14:00:00Z

by Nashaly Soto-Echevarria, Annabel S. Lemma, Mark P. Brynildsen

Stationary-phase cultures contain high abundances of persisters, which are bacterial cells that are hyper-tolerant to antibiotics due to phenotypic reasons. Fluoroquinolones (FQs) are one of the most effective antibiotic classes for the treatment of non-growing bacteria, such as those found in stationary-phase cultures, and persisters in those populations have been found to survive FQ treatment by repairing the DNA damage caused by the antibiotic rather than by avoiding damage through inactivity. Interestingly, previous work demonstrated that transient growth inhibition after the conclusion of FQ treatment significantly increased persister levels from stationary-phase Escherichia coli populations if recA, a mediator of homologous recombination (HR), or uvrD, a component of nucleotide excision repair (NER), were present. Here, we sought to identify additional epistatic interaction partners in that persister recovery network by deleting DNA repair enzymes known to interact with RecA or UvrD. We found that uvrA, uvrB, and mfd also epistatically interact with recA in FQ persister recovery, whereas recB and recC are additional epistatic interaction partners of uvrD. While these results indicated that HR and NER can contribute to persister recovery, different combinations of genetic mutants suggested that the phenomenon is more nuanced than compensation for loss of one repair pathway by another. Specifically, loss of recA had farther reaching epistatic consequences than loss of other HR genes, and loss of uvrD had a greater impact on the network than any other NER gene. Delving deeper into the roles of RecA and UvrD, we found that the recombination function of RecA, via RecA(N304D), and helicase function of UvrD, via UvrD(R284A), were required for their participation in FQ persister recovery. Collectively, the data presented here deepen understanding of the roles of HR and NER machinery in the recovery FQ persisters and further emphasize the important roles of RecA and UvrD in this phenomenon.

Prenatal consequences of GALT deficiency in a rat model of classic galactosemia

2026-09-21T14:00:00Z

by Shauna A. Rasmussen, Catherine M. Lemons, Madelyn M. Seemiller, Sabrina R. Dallas, Milan Cambon Ledesma, Yuhan Wu, Lauren E. Anshen, Ashlyn Farnham, Olivia S. Garrett, Judith L. Fridovich-Keil

Classic galactosemia (CG) is a potentially lethal disease that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Prior reports document elevated galactose metabolites beginning in utero in CG, raising concern that long-term complications in CG might also trace their origins to the prenatal period. However, studies document that elevated galactose metabolites in the postnatal period do not predict later developmental complications, challenging the connection. Here, we explored the relationship between elevated galactose metabolites in utero and fetal outcome using a GALT-null rat model of CG. To modify galactose metabolites in utero, we arranged rat crosses to produce GALT-null pups developing within either a GALT-null or heterozygous dam, and with or without heterozygous siblings. We reasoned that GALT activity present outside the fetus, but within the maternal-fetal compartment, might limit metabolic abnormalities in a developing GALT-null fetus -- and it did. Specifically, while galactose metabolites in GALT-null fetal pups from all crosses remained elevated over controls, the levels varied. When the dam and some siblings were heterozygous, amniotic fluid galactitol from GALT-null fetal pups at GD21 was comparable to the levels reported from second trimester human CG amniotic fluid. When the dam was GALT-null, but some siblings were heterozygous, the median galactitol level in amniotic fluid was 2.45-fold higher. When the dam and all siblings were GALT-null, the median amniotic fluid galactitol level was 5.67-fold higher. GALT-null fetal pups also showed significant growth delay in utero, but only when the dam and all siblings were GALT-null. That growth of GALT-null fetal pups was fully rescued by gestation within a heterozygous dam despite the persistence of moderately elevated galactose metabolites raises the possibility that babies with CG developing within a carrier mother might also be at least partially protected in utero from the adverse consequences of their GALT-deficiency.

Dual contributions of Xrp1 to genome integrity through the DNA damage response and cell competition

2026-09-18T14:00:00Z

by Chaitali Khan, Nasser M. Rusan, Nicholas E. Baker

Model organisms may help understand how p53 suppresses tumorigenesis in mammals. In Drosophila, the primary transcriptional target of p53 is the gene encoding the bZip AT-hook protein Xrp1, which is another transcription factor. We report that Xrp1 mediates multiple functions of p53 in the DNA damage response (DDR), contributing to p53-dependent gene transcription and DNA damage-induced apoptosis. In addition to this role as a p53 effector, a p53-independent role for Xrp1 in cell competition has been described. Cell competition can remove cells whose genome has been altered by DNA damage and repair. During cell competition, Xrp1 is induced by RpS12, which acts as a sensor of defective ribosome biogenesis. In irradiated discs, p53-independent RpS12-dependent Xrp1 function began as the DDR came to an end, and was even more prominent if p53 function was reduced. Such p53 inhibition resulted in persistence of DNA damage after irradiation, revealed by γH2Av accumulation. Thus, Xrp1 limited the accumulation of abnormal cells resulting from genotoxicity through both the acute, p53-dependent DDR, and also a later mechanism consistent with cell competition removing cells where DNA repair did not restore the normal genome. Both these processes might contribute to the tumor suppressor function of p53 in mammals.

Identifying shared polygenic risk across cancers

2026-09-18T14:00:00Z

by Jiaqi Hu, Maiyier Muheyati, Leqi Xu, Andrew DeWan, Hongyu Zhao

Background

Shared genetic susceptibility across cancers has been reported but is generally modest at the genome-wide level. Whether such shared polygenic risk exhibits structured convergence at regional or functional levels remains unclear. We investigated shared genetic risk across cancers by integrating local genetic correlation analyses with cross-cancer polygenic risk score (PRS) associations.

Methods

We estimated pairwise local genetic correlations across 16 specific cancers and one pan-cancer phenotype using SUPERGNOVA. Genome regions harboring multiple cancers with mutually correlated local genetic effects were annotated using genetic correlations with non-cancer phenotypes and associations from the GWAS Catalog. In parallel, cross-cancer PRS associations were evaluated, and significant cancer pairs were identified. Genome-wide PRSs for selected pairs were further decomposed into pleiotropy-informed and pathway-specific components to assess functional enrichment of shared polygenic risk.

Results

Genome-wide genetic correlation analyses identified 20 significantly correlated cancer pairs, whereas local analyses revealed 82 regions with shared genetic signals across 66 cancer pairs. Five regions exhibited mutually correlated cancer clusters, with enrichment in functional domains such as inflammatory functions. Cross-cancer PRS analyses identified five cancer pairs with shared polygenic risk. Decomposition of PRSs indicated that these cross-cancer associations were enriched in specific pleiotropy groups and immune-related pathways rather than reflecting diffuse genome-wide overlap.

Conclusion

Our findings demonstrate that although shared genetic susceptibility across cancers is limited at the genome-wide level, it becomes evident when examined at regional and polygenic scales. Integrating local genetic correlation and PRS decomposition analyses reveals structured patterns of shared genetic risk, providing a framework for investigating cross-cancer polygenic susceptibility.

Beyond years of schooling: Genetic associations across educational milestones in two Norwegian cohorts

2026-09-17T14:00:00Z

by Eirik Haugland Kvalvik, Yunpeng Wang, Kristine Beate Walhovd, Torkild Hovde Lyngstad, Ole Røgeberg

Although educational attainment is heritable, years-of-education (EduYears) measures are not designed to show how genetic associations vary across discrete educational milestones. In the Norwegian Mother, Father and Child Cohort Study (MoBa; N = 120,527) and the Norwegian Twin Registry (N = 8,910), we combined genome-wide association studies (GWAS), polygenic indices (PGIs), and twin models to characterize genetic associations with high-school completion and bachelor’s, master’s, and doctoral attainment. In transition-specific analyses conditional on prior attainment, observed-scale common-variant heritability (h²_SNP) and PGI discrimination followed an inverse-U pattern, peaking for progression from high-school completion to attainment of at least a bachelor’s degree (HS → BSc + ; h²_SNP ≈ 0.14; R²_Tjur ≈ 0.05) and declining at postgraduate transitions. Genetic correlations (r_g) with large-scale GWAS of EduYears (EA4) and intelligence were high at earlier transitions but lower at later ones (for EA4, r_g ≈ 0.92 at HS → BSc+ and ≈ 0.38 at MSc → PhD). In cumulative analyses of attained status in the full cohort, the point-estimate gap between twin- and SNP-based heritability narrowed from ≈ 0.38 at high-school completion to ≈ 0.11 at PhD, while genetic overlap was lower for distant than adjacent milestones (r_g ≈ 0.71 for high-school completion versus PhD and ≈ 0.92 for adjacent milestones). Sensitivity analyses using an alternative intelligence GWAS and additional PGIs showed similar transition-specific trajectories. At the doctoral transition, estimates were obtained among individuals who had attained at least a master’s degree, so attenuation there must be interpreted in light of selection and range restriction. Because EduYears converts distinct credentials and progression steps into a single numerical scale, estimates expressed per additional year should not be interpreted as though one year has the same meaning across the educational sequence. Milestone-preserving analyses make that hidden structure visible and sharpen the interpretation of education GWAS and PGIs.

Arginine Kinase 1 supports energy homeostasis in Drosophila flight muscle development

2026-09-17T14:00:00Z

by Maria Paula Zappia, Anton Westacott, Hannah Cooke, Rhianna Geary, Libby Travers, Lucia de Castro, Oliver Carty, Maxim V. Frolov

In Drosophila, Arginine kinase 1 (Argk1) is involved in maintaining ATP homeostasis during bursts of activity in tissues with high and variable rates of energy turnover such as muscle. However, its role beyond stress conditions is less understood. Argk1 is the sole phosphagen kinase with dynamic expression throughout flight muscle development. Here, we show that at least one of the Argk1 isoforms localizes to mitochondria in the developing myofibers, and its function is also necessary for proper flight muscle development. Depleting Argk1 specifically in the muscles lead to low ATP level and NAD + /NADH ratio, indicative of defects in energy homeostasis, and results in animal lethality. In the wing disc-associated myoblasts, Argk1 knockdown causes a reduction in cell size without changes in cell cycle progression. Single cell RNA-sequencing (scRNA-seq) revealed that the transcriptomes of undifferentiated and differentiating Argk1-depleted myoblasts are not significantly affected compared to control. Furthermore, based on the marker expression and overall composition of scRNA-seq cell clusters, the early states of myoblasts differentiation are not severely disrupted in Argk1-depleted myoblasts. Nonetheless, Argk1 knockdown severely impacts later stages of muscle development. Remarkably, Argk1-depleted muscles completely lack spontaneous muscle contractions, which are required for proper sarcomere maturation in the formation of the indirect flight muscle. Accordingly, Argk1-depleted muscles showed defects related to sarcomere maturation, and mitochondrial morphogenesis; thus, leading to a severe reduction in muscle growth. Therefore, our data reveal an essential role for Argk1 in flight muscle development, presumably by sustaining local ATP levels to meet the energetic demand to support myofibrillogenesis, muscle growth and proper flight muscle function.

Outer membrane proteins mediate unconventional secretion of Pseudomonas peroxidase through crosstalk between the Sec pathway and outer membrane vesicles

2026-09-15T14:00:00Z

by Congying Liang, Wenping Zhu, Lu Lin

Lipoprotein and OmpW are two major components of the outer membrane (OM) in Gram-negative bacteria and play essential roles in various physiological processes, e.g., protein secretion, folding, and localization. They typically assist in maintaining client proteins in a folded state or form pore channels during secretion. However, how OM proteins facilitate the secretion of proteins that lack classical signal peptides remains elusive. Here, we demonstrate that they contribute to the secretion of unconventional B-type dye-decolorizing peroxidase (DypB₂₉₈₅) in Pseudomonas putida. The lipoprotein, Lpp₁₅₂₈, which contains a Sec signal peptide, is translocated to the periplasm through the Sec pathway and anchored in the inner leaflet of the OM. Lpp₁₅₂₈ recognizes the C-terminal hydrophobic region of DypB₂₉₈₅ in the cytoplasm and facilitates its coupling to the Sec machinery for inner membrane translocation, despite DypB₂₉₈₅ lacking a canonical N-terminal Sec signal peptide. Following translocation, the two proteins appear to dissociate in the periplasm. Subsequently, another OM protein, OmpW₄₈₃₆, recognizes the N-terminal hydrophobic region of periplasmic DypB₂₉₈₅ and mediates its incorporation into outer membrane vesicles (OMVs) for extracellular delivery. Our study reveals the crosstalk between the Sec pathway and OMVs in the secretion of a non-canonical peroxidase, in which OM proteins, acting as the molecular tethers, mediate the stepwise secretion process. It expands our understanding of non-classical protein secretion mechanisms and bacterial survival strategies. Moreover, the identified OMV sorting mechanism offers potential for the further functionalization of OMVs as versatile biotechnological platforms.

Assessing Hardy-Weinberg equilibrium in T2T-aligned 1000 genomes project

2026-09-15T14:00:00Z

by Elika Garg, Jaffa Romain, Lei Sun, Andrew D. Paterson

Quality control of markers in genome-wide association studies often includes testing for Hardy-Weinberg equilibrium (HWE). However, this is usually implemented in a homogeneous population without stratifying by sex. Previous work indicates sex-based selection at numerous autosomal loci in cohorts with active recruitment. Sex chromosome sequences can also interfere with autosomal SNPs. These motivate a re-examination of HWE in sex-aware analyses. Using the telomere-to-telomere (T2Tv2)-aligned high-coverage whole genome sequencing data from 2,490 individuals in the 1000 Genomes Project, we examined genome-wide sex-specific deviations from HWE across five super-populations. Our analyses were restricted to bi-allelic SNPs with non-missing genotypes and minor allele frequency (MAF) ≥5% in both sexes of the five super-populations. We applied an allele-based framework to quantify both the magnitude and direction of Hardy–Weinberg disequilibrium (HWD), followed by a second-order omnibus meta-analysis that combined HWD results across populations and sexes. At a genome-wide significance threshold of p < 5e-8, 0.9% of autosomal SNPs exhibited significant deviations from HWE. The majority of these deviations were associated with genomic features indicative of poor sequence quality. Restricting the analysis to reliable genomic regions substantially reduced the number of signals, yielding 255 autosomal SNPs and one non-pseudoautosomal chromosome X SNP. Among these, 140 autosomal SNPs displayed significant heterogeneity across populations but not across sexes. Notably, eight SNPs within a 15-bp region on chromosome 14q31.3 showed excess heterozygosity in both sexes of the African super-population (AFR). Finally, we developed a multivariate predictor of HWD based on sequence features, providing a practical tool that can be integrated into existing quality control pipelines for whole genome sequencing studies.

Life in sediments fosters ‘sexual’ speciation in the Shewanella baltica complex

2026-09-11T14:00:00Z

by Víctor Fernández-Juárez, Francisco Salvà-Serra, Guillem Seguí, Alberto J. Martín-Rodríguez

Understanding how intra- and interspecific differentiation arises in natural microbial populations is central to explaining the processes that drive bacterial evolution. Motivated by the co-occurrence of multiple putative genospecies closely related to Shewanella baltica in Baltic Sea sediments, we investigated the genomic structure of this species complex across fine spatial scales. We analyzed 112 genome sequences from strains collected across several sediment cores and depths (0–6 cm) at Vaxön (Stockholm archipelago, Sweden) as well as earlier isolates from this site and allopatric strains from surrounding locations obtained from both sediments and the water column. Using a reverse-ecology population genomics approach, we found unprecedented genomic diversification among sediment-associated strains, which form a species complex resolving into three cohesive evolutionary groups (G1, G2, and G3) with distinct signatures of metabolic specialization including sulfite respiration. While G1 consists predominantly of a single species (S. baltica) with high gene turnover, G2 and G3 comprise an array of divergent putative genospecies and previously reported species consistently recovered from sediments. Patterns of homologous recombination indicate that diversification of the lineages within G2 and G3 is primarily recombination-driven (‘sexual’) and is associated with specialization in sulfite reduction and utilization of certain carbon sources. The extent of diversity uncovered here far exceeds that reported for S. baltica from other environments, suggesting that a sediment-associated lifestyle promotes the emergence of novel genotypes. These findings expand the known limits of sympatric speciation in prokaryotes beyond subspecific ecotypes, demonstrating that bacterial species can diverge and persist as distinct lineages in the absence of spatial segregation and at microgeographic scales. Furthermore, our results suggest that collective interactions and ecological differentiation can structure sediment-associated bacterial populations strongly enough to drive divergence at the species level.

EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans

2026-09-08T14:00:00Z

by Vedant D. Jain, Andrew M. Johannesen, Felipe L. Teixeira, Erik A. Lundquist

Hox genes have been broadly implicated in nervous system development, but the molecular and genetic mechanisms that act downstream of Hox factors remain to be identified. The MAB-5 antennapedia-like Hox transcription factor is both necessary and sufficient to cause posterior migration of the Q neuroblast descendants in Caenorhabditis elegans. In response to MAB-5, the left-side QL descendants QL.a and QL.ap undergo a three-stage migration process, with each stage characterized by a posterior lamellipodial protrusion followed by cell body migration. The QL.ap cell differentiates into the PQR neuron posterior to the anus. Previous studies showed that the MAB-5-regulated gene efn-4/Ephrin was required for the third and final stage of QL.ap migration, with efn-4 mutation resulting in placement of PQR immediately anterior to the anus. This subtle and previously-undescribed phenotype opens the possibility that other known neuronal development genes could be involved. In this work, we screened known signaling mutants for third-stage PQR migration defects. We found that mutations in SAX-3/Robo signaling, UNC-6/Netrin signaling, and heparan sulfate proteoglycans (HSPGs) all displayed third-stage PQR migration defects. The effects in single mutants were weak compared to efn-4, and double mutant analysis revealed lack of genetic synergy, consistent with all of these molecules converging on a common pathway. This genetic analysis is consistent with physical interaction studies in vitro from another group that suggest that these molecules form connected communities of interacting extracellular domains, raising the possibility that they are all components of a large extracellular signaling complex required for posterior QL.ap migration. In this model, we envision that MAB-5/Hox drives EFN-4/Ephrin expression in QL.ap, which then seeds the formation of an extracellular signaling complex containing SAX-3/Robo signaling, UNC-6/Netrin signaling, and HSPGs that drives posterior lamellipodial formation and posterior migration.

ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans

2026-09-08T14:00:00Z

by Liying Guan, Tong Zhang, Zhigao Zhan, Yingchun Wang, Xun Huang, Mei Ding

Disruption of endoplasmic reticulum (ER) homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Although defects in the secretory machinery can induce ER stress, whether specific trafficking components actively couple cargo handling to UPR signaling remains unclear. Here, using Caenorhabditis elegans genetics, imaging, and biochemical assays, we show that neuronal overexpression of the gap junction protein UNC-9 cell-autonomously activates the IRE-1-XBP-1 branch of the ER UPR. Loss of the early secretory pathway proteins ERGI-2 or ERGI-3 suppresses this response and disrupts UNC-9 localization, revealing functions for these proteins that extend beyond cargo trafficking. ERGI-2 and ERGI-3 interact with both UNC-9 and the ER chaperone HSP-4/BiP, suggesting that they couple the handling of excessive UNC-9 to UPR activation. This requirement is cargo-selective: ERGI-2 and ERGI-3 are dispensable for UPR activation induced by overexpression of another innexin, UNC-7, or unrelated proteins. Moreover, activation of the IRE-1-XBP-1 pathway reduces abnormal UNC-9 accumulation in ergi-2 and ergi-3 mutants. Together, our findings identify ER-to-Golgi trafficking proteins as cargo-selective regulators that link secretory-pathway demand to adaptive UPR.

Fission yeast RPA–TERT–Tpz1^TPP1 complex promotes telomere extension and suppresses telomere recombination

2026-09-08T14:00:00Z

by Bettina A. Moser, Madeline Points, Sourav Agrawal, Adam C. Didier, Amanda K. Mennie, Ci Ji Lim, Yong-jie Xu, Toru M. Nakamura

Telomerase maintains chromosome ends by extending telomeric DNA, yet how recruited telomerase becomes productively engaged remains poorly understood. Recent studies found that Replication Protein A (RPA) contributes to telomerase stimulation through interaction with TERT in humans and with the TPP1 ortholog Est3 in budding yeast, suggesting a direct role in telomerase activation. Here, we provide genetic and structural modeling evidence for a RPA-Trt1^TERT-Tpz1^TPP1 ternary complex that promotes telomere extension while suppressing recombination in fission yeast. Guided by results from genetic screen, followed by AlphaFold3 modeling and systematic mutagenesis of RPA, Trt1, and Tpz1, we identify four key interfaces supporting telomerase function: Ssb1^RPA1-Trt1, Ssb2^RPA2-Trt1, Ssb2^RPA2-Tpz1, and the TEL-patch-mediated Trt1-Tpz1 interaction. Notably, Tpz1-R81, previously assigned as the TEL patch, instead contacts Ssb2 in the complex. Epistasis and suppressor analyses indicate that the newly identified RPA-Trt1 and RPA-Tpz1 interfaces collaborate with the Trt1-Tpz1 interface to allow telomerase activation after recruitment. Furthermore, comparative analyses using AlphaFold3 suggest that these interactions are likely conserved in budding yeast and humans. Collectively, these findings support a model in which RPA serves as an essential component of the active telomerase complex, coordinating TERT and TPP1-like factors to enable productive telomerase engagement.

The highly heterozygous European amphioxus (Branchiostoma lanceolatum) at the edge of panmixia

2026-09-08T14:00:00Z

by Marina Brasó-Vives, Diego A. Hartasánchez, Angélica Pulido, Stéphanie Bertrand, Hector Escriva, Marc Robinson-Rechavi

Amphioxus (Cephalochordata) are small marine chordates that have broad ecological ranges, yet as adults form local settlements and exhibit limited mobility. Genomic surveys of two amphioxus species have suggested that they rank among the most genetically diverse metazoans. Here, we present the first accurate assessment of genomic diversity in the European amphioxus (Branchiostoma lanceolatum) and investigate the processes underlying this diversity. We leverage whole-genome sequencing data from multiple individuals sampled at two geographically distant Atlantic and Mediterranean locations. Consistent with previous estimates in other amphioxus species, we measure exceptionally high genomic diversity, with an average heterozygosity of 2.73% in B. lanceolatum. Despite the large geographic separation between sampling sites, population differentiation is minimal, indicating extensive gene flow among distant adult settlements. Phylogenetic analyses combined with population genetic simulations confirm that this elevated genomic diversity is primarily driven by a large effective population size. Although adult amphioxus have limited mobility, our results indicate that long-distance larval dispersal mediated by ocean currents is sufficient to generate a near-panmictic population structure across their broad ecological range.

Development of a low-coverage whole genome sequencing screen for apomixis using a diverse set of Malus germplasm

2026-09-08T14:00:00Z

by Charity Z. Goeckeritz, Václav Polcar, Benjamin Gutierrez, Tomáš Urfus, Alex Harkess

In the past decade, plant biologists have made several major discoveries pertaining to the genetic basis of apomixis (clonal propagation by seed) that have shown promise in preserving high-value hybrid rice and sorghum genotypes. This progress was made possible by foundational gene discovery efforts in model species and natural apomicts, but pleiotropic obstacles still limit its broad agricultural adoption, especially in eudicots. Thus, it follows that investigations of novel apomicts should lead to the development of new molecular tools for plant breeding. The two most common ways to identify clonal seed production are flow-cytometry seed screens and genome sequencing to compare the DNA sequences of the maternal parent and progeny, traditionally using low-throughput markers. While flow-cytometry has been the dominant method for more than two decades, it provides indirect information on the genetics of a resulting embryo and can be ineffective in certain species. Here we developed a method using short-read whole-genome sequencing at moderately low coverage (averaging 3X and 6X) to screen diverse Malus genotypes maintained in a USDA germplasm collection for clonal seed production. In total, we sequenced 55 genotypes, 1,216 of their embryos, and identified 17 previously undescribed apomictic genotypes. Several more were detected with the flow cytometry seed screen, which helped resolve certain types of reproduction and sources of noise in low-coverage datasets. This low-pass screening-by-sequencing method is a relatively low-cost, rapid method for detecting apomictic genotypes in diverse plant germplasm and when used thoughtfully in conjunction with flow cytometry, provides a new way to visualize the genetic outcomes of sexual and asexual reproduction in plants.

Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments

2026-09-08T14:00:00Z

by Marina M. Watowich, Rachel M. Petersen, Layla Brassington, Audrey M. Arner, Grace Rodenberg, Tan Bee Ting A/P Tan Boon Huat, Kar Lye Tam, Em Schellenberg, Izandis bin Mohd Sayed, Echwa John, John C. Kahumbu, Benjamin Muhoya, Michael Gurven, Benjamin C. Trumble, Sospeter Ngoci Njeru, Dino Martins, Julien F. Ayroles, Yvonne A. L. Lim, Vivek V. Venkataraman, Ian J. Wallace, Thomas S. Kraft, Amanda J. Lea

The apolipoprotein ε4 (APOE ε4) isoform directly alters cholesterol and immune biology and is associated with an increased risk of neurodegenerative and cardiometabolic disease in industrialized settings; nevertheless, APOE ε4—which is ancestral in humans—has persisted over evolutionary time. One potential explanation is that the costs and benefits of APOE ε4 were significantly different in the environments in which humans evolved compared to those we experience today. In support, previous work has suggested that living in a high pathogen environment, engaging in high levels of physical activity, or eating a low fat diet can dampen the detrimental effects of APOE ε4, and has revealed positive effects for fertility. However, direct tests of whether APOE isoforms are associated with different biological outcomes in non-industrial versus industrialized contexts are lacking. Working with the Turkana of Kenya and the Orang Asli of Peninsular Malaysia—two Indigenous groups in which individuals of shared ancestry span a continuum of subsistence, non-industrial to urban, industrialized lifestyles—we investigated how APOE genotypes impact cholesterol, immunological, and reproductive traits and directly tested for genotype x environment (GxE) interactions. First, we confirmed established genotype effects across lifestyles, showing that having more APOE ε4 alleles is associated with higher total cholesterol, higher LDL cholesterol, and lower HDL cholesterol. Second, we tested for lifestyle interactions, finding lifestyle-dependent effects of genotype on innate immune biomarkers in the Orang Asli but not Turkana. Finally, we show that having more APOE ε4 alleles is correlated with an extended reproductive lifespan, however this effect is relatively weak, is not consistent across populations, and does not correspond with a higher reproductive output. Together, our study provides evidence that industrialized environments can modify the biology of APOE ε4; however, we find that APOE ε4 is not universally beneficial in non-industrial contexts, highlighting the role of local environmental variation in determining its specific costs and benefits.

FM-GPT: Bayesian fine mapping for phenome-wide transcriptome-wide association studies

2026-09-08T14:00:00Z

by Travis Canida, Zhenyao Ye, Shao-Hsuan Wang, Hsin-Hsiung Huang, Yezhi Pan, Menglu Liang, Shuo Chen, Tianzhou Ma

Transcriptome-wide association studies (TWAS) integrate genome wide association studies with expression quantitative trait locus reference panels to identify genes associated with traits of interest. However, linkage disequilibrium and correlated gene expression can induce spurious TWAS signals, motivating fine mapping methods to prioritize putatively causal genes within associated loci. The rapid growth of large-scale phenomic resources (e.g., electronic health records (EHRs)) has shifted genetic studies from single-trait analyses to phenome-wide investigations that jointly evaluate many closely related phenotypes. We introduce FM-GPT (Fine-mapping of causal Genes for Phenome-wide Transcriptome-wide association studies), a novel Bayesian fine mapping method for prioritizing causal genes across multiple correlated phenotypes with potentially mixed outcome types (e.g., continuous, binary, multinomial or count) in phenome-wide TWAS. FM-GPT performs gene-guided dimension reduction of the phenotypes and reveals pleiotropic or phenotype-specific effects of the identified genes. In simulations, FM-GPT identified true causal genes more accurately than other fine mapping methods while controlling false positives. We applied FM-GPT to two applications using data from UK Biobank: a brain-wide genetic analysis of MRI data derived regional cortical thickness measures and a phenome-wide genetic analysis of clinical phenotypes derived from EHR data. FM-GPT greatly narrowed down the set size of putatively causal genes and identified: 1. genes with pleiotropic effects on regional cortical thickness across the cerebral cortex, including five genes BCAS3, LRRC37A, NOS2P3, ARL17B and UBB on chromosome 17 regulating neuronal morphology and cortical organization; and 2. genes that influence multiple medical conditions across the circulatory, metabolic, digestive, respiratory and genitourinary systems, revealing two major axes of variation among these conditions that point to a potential trade-off in gene regulation between immune and metabolic functions. These results highlight FM-GPT’s power to disentangle complex gene–phenotype relationships in large-scale phenome-wide studies, revealing biological mechanisms underlying diverse human traits and advancing translational and comorbidity research.

OsDUF1223 negatively regulates seedling drought tolerance and modulates nitrate-dependent root growth in rice

2026-09-03T14:00:00Z

by Xiulin Zhao, Ziyi Wang, Mingfei Chen, Lingxiang Lu, Hui Lin, Xiaofei Zan, Xiaomei Jia, Xiaoying Ye, Rongjun Chen, Jianqing Zhu, Jun Zhu, Lihua Li

Rice (Oryza sativa L.) is a major staple food crop worldwide. Drought stress induced by extreme weather severely limits its growth and yield. Proteins containing domains of unknown function (DUF) play important roles in plant stress responses, but their regulatory mechanisms remain largely unclear. In this study, we demonstrate that the plasma membrane-localized protein OsDUF1223 functions as a negative regulator of drought tolerance in rice seedlings. Under drought stress, OsDUF1223-overexpressing lines exhibited lower survival rates, higher water loss rates, and reduced antioxidant enzyme activities and osmolyte accumulation. Transcriptomic and physiological analyses revealed that OsDUF1223 modulates drought responses through ABA signaling and nitrogen response pathways. Collectively, this study elucidates that OsDUF1223 regulates drought tolerance at the seedling stage in rice through functional association with the ABA and nitrogen signaling pathways, thereby providing a candidate gene resource for the genetic improvement of drought tolerance in rice.

The SigD regulon of Mycobacterium abscessus determines cell envelope composition and antibiotic susceptibility

2026-09-02T14:00:00Z

by Sean R. Jones, Kelly Maune, Kelley Hurst-Hess, Pallavi Ghosh

A major determinant of the exceptional intrinsic resistance of M. abscessus is the lipid-rich cell envelope, yet the regulatory systems that remodel envelope-associated pathways remain poorly defined. Here, we determine the σ^D regulon in M. abscessus and establish its role in cell envelope homeostasis and intrinsic resistance to hydrophobic antibiotics. RNA-Seq analysis of a MabΔsigD mutant identified 447 differentially expressed genes, while ChIP-Seq mapped 72 σ^D binding sites and defined a conserved promoter motif (GTAACA/G-N₁₆-CGAT). Using a combination of σ^D binding, motif orientation and expression data, we identified a core set of directly regulated genes, distinct from what was previously observed in M. tuberculosis, many of which encode proteins involved in envelope-associated functions. These include loci involved in trehalose polyphleate (TPP) biosynthesis, the antigen 85 complex and peptidoglycan remodeling enzymes. Deletion of sigD resulted in a significant reduction in TPPs in the cell envelope and an increase in ethidium bromide accumulation. Consistent with these changes, loss of σ^D selectively sensitized M. abscessus to hydrophobic antibiotics, including rifampicin and tigecycline. Deletion of mmpL10, which is required for transport of TPP precursors, recapitulated the drug sensitivity of MabΔsigD, implicating envelope composition as a key effector of the phenotype. Expression of the σ^D regulon further increased during starvation and in response to SDS, isoniazid, and ethambutol, mediated by degradation of RsdA, consistent with a role in stress-responsive envelope adaptation. Together, these findings demonstrate σ^D is active during logarithmic growth in rich media where it regulates the expression of envelope-associated genes that influence envelope permeability and basal level susceptibility to hydrophobic antibiotics; its activity further increases in response to cell envelope stress, presumably promoting envelope remodeling to counteract damage.

Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions

2026-09-02T14:00:00Z

by Carolyn Sangokoya, Isabella R. Rosso, Rana Ghandehari-Alavijeh, Robert Blelloch

Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation, yet how RBPs and microRNAs coordinate in developmental time to regulate cell fate remains poorly understood. Here, we demonstrate that post-transcriptional regulation of the Profilin 2 (Pfn2) transcript is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3’untranslated region has both an Iron Regulatory Protein binding site (IRE) and a nearby binding site for ESC enriched microRNAs. Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation. In contrast, deletion of the IRE leads to decreased PFN2, a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. We further find that loss of the IRE site results in a cell autonomous defect in Wnt signaling and mesendodermal differentiation. The IRE site acts to stabilize beta-catenin, as disruption of the site leads to reduced nuclear beta-catenin levels. Together, these findings reveal the Pfn2 microRNA-IRE regulatory axis as a critical post-transcriptional regulatory node governing the switch from pluripotency to somatic differentiation.

Multi-organ single-cell transcriptomic atlas identifies QrIAA14 as a candidate negative regulator of adventitious root development in Quercus robur

2026-09-01T14:00:00Z

by Wenkai Hui, Jiayue Li, Hao Li, Hongyi Wu, Yi He, Shuangying Yang, Xiong Huang, Hanbo Yang, Gang Chen, Peng Zhu, Xiaohong Chen, Xingcui Xiao, Yu Zhong, Zhenfeng Xu, Fang He

Plant organ development involves coordinated cell fate transitions across multiple tissues, yet the cellular programs underlying organ-specific differentiation in woody plants remain poorly understood, particularly the mechanisms limiting efficient root development during vegetative propagation of oak species. Here, we generated a comprehensive single-cell transcriptomic landscape of leaf, stem, and root tissues of Quercus robur to resolve developmental trajectories at cellular resolution. A total of 41,471 high-quality cells were classified into 30 distinct clusters, enabling the identification of major cell types and organ-specific transcriptional features across three vegetative organs. Pseudotime analyses exhibited the developmental programs related to guard cell differentiation in leaves, vascular formation in stems, and root tissue development. Additionally, combining scRNA-seq, bulk transcriptome profiling, and phytohormone investigations, we identified auxin signaling as an important regulator during adventitious root development process. Notably, QrIAA14-1, an IAA14 homolog, was preferential enrichment in root hair, near-root hair cells and root cap along root developmental trajectories, which was further supported by RT-qPCR and in situ hybridization assays. Furthermore, the overexpression of QrIAA14-1 significantly inhibited oak root elongation, resulting in around 64.46% reduction in adventitious root length compared with control plants, providing mechanistic insight into the limitations of root development in oak. Together, this study provides the first high-resolution single-cell atlas of cellular organization and developmental dynamics across oak vegetative organs and identifies the candidate regulator genes associated with root development, offering new insights into the regulatory mechanisms of woody plant root regeneration and clonal propagation.

Abdominal-B regulates the male seminal fluid transferome and new fecundity factors required for sperm sex peptide binding

2026-09-01T14:00:00Z

by Kathrin Steck, Lina Verbakel, Peter Kerwin, Vladimir Trajanovikj, Katarzyna Kjøge, Jan J. Enghild, Anne C. von Philipsborn

Seminal fluid proteins determine reproductive success in a wide range of animals. In the Drosophila male accessory gland, seminal fluid is mainly produced by two cell types, a majority of main cells and a small number of secondary cells that possess a specialized secretory apparatus with unusually enlarged dense core granule vesicles. Loss of Abdominal-B expression from secondary cells in the enhancer mutant iab-6^cocu disrupts their transcriptional and secretory identity. Consequently, mutant males fail to induce the long-term post-mating response in females, which is characterized by a loss of receptivity and sustained egg laying. Here, we determine how secondary cells shape the seminal transferome and the female response by assessing iab-6^cocu male accessory gland and female mate reproductive tract proteomes. We find downregulation of seminal fluid proteins that constitute a signaling network enabling sperm binding and the sustained action of the key regulator Sex Peptide. We identify two new Sex Peptide network proteins crucial for female fecundity, Cornutus (CG1701) and Hanrej (CG42564). Cornutus is required for mating dependent dense core granule vesicle release, providing a link between the products of these compartments and the female long-term post-mating response. Our data highlights the importance of secondary cell signaling and secretion for overall seminal fluid composition and Sex Peptide network function as well as the interdependence of main and secondary cells and their secretory products, advancing the general understanding of how seminal fluid signaling pathways modulate female physiology, sperm use and offspring production.

Characterization of METTL3/14-mediated m⁶A modification in human transcriptome using Nanopore direct RNA sequencing

2026-09-01T14:00:00Z

by Emily Kurtyan, Andrew J. Stein, Kelly J. Abdalla, Zhangerjiao Yuan, Miten Jain, Fadia Ibrahim

Post-transcriptional RNA modifications modulate diverse aspects of RNA metabolism. N⁶-methyladenosine (m⁶A), one of the most abundant internal RNA modifications, is deposited by the core methyltransferase complex, METTL3 and METTL14. Oxford Nanopore Technologies (ONT) platform permits direct, single RNA molecule sequencing while preserving native modifications. However, without rigorous benchmarking, the accuracy and reproducibility of modification detection remain uncertain. Here, we leveraged ONT to comprehensively profile bona fide m⁶A modifications in cellular RNAs at single-nucleotide resolution by integrating two direct RNA sequencing chemistries (RNA002 and RNA004) with the m6Anet and Dorado modification-detection models. We independently depleted METTL3 and METTL14 in human cells and rigorously validated modification calls through several assays and independent orthogonal methods (GLORI and miCLIP). We find that Dorado detected a higher number of m⁶A events and enabled simultaneous detection of other RNA modifications (5-methylcytosine, pseudouridine, and inosine). Pairing Dorado with an in vitro transcribed, unmodified control under stringent filtering, we provide compelling evidence supporting a global reduction in m⁶A sites and stoichiometry within coding sequences and across genes, particularly in highly modified genes and sites, and at consensus DRACH motifs. We report a differential and complex regulation of modified transcripts, accompanied by a global reduction in poly(A) tail length. Notably, METTL3 and METTL14 depletion produced distinct transcript-specific effects, supporting non-redundant roles within the m⁶A writer complex. Together, our study illustrates a notable advancement of ONT capabilities and establishes a robust transcriptome-wide framework for RNA modification detection, thereby laying the groundwork for exploring the contribution of METTL3/METTL14 to cellular functions and disease.

A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG

2026-08-31T14:00:00Z

by Miriam C. Aziz, Jennie Wilson, Clement Y. Chow

PIGA-CDG is a congenital disorder of glycosylation caused by pathogenic partial loss-of-function variants in the PIGA gene. PIGA encodes an enzyme responsible for the catalytic transfer of N-acetylglucosamine to phosphatidylinositol during the first step of glycosylphosphatidylinositol anchor biosynthesis. Loss of this enzyme has a widespread phenotypic impact, but primarily results in neurological symptoms including seizures, intellectual disability, and developmental delay. Currently, treatments are limited and focus on symptom management. We developed an eye model of PIGA-CDG that has a reduced eye size. We screened a library of 98% 1,520 FDA/EMA-approved compounds to find drugs that improved the small eye phenotype. This screen revealed numerous drugs that improved eye size, including those that targeted dopamine signaling and cyclooxygenases. Using pharmacological and genetic approaches, we show that modulating dopamine signaling improves the eye size. Genetic inhibition of dopamine 2 receptor signaling and dopamine reuptake improve both the eye model and neurologically relevant PIGA-CDG phenotypes, including seizures and locomotor deficits. We also pharmacologically and genetically validate cyclooxygenase targeting drugs in the eye model. These findings reveal novel biology underlying PIGA-CDG and point towards candidate therapeutic approaches.

Fungal appressoria as mechanochemical organelles for polyurethane degradation

2026-08-31T14:00:00Z

by Fan Fei, Zhenjie Su, Rui Liu, Rongrong Gao, Chaomin Sun

Polyurethane (PU) is a synthetic polymer characterized by highly stable urethane linkages that hinder biological turnover. Although fungi have been implicated in PU degradation, the molecular mechanisms that couple polymer surface sensing to enzymatic depolymerization remain largely undefined. Here we show that the marine-derived fungus Alternaria alternata FB1 employs a surface-sensing signaling pathway that drives appressorium-mediated degradation of both polyester and polyether PUs. Contact with hydrophobic polymer surfaces rapidly induces melanized appressoria that mechanically penetrate the polymer matrix and promote its oxidative and hydrolytic depolymerization. Integrative transcriptomic analysis and targeted gene disruption identify the mucin-like surface sensor Msb2 as an upstream component of the polyurethane surface-sensing machinery. Loss of Msb2 disrupts MAPK and Ca²⁺ signaling, impairs appressorium differentiation, and reduces expression of degradative enzymes. Biochemical profiling further reveals multiple urethane-hydrolyzing enzymes that expand the known catalytic repertoire for PU bond cleavage. Together, these findings establish a mechanistic framework linking surface recognition, appressorium development, and polymer degradation, providing insight into how fungi transform recalcitrant polyurethane materials.

Convergent latitudinal erosion of circadian systems in a rapidly diversifying order of fishes

2026-08-31T14:00:00Z

by Daniel B. Wright, Yangfan Zhang, Jacob M. Daane

Biological clocks allow organisms to anticipate cyclical environmental changes, yet in high-latitude or deep-sea habitats, the diel cues that entrain these rhythms are often seasonally diminished or absent. Fishes of the order Perciformes have rapidly diversified across these arrhythmic ecosystems, raising the question of whether changes to circadian rhythms and biological clock genetic architecture are a component of their evolutionary success. Here, we used a comparative genomic approach to investigate patterns of core biological clock gene loss across 96 perciform and five outgroup species. We found widespread and lineage-specific loss in core clock genes, particularly in the convergently evolving polar and deep-sea suborders Notothenioidei and Cottoidei. This trend of clock gene loss was significantly amplified with higher-latitude species. To determine if these genomic signatures reflect a functional loss of rhythmicity, we performed metabolic phenotyping on three notothenioid species. We found a consistent lack of circadian metabolic oscillations during the late austral fall across all notothenioids, including the sub-Antarctic sister lineage to the cryonotothenioid adaptive radiation, Eleginops maclovinus. Experimental data across Perciformes, combined with suborder-wide patterns of gene loss, suggest that a release from circadian constraints occurred early in their diversification, potentially facilitating the repeated expansion of these fishes into polar and deep-sea habitats.

Proteobacteria with chemosynthetic potential are highly prevalent in the gills of Hypoplectrus reef fishes

2026-08-28T14:00:00Z

by Sabrin Abdelghany, Martin Helmkampf, Matthew S. Schechter, Iva A. Veseli, Matthieu Leray, A. Murat Eren, Oscar Puebla

Fishes host a diverse microbiome in their gills, but a broad characterization of this microbiome at the metagenomic level is lacking. Here, we apply genome-resolved metagenomics to the gills of the hamlets (Hypoplectrus spp), a group of reef fishes from the Greater Caribbean. The analysis of 353 gill samples from 15 hamlet species collected at eight locations over 13 years revealed a stark contrast between the gill microbiota and reef water microbial communities, indicating a distinct and specific gill microbiome. A total of 70 gill-associated metagenome-assembled genomes (MAGs) were recovered. These MAGs belong to 17 lineages, most of which are novel. They relate to known fish gill pathogens, fish gut microbes, free-living and biofilm-associated taxa, indicating that the gill microbiome was assembled from a collection of distinct eco-evolutionary trajectories. The MAGs harbor diverse metabolic modules, involved notably in nitrogen cycling, antibiotic production and biofilm formation, revealing a highly dynamic microbial ecosystem. One lineage in the Burkholderiaceae family was outstandingly prevalent across fish host species, sampling locations and years. Its genome encoded complete metabolic modules for carbon fixation and sulfur oxidation, indicating chemosynthetic potential. To the best of our knowledge, this is the first line of evidence that fishes may host sulfur-oxidizing chemosynthetic bacteria in their gills. The functional significance of this chemosynthetic potential for the fish host or other members of the gill microbiome remains to be established. The high prevalence of this lineage allowed to build a pangenome. It revealed large-scale geographic structure (western Caribbean, eastern Caribbean and Gulf of Mexico), which parallels the phylogenomic pattern observed in the hamlets. Overall, our findings point to complex fish host-microbe and microbe-microbe eco-evolutionary interactions in the gills that may influence fish physiology, homeostasis and immune response.

Pervasive context-dependent effects in the genetic architecture of complex and quantitative traits revealed by a powerful multiparent mapping population in yeast

2026-08-27T14:00:00Z

by Gareth A. Cromie, Russell S. Lo, Lauren Ames, Trey S. Morgan, Katherine Owens, Anne E. Clark, Martin S. Timour, Julee Ashmead, Michelle Tang, J. Nathan Kutz, Joshua M. Akey, Aimée M. Dudley

The genetic dissection of complex traits remains a major challenge in basic and biomedical research, but is essential for understanding the molecular pathways that shape phenotypic variation and for developing predictive models of trait and disease susceptibility. Here, we leverage a novel multiparent mapping population of budding yeast, CYClones, comprising 9,344 haploid strains derived from eight genetically diverse founders (~270,000 SNVs, ~ 1 per 44 bp, capturing 56% of common variants and 32% of all variants with a minor allele frequency greater than 0.005 in the global population), to identify quantitative trait loci (QTL) and systematically investigate the genetic architecture of growth rates across ten environmental conditions. In total, we identified 349 QTL (ranging from 18 to 49 QTL per growth condition) that explained between 60% and 100% of narrow sense heritability across traits. The high power and resolution of CYClones revealed that growth traits exhibited distinct, condition-specific genetic architectures with extensive allelic heterogeneity, where a QTL was the result of multiple tightly linked causal variants. We also observed pleiotropy among QTL with complex, trait-dependent allele effects that are also consistent with allelic heterogeneity. Genetic complexity varied widely, with some traits showing nearly Mendelian architectures, while others were highly polygenic. Introgressed loci played a prominent role in the landscape of growth rate QTL, including a QTL localized to a 2.4 kb interval in the PCA1 cadmium transporter that explains 72% of variation in cadmium resistance and is largely driven by an introgression, and a non-additive interaction between the GAL3 regulator and introgressed GAL1/7/10 alleles, extending a previously described three-locus GAL-pathway incompatibility to a four-locus interaction. In both cadmium and galactose conditions, we show that allelic variation at a small number of loci stratifies the population into regulatory or physiological subgroups, each with distinct genetic architectures, a specific manifestation of epistasis we term allele-dependent stratification. Collectively, our results provide novel insights into the genetics of growth rates in budding yeast, the architectural features of genetic complexity, and demonstrate that CYClones is a powerful platform for revealing the molecular basis of complex trait variation.

DDI-4 induces a temperature-sensitive exocytotic remodeling during C. elegans spermiogenesis via nsun-2–dependent sphingosine signaling

2026-08-27T14:00:00Z

by Yoshihiro Shimada, Riona Shiraki, Chihiro Ogawa, Nana Kanazawa-Takino, Yukiko Karuo, Kentaro Kawai, Masaharu Hashimoto, Ayaka Yoshida, Arata Honda, Jun Adachi, Jun-Dal Kim, Akiyoshi Fukamizu, Masaaki Omote, Hitoshi Nishimura

Exocytotic sperm remodeling is essential for fertilization, yet whether conserved molecular mechanisms underlie this process across species remains unclear. In Caenorhabditis elegans, membranous organelle fusion (MOF), an exocytotic event cytologically analogous to the mammalian acrosome reaction (ASR), occurs during spermiogenesis and likely contributes to the acquisition of fertilization competence. Here, we identify DDI-4, a benzylamine analog as a small-molecule inducer of both MOF and ASR, revealing a shared sensitivity between these evolutionarily distant systems. DDI-4–induced MOF was selectively impaired in spermatids from males raised at elevated temperatures, whereas conventional protease–induced MOF remained unaffected. Through forward genetics, we isolated the nyg20 mutant, which was specifically defective in DDI-4 responsiveness. Complementation and genetic analyses suggested that the nyg20 phenotype is associated with impaired function of nsun-2, encoding a tRNA methyltransferase, despite the absence of detectable mutations in the nsun-2 coding, intronic, and flanking regions. Consistent with this, an nsun-2 deletion mutant exhibited defects in temperature-sensitive MOF and meiosis. In silico docking analysis further implicated sphingosine kinases (SPHKs) as candidate targets of DDI-4; indeed, loss of sphk-1 phenocopied the nsun-2 mutant. Moreover, we tested sphingosine (SPH) and its analog FTY720 as MOF activators, using mutants lacking sphk-1 or spin-4, which encodes a transporter of phosphorylated SPH. Intriguingly, DDI-4 and SPH activated MOF in an SPHK-1–dependent but SPIN-4–independent manner, whereas FTY720 required both SPHK-1 and SPIN-4 for MOF activation. Because DDI-4 lacks hydroxyl groups that SPHKs typically phosphorylate, these findings suggest that SPHK-1 may function not only as a kinase but also as a scaffold for downstream signaling. Together, our results reveal a temperature-sensitive, NSUN-2–dependent SPH-mediated signaling axis that regulates organelle exocytosis during spermiogenesis and suggest an evolutionarily conserved mechanism underlying fertilization competence.

PLOS Genetics: New Articles

METTL1-mediated m7G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis

Bacterial chromosomal gene positioning is likely shaped by selection on both mean and growth-dependent expression

Genetic analysis of epistasis between nucleotide excision repair and homologous recombination in the recovery of persisters after fluoroquinolone treatment

Prenatal consequences of GALT deficiency in a rat model of classic galactosemia

Dual contributions of Xrp1 to genome integrity through the DNA damage response and cell competition

Identifying shared polygenic risk across cancers

Beyond years of schooling: Genetic associations across educational milestones in two Norwegian cohorts

Arginine Kinase 1 supports energy homeostasis in Drosophila flight muscle development

Outer membrane proteins mediate unconventional secretion of Pseudomonas peroxidase through crosstalk between the Sec pathway and outer membrane vesicles

Assessing Hardy-Weinberg equilibrium in T2T-aligned 1000 genomes project

Life in sediments fosters ‘sexual’ speciation in the Shewanella baltica complex

EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans

ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans

Fission yeast RPA–TERT–Tpz1TPP1 complex promotes telomere extension and suppresses telomere recombination

The highly heterozygous European amphioxus (Branchiostoma lanceolatum) at the edge of panmixia

Development of a low-coverage whole genome sequencing screen for apomixis using a diverse set of Malus germplasm

Divergent biological consequences of APOE isoforms across industrialized and non-industrial environments

FM-GPT: Bayesian fine mapping for phenome-wide transcriptome-wide association studies

OsDUF1223 negatively regulates seedling drought tolerance and modulates nitrate-dependent root growth in rice

The SigD regulon of Mycobacterium abscessus determines cell envelope composition and antibiotic susceptibility

Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions

Multi-organ single-cell transcriptomic atlas identifies QrIAA14 as a candidate negative regulator of adventitious root development in Quercus robur

Abdominal-B regulates the male seminal fluid transferome and new fecundity factors required for sperm sex peptide binding

Characterization of METTL3/14-mediated m6A modification in human transcriptome using Nanopore direct RNA sequencing

A drug repurposing screen reveals dopamine signaling as a candidate therapeutic pathway for PIGA-CDG

Fungal appressoria as mechanochemical organelles for polyurethane degradation

Convergent latitudinal erosion of circadian systems in a rapidly diversifying order of fishes

Proteobacteria with chemosynthetic potential are highly prevalent in the gills of Hypoplectrus reef fishes

Pervasive context-dependent effects in the genetic architecture of complex and quantitative traits revealed by a powerful multiparent mapping population in yeast

DDI-4 induces a temperature-sensitive exocytotic remodeling during C. elegans spermiogenesis via nsun-2–dependent sphingosine signaling

METTL1-mediated m⁷G modification regulates hair follicle cycle via the HOXC13/FOXN1/DSG4 axis

Fission yeast RPA–TERT–Tpz1^TPP1 complex promotes telomere extension and suppresses telomere recombination

Characterization of METTL3/14-mediated m⁶A modification in human transcriptome using Nanopore direct RNA sequencing