PLOS Genetics: New Articles

The AF-2 domain of estrogen-related receptor interacts with PPRC1 to modulate larval epidermal marking in Bombyx mori

2026-10-12T14:00:00Z

by Jinxin Wu, Die Liu, Haoran Xu, Lingqing Zeng, Ping Lin, Ping Zhao, Guanwang Shen

Estrogen-related receptors (ERRs) have no natural ligands, vertebrate ERRs rely on their activation function-2 (AF-2) structural domain to recruit coactivators for transcriptional regulation. While metabolic regulation in insects differs significantly from that in vertebrates, it remains unclear whether the regulatory function of insect ERR requires coactivators. Using silkworms as the research subject, this study aims to analyze the molecular mechanisms of ERR-regulated metabolism in insects and refine the metabolic regulatory network. This study applied CRISPR/Cas9 gene editing technology to knock out the AF-2 domain of BmERR in the lepidopteran silkworms and examined its effects on functional role, associated interacting factors, and related physiological processes. Disruption of the BmERR AF-2 domain inhibited the expression of melanin metabolism-related genes BmTH, BmDDC, BmAA-NAT, Bmebony, and Bmtan, leading to the accumulation of tyrosine and dopa, thereby causing aberrant melanin metabolism and loss of epidermal markings. By contrast, BmERR overexpression enhanced the pathway, resulting in intensification of epidermal markings. The homologous gene of the ERR coactivator, BmPPRC1, showed highly consistent expression with BmERR in the epidermis. The immunofluorescence signal of BmPPRC1 was localized to the nucleus and highly overlapped with that of BmERR. BmPPRC1 interacts with the AF-2 domain of BmERR, and deletion of this region weakens the regulation of melanin metabolism-related genes in silkworm embryonic cells. The ERR function and mode of action are evolutionarily conserved, and its AF-2 structural domain binds equally well to the coactivator BmPPRC1, providing new perspectives for studying the modulability of insect mottle formation.

An NKX2-3/5/6 homolog is required downstream of BMP signaling to pattern the sensory-adhesive organ of a tunicate larva

2026-10-12T14:00:00Z

by Christopher J. Johnson, Joshua Kavaler, Timethea Slade, Kayla Wilson, Christina D. Cota, Alberto Stolfi

Tunicates are the sister group to vertebrates within the chordate phylum, yet unlike other chordate groups, they evolved a biphasic lifecycle alternating between motile larvae and sessile adults. The papillae of most tunicate larvae are the key sensory-adhesive organ regulating their settlement and metamorphosis. The papillae are nearly always arranged as a group of three morphologically identical organs that arise from an anterior neural plate border region nested between ventral epidermis and more dorsal/posterior neural tube progenitors. Due to their embryonic origin and molecular signatures, this anterior border has been evolutionarily linked to vertebrate placode regions. It was previously shown that the specification, patterning, and morphogenesis of the embryonic papilla region all depend on BMP signaling, though downstream mechanisms remain poorly understood. Here we show that the NKX2-3/5/6 ortholog NK4 is a key transcription factor that acts downstream of BMP signaling to pattern the papillae in the Ciona embryo. We present evidence that NK4 is activated by BMP signaling and encodes a transcriptional repressor that is required to restrict the expression of the papilla regulatory gene Foxg to three cell clusters that give rise to the three papillae. Loss of NK4 function results in the formation of a single large papilla. In contrast, overexpression of NK4 represses Foxg, eliminating the papillae. We also show that the expression of NK4 is restricted dorsally by the BMP antagonist Chordin, while the ventrally-expressed transcription factor Msx can alleviate the repressive effect of NK4, potentially allowing for the characteristic tripartite patterning of the papillae.

Combined lactate- and phosphate-dependent cytoplasmic acidification is associated with Mycobacterium tuberculosis growth arrest at acidic pH

2026-10-09T14:00:00Z

by Adam P. Kibiloski, Shelby J. Dechow, Bassel J. Abdalla, Heather M. Murdoch, Anna D. Tischler, Robert B. Abramovitch

Mycobacterium tuberculosis (Mtb) cultured in minimal medium at acidic pH arrests growth when provided specific single carbon sources, including glycerol, propionate, and lactate, a phenomenon we refer to as acid growth arrest. To define the mechanisms of acid growth arrest on lactate, we selected transposon mutants that grew under these conditions. Five mutants carried insertions in phoT or pstC2, which encode components of a phosphate ABC transporter. Depleting phosphate restored Mtb growth in minimal medium supplemented with lactate at acidic pH, demonstrating that growth arrest on lactate depended on phosphate. The combination of lactate and phosphate at acidic pH acidified the cytoplasm to below pH 6.7, whereas the phoT mutant maintained a cytoplasmic pH > 7.2. Lactate slightly decreased membrane potential in a dose-dependent manner in wild-type Mtb, whereas the phoT mutant maintained a higher membrane potential. Transcriptional profiling identified a lactate-associated PMF stress signature, including upregulation of electron transport chain genes. Together, these findings associate lactate- and phosphate-dependent cytoplasmic acidification with proton motive force (PMF) stress and acid growth arrest. The phoT mutant grown in lactate at acidic pH upregulated the senX3/regX3 regulon. Using a regX3 mutant, we found that growth on lactate under low-phosphate conditions required regX3. We propose a model in which (1) acidic pH, lactate, and phosphate together modulate cytoplasmic pH homeostasis and are associated with PMF stress and acid growth arrest; and (2) low phosphate induces SenX3-RegX3 activity, which may alter cell-envelope physiology through ESX-5- and PE/PPE-dependent pathways and promote growth on lactate at acidic pH.

New insights into Müllerian duct differentiation provided by single cell transcriptomics in the chicken embryo

2026-10-09T14:00:00Z

by Juan Lan Tan, Adele Barugahare, Andrew Thomas Major, Craig Allen Smith

In vertebrate embryos, Müllerian ducts give rise to the female reproductive tract. Here, we present a comprehensive analysis of Müllerian duct differentiation using single cell transcriptomics in the chicken embryo, a unique model for duct development. The data reveal greater cellular complexity of Müllerian duct differentiation than previously understood. Transcriptomic profiling of early formed Müllerian ducts identifies molecular signatures for the Müllerian duct Epithelium (MDE) and the Müllerian Duct Mesenchyme (MDM), the two principle compartments of the Müllerian duct. The MDE expresses PAX2, LHX1, WNT7, LGR5, PDGFA/D, and CDH1/2. The MDM is marked by WNT4, EMX2, POSTN, OSR1, VIM,DMRT and the EMT markers ZEB1/2. In the male, the regressing mesenchyme (MDM) has a unique molecular signature, expressing the transcription factors MSX1, MSX2, RUNX2, GATA5, DLX3 and DLX5, and the signaling regulators DKK4 and NRG1 (Neuregulin). Single cell transcript profiling of the regressing male mesenchyme identifies new genes implicated in duct regression, including the WNT antagonist, DKK4. DKK4, responds to Anti-Mullerian Hormone induction and can induce duct regression when ectopically expressed in females. The duct mesenchyme in the female follows a different fate, with a molecular signature comprising SMARCA2/ HMGA2/ZEB1/2/TWIST1/2/DMRT2 and persistent expression of FOXE1, OSR2 and HGF (Hepatocyte Growth Factor). Cell clusters in the developing female ducts reflects spatial pre-patterning of the duct prior to later regionalisation. In contrast to AMH-mediated bilateral Müllerian duct regression in males, female chicken embryos show an unusual pattern of left duct differentiation and contralateral right duct regression. We find that right female duct does not regress in the same manner as in males, being transcriptionally distinct and lacking a population of regressing mesenchyme, despite presumably being mediated by AMH, as in males.

Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling

2026-10-08T14:00:00Z

by Vinoth Sigamani, Mohd Yousuf, Daniel L. Johnson, Brian D. Strahl, R. Nicholas Laribee

Chromatin is dynamically regulated in response to nutrient flux to promote the transcriptional changes needed for adaptation. The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation.

ZBED6 deficiency drives pathological cardiac hypertrophy through MEOX1–ERK1/2–dependent autophagy dysfunction

2026-10-08T14:00:00Z

by Xiao Zhang, Xiaopeng Liu, Ruirui Pan, Huan Liu, Junying Xiao, Xiangkai Leng, Hongmei Zhang, Dengke Pan, Shengzhong Duan, Jiangwei Wu

Pathological cardiac hypertrophy, a major risk factor for heart failure, is regulated by complex transcriptional networks. We previously identified the transcription factor ZBED6 as a key regulator for skeletal muscle hypertrophy, its role in the cardiac hypertrophy remains unexplored. Here, we report that ZBED6 is a key suppressor of pathological cardiac hypertrophy. ZBED6 is markedly reduced in myocardial tissues from patients with cardiac hypertrophy. ZBED6-deficient pigs exhibited cardiac hypertrophy with diastolic dysfunction. Integrative transcriptomic and ChIP-seq analyses identified MEOX1 as a direct negative target of ZBED6. Loss of ZBED6 upregulates MEOX1 transcription, which subsequently activated ERK1/2 signaling, leading to impaired autophagy-induced hypertrophy. Knockdown of MEOX1 reduced ERK1/2 phosphorylation and mitigated cardiomyocyte hypertrophy induced by ZBED6 deficiency. Similarly, pharmacological inhibition of ERK1/2 restored autophagy and alleviated hypertrophy in ZBED6-depleted cardiomyocytes. Collectively, these findings define a previously unrecognized ZBED6–MEOX1–ERK1/2 axis that critically regulates cardiac hypertrophy and represents a potential therapeutic target.

Heat stress promotes GTBP-1 association with perinuclear P-bodies in the C. elegans germline

2026-10-07T14:00:00Z

by Diya Zang, Yifan Jing, Xinya Huang, Yan Kuang, Jiewei Cheng, Wenkai Wang, Demin Xu, Chengming Zhu, Di Chen, Zhongying Zhao, Xuezhu Feng, Shouhong Guang

Stress granules (SGs) are dynamic ribonucleoprotein condensates that enable cells to adapt to environmental stress, yet their functions and regulation in the germline remain incompletely understood. Here, we characterize GTBP-1, the Caenorhabditis elegans homolog of human G3BP1, and investigate its role in heat stress responses and reproductive homeostasis. gtbp-1 mutants exhibit temperature-dependent reproductive phenotypes. Under normal growth conditions, GTBP-1 is diffusely distributed in the cytoplasm, whereas heat stress induces the formation of prominent GTBP-1 granules in the germline. Domain analysis revealed that the NTF2 domain is required for heat stress-induced GTBP-1 enrichment in granules, while the IDR, RRM, and RGG domains contribute to GTBP-1 granule dynamics. Among the known germ granule compartments, GTBP-1 granules showed the strongest association with P-bodies, and disruption of P-body components markedly reduces GTBP-1 enrichment. RNAi-based candidate screening identified PQN-59, LAF-1, and SMO-1 as regulators of GTBP-1 enrichment, while a forward genetic screen revealed that loss of the mTOR effector RSKS-1 suppresses the fertility defect of gtbp-1 mutants and alters heat stress-induced GTBP-1 enrichment. Together, these findings identify a role for GTBP-1 in temperature-dependent reproductive homeostasis and reveal an association between heat stress-induced GTBP-1 granules and P-bodies in C. elegans.

GPC: An expressive and tractable deep generative model for genetic variation data

2026-10-06T14:00:00Z

by Prateek Anand, Anji Liu, Meihua Dang, Boyang Fu, Xinzhu Wei, Guy Van den Broeck, Sriram Sankararaman

Generative models play an important role in population genetics, being used to generate artificial genomes (AGs) that help benchmark methods, test evolutionary hypotheses, and construct reference panels for imputation while working around data-sharing restrictions. Existing generative models of genetic variation, however, struggle to faithfully express dependencies in the data while retaining tractability and preserving privacy. We introduce Genetic Probabilistic Circuits (GPC), a deep generative model for genetic variation data based on hidden Chow-Liu trees represented as probabilistic circuits. GPC generalizes traditional hidden Markov models by allowing arbitrary tree structures over latent variables, enabling it to capture long-range dependencies among SNPs. GPC is tractable, supporting exact computation of marginal and conditional probabilities that enables both AG generation and direct genotype imputation (avoiding the need for simulating AGs). We show that GPC generates AGs that accurately reproduce population structure and linkage disequilibrium patterns across a range of length scales. Compared to other deep generative approaches, GPC consistently improves imputation accuracy, with particularly strong gains for low-frequency variants and in populations that are not well-represented in public reference panels. Finally, we show that GPC better preserves privacy of the training data, thereby providing a practical framework for AG generation in settings with limited data access.

Epigenetic maintenance of PRC2-repressed chromatin requires RTT109 but not H3K56 acetylation

2026-10-05T14:00:00Z

by Rochelle E. Yap, Felicia Ebot-Ojong, Abigail J. Ameri-Solanky, Zachary A. Lewis

In animals, plants, and some fungi, Polycomb Repressive Complex 2 (PRC2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to establish transcriptionally repressed chromatin. Here, we identify the histone acetyltransferase RTT109 as a key regulator of PRC2-repressed domains in the model fungus Neurospora crassa. Although RTT109 interacts with the Vps75 homolog Nucleosome Assembly Factor 2 (NAF-2), we show that proper structure and function of PRC2-methylated chromatin require RTT109 catalytic activity but are independent of NAF-2 and H3K56 acetylation. We further demonstrate that H3K27me3 can be stably propagated over multiple rounds of mitosis in the absence of sequence-specific PRC2 targeting, and that RTT109 is essential for maintenance of the repressed state. These findings uncover a replication-linked mechanism for epigenetic memory and establish RTT109 as a key regulator of Polycomb-mediated chromatin inheritance.

Decoupling metabolic defense: Mutational and recombinational chaos in Sod1-deficient cells

2026-10-05T14:00:00Z

by Yang Sui, Dao-Qiong Zheng, Yeke Wang, Shan-Shan Zhao, Ke-Jing Li, Cunqi Ye, Ke Zhang

Superoxide dismutase 1 (Sod1) is long recognized as a frontline antioxidant, yet its broader role in safeguarding the eukaryotic genome remains under-explored. Here, using a yeast model, we reveal that Sod1 is an indispensable guardian of genomic integrity. Its absence unleashes a genomic storm: whole-genome sequencing uncovered a dramatic surge in single nucleotide variations (13-fold), loss of heterozygosity (12-fold), chromosomal rearrangements (4-fold), and a staggering 48-fold increase in aneuploidy. Remarkably, this genomic instability was completely abolished under anaerobic conditions, identifying reactive oxygen species as the sole executioner. We demonstrate that Sod1 deficiency sculpts a unique mutational landscape dominated by C:G to A:T transversions—a molecular fingerprint of 8-oxoguanine overproduction. Mechanistically, these lesions are exacerbated by error-prone DNA polymerase ζ but mitigated by the concerted actions of Ogg1-mediated excision and DNA polymerase η. Critically, we show that Amyotrophic Lateral Sclerosis-associated variants are not created equal: the H48Q mutation shatters genome stability, whereas others (A4V, G36R, and G93A) remain benign in this context. Unlike yeast Sod1, human Sod1 is highly resistant to amino acid substitutions outside copper-binding sites, thus preventing the loss of enzyme function. Overall, our findings provide a mechanistically framework for understanding how Sod1 dysfunction drives genome instability in eukaryotic cells.

Genetic architecture of basal heart rate and its modulation by dietary salt in Drosophila melanogaster

2026-10-05T14:00:00Z

by Gulnur Ipek Erdemli, Murat Yilmaz, Alp Mete Ummet, Fatih Akdemir, Ergi Deniz Ozsoy

Heart rate (HR) is a complex quantitative phenotype that is influenced by both genetic and environmental factors, and it is a critical factor in the regulation of cardiac physiology. Despite the discovery of numerous genes associated with HR variation in humans and other organisms, the mechanisms by which these genes interact to affect HR changes in natural environments and their responses to environmental stressors remain incompletely understood. In this study, the genetic basis of basal HR and the response to salt stress were examined using the Drosophila Genetic Reference Panel (DGRP). The 154 DGRP lines exhibited moderate broad-sense heritability and substantial genetic variation in HR measurements during the third larval stage, with males and females analyzed separately, under both standard and 0.1% NaCl-containing medium conditions. The mixed-effects model revealed that the interaction between genotype and environment significantly influences HR. Genome-wide association analysis identified gene variants associated with critical biological processes such as ion transport, cardiac development, protein homeostasis, metabolism, and stress response. The identification of different genes under standard and saline (NaCl-supplemented) conditions suggests that environmental stress unlocks cryptic genetic variation. Candidate genes were tested using heart-specific GAL4 drivers in RNAi experiments, and a considerable number of these genes were found to significantly affect HR based on sex and the environment. These findings reveal that HR variation is strongly shaped by genotype-by-environment interactions and sex-specific genetic effects, with distinct sets of genes contributing under basal and stress conditions. The identification of environment-dependent genetic architectures suggests that salt stress can expose cryptic genetic variation influencing cardiac function. By integrating genome-wide association analyses with targeted RNAi-based functional validation, this study provides a framework for linking natural genetic variation to physiological phenotypes in a context-dependent manner.

Forward genetics reveals a conserved CNBHD-CNBHD interface that restrains EAG channel activation to regulate sleep

2026-10-01T14:00:00Z

by Xinyu Huang, Sudharsan Kannan, Gail A. Robertson, Han Wang

KCNH voltage-gated potassium channels regulate neuronal excitability, yet how their hallmark cyclic nucleotide-binding homology domains (CNBHDs) influence channel gating to regulate behavior remains unclear. Using an unbiased forward genetic screen in Caenorhabditis elegans, we identified a gain-of-function mutation in the EAG-subfamily KCNH channel EGL-2 that suppresses sleep. The mutation (G574E) alters a highly conserved glycine residue at the interface between CNBHDs of adjacent channel subunits. EGL-2 functions cell-autonomously in the central sleep-promoting neuron ALA. In vivo calcium imaging showed that the gain-of-function mutation suppresses sleep by inhibiting ALA neuronal activity, consistent with enhanced potassium channel activity. Genetic analysis demonstrated that the sleep-suppressing phenotype of G574E requires both an intact potassium selectivity filter and the intrinsic ligand-occupied CNBHD. A second substitution at the same glycine (G574R), which introduces a positively charged side chain in contrast to the negatively charged side chain in G574E, similarly suppresses sleep, indicating that perturbation of the CNBHD-CNBHD interface, rather than the specific amino acid change, underlies the phenotype. Moreover, mutations at the corresponding residue in the ERG-subfamily KCNH channels C. elegans UNC-103 and human hERG also produce gain-of-function effects, and electrophysiological analysis showed that hERG(G749R) shifts voltage-dependent channel activation to more negative potentials and accelerates activation kinetics. These findings identify EGL-2 as an important sleep regulator and uncover a conserved gating mechanism by which the intersubunit CNBHD-CNBHD interface restrains KCNH channel activation to regulate neuronal excitability and behavior.

Immune markers mediate genetic relationships between immune diseases and psychiatric disorders

2026-09-30T14:00:00Z

by Sophie Breunig, Kristen M. Kelly, Lukas S. Schaffer, Jeremy M. Lawrence, Younga Heather Lee, Elizabeth W. Karlson, Andrew D. Grotzinger

This study explored the genetic links between 11 immune-mediated diseases and 13 psychiatric disorders, addressing the limited understanding of the underlying biological mechanisms linking these illnesses. Utilizing genomic structural equation modeling, we investigated whether the genetic liability for 14 immune markers (e.g., C-reactive protein [CRP], interleukin-6 [IL-6]) mediated associations between latent genomic factors of immune-mediated diseases (e.g., autoimmune) and psychiatric disorders (e.g., internalizing). While the literature extensively describes the psychiatric relevance of CRP, results indicated this is better explained by its biological precursor, IL-6. This is evidenced by highly attenuated associations of psychiatric traits with CRP when accounting for overlapping signal of IL6. Overall, the genetic liability of six immune markers significantly mediated 11 psychiatric-immune disease genetic relationships. For example, IL-6 mediated 60% of the genetic link between an internalizing factor and Crohn’s disease. Identified markers often evinced mediating effects for multiple disorder clusters and many immune-psychiatric relationships were mediated by multiple markers. At the same time, highlighting their diagnostic relevance, only a subset of examined immune markers were significant mediators. These findings provide mechanistic insight by pinpointing the immune markers that may be most critical to the psychiatric-immune disease link, which notably did not include CRP.

The prevalence of protein misfolding as a mechanism for hereditary deafness

2026-09-30T14:00:00Z

by Rose A. Gogal, Genevieve M. Cox, Diana L. Kolbe, Amanda M. Odell, Chloe E. Ovel, Katherine I. McCormick, Brian Hong, Hela Azaiez, Thomas L. Casavant, Richard J. H. Smith, Terry A. Braun, Michael J. Schnieders

Hearing loss is the most common sensory deficit impacting ~5% of the world’s population. The Deafness Variation Database (DVD) is a public resource of deafness variants, containing 381,924 missense variants across 224 genes, with 303,577 classified as a variant of uncertain significance (VUS). To address the challenge of evaluating each deafness associated VUS, we evaluate a family of probabilistic frameworks to quantify the strength of computational evidence based on ACMG/AMP recommendations. First, CADD and REVEL are compared using Bayesian models parameterized using either a ClinVar 2019 dataset or labeled DVD variants. The REVEL model built using the DVD dataset demonstrates the best accuracy, sensitivity, and specificity. Incorporation of (in)tolerance to missense variation based on sorting each gene into three bins (tolerant, average, intolerant) shows that intolerant DVD genes are consistent with a higher prior probability of being pathogenic (25.7%) than average (10.7%) or tolerant (8.7%) genes. Finally, the impact of protein folding stability was incorporated into the Bayesian model and surpassed the simpler versions while also offering a biophysical rationale for the disease mechanism. The 28,866 VUSs that reach a posterior probability of pathogenicity above 98% based on the protein-folding informed Bayesian model were prioritized as likely to be pathogenic. Overall, 54,752 missense variants (14.3% of 381,924) are predicted to cause modest protein folding destabilization of greater than 1.0 kcal/mol, while 18,706 of these are prioritized VUSs (34% of 54,752). 22,237 missense variants (6.2% of 381,924) are predicted to cause more severe protein folding destabilization of at least 2 kcal/mol with 12,424 being prioritized VUSs (55.8% of 22,237). From these VUSs, we identify twelve probands where the patient’s genetic diagnosis is upgraded to likely pathogenic/pathogenic. We highlight two variants that cause clear structural disruption, demonstrating the impact of biophysical characterization on variant evaluation.

Altered regulation of septal peptidoglycan synthesis modulates β-lactam susceptibility in Pseudomonas aeruginosa

2026-09-28T14:00:00Z

by Jake Colautti, Alexander C. Anderson, Wyatt P. K. Clark, Lindsey S. Marmont

Bacterial cell division requires precise regulation of septal peptidoglycan (PG) synthesis by the essential SEDS-bPBP synthase FtsWI. Activation of FtsWI is thought to occur through an allosteric cascade initiated by the late-arriving divisome protein FtsN and transmitted via the FtsQ-FtsL-FtsB (FtsQLB) complex, but the molecular details of this process remain incompletely defined and differ across species. Here, using the conditional essentiality of ftsN in Pseudomonas aeruginosa, we identify substitutions in the non-enzymatic pedestal domain of FtsI that bypass the requirement for FtsN. These mutations restore cell division in ΔftsN cells, suppress dominant-negative phenotypes of activation-defective ftsL alleles, and reduce cell length in an otherwise wild-type background, demonstrating that they alter FtsWI regulation to overcome the requirement for stimulation by both FtsN and FtsQLB. Mapping these mutations onto the P. aeruginosa FtsQLBWI structure reveals that they cluster on distinct surfaces of the pedestal domain. Because some of these substitutions have been identified in clinical P. aeruginosa isolates with increased aztreonam resistance, we next asked whether these regulatory substitutions alter β-lactam susceptibility. Variants at the FtsI-FtsL interface modestly reduce susceptibility to multiple β-lactam antibiotics, whereas a variant on the opposite face of the pedestal domain produces striking FtsN-dependent hypersusceptibility to the same molecules. These findings show that the FtsI pedestal domain plays a central role in the regulation of FtsWI and reveal a previously unrecognized relationship between divisome regulation and β-lactam susceptibility. More broadly, our work identifies the pedestal domain as a regulatory hub that integrates multiple inputs controlling septal PG synthesis and highlights its potential relevance to β-lactam resistance in clinical P. aeruginosa isolates.

Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish

2026-09-28T14:00:00Z

by Siyao Wang, Laura Childers, Fernando Martinez III, Michel Bagnat, Jieun Park

Lysosome-rich enterocytes (LREs) are a specialized population of intestinal cells that mediate the uptake and absorption of dietary proteins in fish and neonatal mammals. Loss of LRE function causes inhibited growth and poor survival due to protein malnutrition. Previously, we reported that in zebrafish loss of Plasmolipin (pllp), an endosomal membrane protein highly expressed in LREs, impairs LRE differentiation and dietary protein absorption, resulting in marked reduction in survival rates. Raising pllp homozygous mutants surviving to adulthood and in-crossing them for multiple generations resulted in a recovery of survival and growth, even when fed a low protein diet. To uncover mechanisms underlying this phenomenon, we compared the older adapted pllp allele with genetically related wild type (WT) fish and a newly generated pllp mutant allele. Using transcriptome profiling and quantitative protein absorption assays, we found that the adapted pllp mutants exhibit upregulation of LRE endocytic components associated with a capacity for protein absorption that exceeds that of WT. This hyperactivation of LRE endocytic and absorptive activity is accompanied by transcriptional regulation of immune genes that may contribute to the enhanced survival of pllp mutants in the face of increased exposure to environmental antigens. Genetic analyses indicate that these divergent phenotypes emerge gradually over generations and can recur in an independently generated pllp allele upon inbreeding and natural selection. Overall, our study illustrates that genome-wide transcriptional changes are associated with stable improvements in intestinal function and organismal survival in response to protein malnutrition.

The SynMuvA lin-15A licenses natural transdifferentiation by antagonizing identity safeguarding mechanisms

2026-09-25T14:00:00Z

by Sarah Frieda Becker, Marie-Charlotte Morin, Julien Lambert, Shashi Kumar Suman, Francesco Nicola Carelli, Alex Appert, Stéphane Roth, Sarah Hoff-Yoessle, Jessica D. Medina-Sanchez, Manuela Portoso, Julie Ahringer, Sophie Jarriault

The mechanisms that restrict or enable latent cellular plasticity have attracted growing interest over the past decade, with important implications for cancer and regenerative therapies. However, the diversity of both pro- and anti-plasticity mechanisms remains incompletely understood. Here, we identify the THAP domain gene lin-15A as a novel factor involved in the natural rectal-to-neuronal Y-to-PDA transdifferentiation in Caenorhabditis elegans. Our genetic analyses show that lin-15A acts in parallel to previously described plasticity factors. Null mutant suggests that, rather than driving the process, LIN-15A licenses its initiation by antagonizing several chromatin-modifying complexes known to safeguard differentiated cell identities. In addition, our data show that even cells developmentally programmed to undergo transdifferentiation exhibit reprogramming barriers. Interestingly, lin-15A is not a core plasticity factor per se but acts as one specifically in the Y cell context. Together, our findings support a model in which diverse molecular activities coordinate controlled cell identity conversions: plasticity factors function as Drivers, while others like lin-15A, termed here transdifferentiation Licensers, attenuate identity safeguarding mechanisms, thereby facilitating transdifferentiation.

Role of the m⁶A methyltransferase Mettl16 in Drosophila development

2026-09-24T14:00:00Z

by Penghui Song, Lijuan Ma, Dong Yan

N⁶-methyladenosine (m⁶A), one of the most abundant chemical modifications on RNA, is installed by METTL3 and several other methyltransferases, including METTL16. Although METTL16 has been characterized in several model organisms, its function in Drosophila remains unknown. Here, we show that, unlike in mammals, Drosophila Mettl16 mutants are viable but exhibit multiple developmental and behavioral defects. Both male and female mutants are sterile, with severe gametogenesis defects. Mettl16 mutant germ cells can pass the mitotic and meiotic stages, but are defective in spermatid elongation and individualization. Mettl16-GFP localizes predominantly to the nucleus, and its absence does not impair global protein synthesis in wing disc epithelial cells. MeRIP-Seq analysis indicates that Mettl16 loss affects m⁶A on only a small subset of transcripts, in contrast to the broad effect of Mettl3. We further demonstrate that Mettl16 interacts with U6 snRNA and is required for its m⁶A modification. Accordingly, Mettl16 mutants display widespread alterations in alternative splicing. Together, the pleiotropic phenotypes of Mettl16 mutants likely stem from its role in m⁶A deposition and U6-dependent splicing regulation of specific target transcripts.

Univariate-guided sparse regression for Biobank-scale high-dimensional omics data

2026-09-23T14:00:00Z

by Joshua Richland, Tuomo Kiiskinen, William Wang, Wenhui Sophia Lu, Balasubramanian Narasimhan, Trevor Hastie, Manuel Rivas, Robert Tibshirani

We present a scalable framework for computing polygenic risk scores (PRS) in high-dimensional genomic settings using the recently introduced Univariate-Guided Sparse Regression (uniLasso). UniLasso is a two-stage penalized regression procedure that leverages univariate coefficients and magnitudes to stabilize feature selection and produce sparse predictive models. Building on its theoretical and empirical advantages, we adapt uniLasso for application to the UK Biobank, a population-based repository comprising over one million genetic variants measured on hundreds of thousands of individuals from the United Kingdom. We further extend the framework to incorporate external summary statistics via uniLasso ES (external scores). These signals guide the regression toward variants with prior evidence of association by informing penalty weights and sign constraints. Both uniLasso ES and uniLasso ultimately fit multivariate models using individual-level target data; the external statistics guide, rather than replace, this fitting. Our results demonstrate that uniLasso attains predictive performance comparable to standard Lasso while selecting substantially fewer variants, yielding sparser and potentially more interpretable models. Moreover, it remains competitive with other PRS estimation methods, such as PRS-CS and lassosum2.

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.

PLOS Genetics: New Articles

The AF-2 domain of estrogen-related receptor interacts with PPRC1 to modulate larval epidermal marking in Bombyx mori

An NKX2-3/5/6 homolog is required downstream of BMP signaling to pattern the sensory-adhesive organ of a tunicate larva

Combined lactate- and phosphate-dependent cytoplasmic acidification is associated with Mycobacterium tuberculosis growth arrest at acidic pH

New insights into Müllerian duct differentiation provided by single cell transcriptomics in the chicken embryo

Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling

ZBED6 deficiency drives pathological cardiac hypertrophy through MEOX1–ERK1/2–dependent autophagy dysfunction

Heat stress promotes GTBP-1 association with perinuclear P-bodies in the C. elegans germline

GPC: An expressive and tractable deep generative model for genetic variation data

Epigenetic maintenance of PRC2-repressed chromatin requires RTT109 but not H3K56 acetylation

Decoupling metabolic defense: Mutational and recombinational chaos in Sod1-deficient cells

Genetic architecture of basal heart rate and its modulation by dietary salt in Drosophila melanogaster

Forward genetics reveals a conserved CNBHD-CNBHD interface that restrains EAG channel activation to regulate sleep

Immune markers mediate genetic relationships between immune diseases and psychiatric disorders

The prevalence of protein misfolding as a mechanism for hereditary deafness

Altered regulation of septal peptidoglycan synthesis modulates β-lactam susceptibility in Pseudomonas aeruginosa

Genome wide transcriptional changes underlie gradual and recurrent adaptation to protein malnutrition in zebrafish

The SynMuvA lin-15A licenses natural transdifferentiation by antagonizing identity safeguarding mechanisms

Role of the m6A methyltransferase Mettl16 in Drosophila development

Univariate-guided sparse regression for Biobank-scale high-dimensional omics data

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

Role of the m⁶A methyltransferase Mettl16 in Drosophila development

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