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At least 19 recordsLinked to original sources
PubMed2026

Context-specific genetic effects inform endotypes and treatment in asthma.

BACKGROUND: Asthma has heterogeneous risk factors, subtypes, and treatments. It is often unclear how to stratify this heterogeneity in scientific studies and clinical care. Genetics could explain root causes of this clinical heterogeneity, called endotypes, but prior studies have used models that are not designed for complex diseases like asthma. OBJECTIVE: We aimed to find genetic effects that partly explain different asthma endotypes. METHODS: We used recent powerful and robust statistical models of context-specific genetic effects in complex traits. We identified genetic subtypes by clustering clinical asthma features in a case-control cohort, GALA II. We replicated the genetic endotypes in the UK Biobank with gene-context interaction tests. RESULTS: Asthma-associated single nucleotide polymorphisms, polygenic scores, and genome-wide heritability revealed subtype-specific genetic endotypes correlated with type 2 inflammation, allergy, and neuroticism. We validated the type 2 associations with molecular data including nasal RNA sequencing. In the UK Biobank, we replicated these endotypes and found they interact with several polygenic scores and drug-relevant genes. CONCLUSION: Our results show how context-specific genetic effects can unravel biomedically meaningful endotypes of complex disease and suggest novel precision treatment strategies.

Humans↗
PubMed2026

ReGAIN: a bioinformatics platform for assessing probabilistic co-occurrence between resistance genes in bacterial pathogens.

MOTIVATION: Multidrug-resistant bacterial pathogens continue to rise globally, yet scalable methods are needed to infer how resistance determinants co-occur across pathogen populations and to quantify conditional dependencies underlying co-occurrence and shared genetic context. RESULTS: We present ReGAIN (Resistance Gene Association and Inference Network), an open-source platform that applies Bayesian network structure learning to infer probabilistic, conditional dependency relationships among antibiotic resistance, heavy metal tolerance, stress response, and virulence determinants in bacteria. In contrast to pairwise co-occurrence analyses, ReGAIN reports conditional probabilities, relative risks, and absolute risk differences with confidence intervals to prioritize candidate relationships for downstream prioritization. Applied across ESKAPEE pathogens, ReGAIN recapitulated established resistance gene relationships and identified additional candidate patterns consistent with co-selection and shared genetic context. Together, these results support scalable, reproducible population-wide analysis of resistance networks for surveillance, comparative genomics and epidemiology. AVAILABILITY: ReGAIN analyses are performed using Python v3.11.5 and R v4.4.1 and is available as open-source software through Bioconda at {https://anaconda.org/bioconda/regain-cli}. Source code and documentation can be found at {https://github.com/ERBringHorvath/regain_CLI}. All genomes used in this publication were downloaded from the National Center for Biotechnology Information database. Large supplementary tables and results data from the ESKAPEE pathogen example network analyses can be downloaded from https://figshare.com/articles/dataset/ReGAIN_command_line_software_and_supplemental_figures_/28959431.

Computational Biology↗
PubMed2025

Computational modeling of human genetic variants in mice.

Mouse models represent a powerful platform to study genes and variants associated with human diseases. While genome editing technologies have increased the rate and precision of model development, predicting and installing specific types of mutations in mice that mimic the native human genetic context is complicated. Computational tools can identify and align orthologous wild-type genetic sequences from different species; however, predictive modeling and engineering of equivalent mouse variants that mirror the nucleotide and/or polypeptide change effects of human variants remains challenging. Here, we present H2M (human-to-mouse), a computational pipeline to analyze human genetic variation data to systematically model and predict the functional consequences of equivalent mouse variants. We show that H2M can integrate mouse-to-human and paralog-to-paralog variant mapping analyses with precision genome editing pipelines to devise strategies tailored to model specific variants in mice. We leveraged these analyses to establish a database containing > 3 million human-mouse equivalent mutation pairs, as well as in silico-designed base and prime editing libraries to engineer 4,944 recurrent variant pairs. Using H2M, we also found that predicted pathogenicity and immunogenicity scores were highly correlated between human-mouse variant pairs, suggesting that variants with similar sequence change effects may also exhibit broad interspecies functional conservation. Overall, H2M fills a gap in the field by establishing a robust and versatile computational framework to identify and model homologous variants across species while providing key experimental resources to augment functional genetics and precision medicine applications. The H2M database (including software package and documentation) can be accessed at https://human2mouse.com.

Journal Article↗
PubMed2026

Emergence of a Tn7-associated blaVIM-1 within IncC plasmids in ST46 Providencia stuartii from Northern Italy.

OBJECTIVES: To characterize the genomic features and resistance determinants of carbapenem-resistant Providencia stuartii isolates circulating in Northern Italy, with a focus on the genetic context of blaVIM-1. METHODS: Five P. stuartii isolates collected between 2022 and 2024 from interconnected healthcare facilities underwent molecular characterization. Antimicrobial susceptibility testing was performed according to EUCAST 2025 criteria. Whole-genome sequencing was conducted using Illumina technology, followed by resistome, plasmidome, and phylogenetic analyses. Comparative genomics was used to investigate the genetic environment of blaVIM-1. RESULTS: All isolates belonged to the emerging ST46 lineage and exhibited an extensively drug-resistant phenotype, remaining susceptible only to amikacin. The blaVIM-1 gene was located on a &#x223c;100 kb mobilizable IncC plasmid shared across all isolates. Notably, blaVIM-1 was embedded within a 13 kb Tn7 transposon carrying a complete set of transposition genes and inserted into a class 1 integron structure. Comparative analysis revealed no full homology with previously described IncC plasmids, suggesting a novel genetic arrangement. Phylogenetic analysis demonstrated close relatedness among Italian isolates (<33 SNPs), supporting local clonal circulation, while showing clear separation from previously described NDM-producing ST46 strains. CONCLUSIONS: This study describes the rare association of blaVIM-1 with a Tn7 transposon in P. stuartii, highlighting the genomic plasticity of IncC plasmids and their role in the emergence of new resistance platforms. The identification of this structure in a high-risk lineage underscores the potential for further dissemination of carbapenem resistance in healthcare settings.

IncC↗
PubMed1976

[Re-issue of "From Anguish to Ectasy"].

Pierre Janet noteworthy works keep, after half a century, its interest and originality. Through his writings, he gives the main character of an unique system including all the psychopathology. An important place is given to the feelings and their psychological rules, this in a genetical context. Pierre Janet does not accept to give to the traumatic events a main importance, his conception is this of a unity of the mental pathology. Conception which is built on an innovation giving all the attract of this work: the notion of belief, the distinction between its structure and its object, the explanation of its importance in genetical evolution and in psychopathology. Pierre Janet shows by this research an unexplored way which can constitute a new phase in the modern psychopathology.

Depression↗
PubMed2025

Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network.

TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3-Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.

Animals↗
PubMed2026

Multi-omics evidence reveals robust airborne-human resistome connectivity driven by high-risk ARGs and mediated by Staphylococcus.

Airborne microbiomes are considered an important source of human antimicrobial resistance (AMR) exposure, yet multi-omics evidence linking airborne and human nasal resistomes remains limited. Here, we integrated metagenomic sequencing and whole-genome sequencing of antibiotic-resistant Staphylococcus isolates to investigate the connectivity between air and human nasal resistomes in dairy farm environments. Metagenomic taxonomic profiling showed that Staphylococcus was prominent in total suspended particles (TSP) and consistently detected across all samples. Among environmental reservoirs, TSP resistomes exhibited the strongest similarity to human nasal resistomes. This connectivity was supported by multiple lines of evidence, including highly similar resistome profiles, extensive homologous antibiotic resistance gene (ARG) pairs, strain-level similarity of resistant Staphylococcus isolates, and conserved mobile ARG genetic contexts. Notably, this connectivity was primarily driven by high-risk ARGs, while Staphylococcus was frequently associated with mobile ARGs and represented the only shared pathogenic genomes carrying both ARGs and virulence factor genes between airborne and nasal samples. Although lower ARG diversity, nasal resistomes exhibited higher ARG burden, risk scores, antibiotic-resistant bacterial genome abundance, and prevalence of resistant Staphylococcus. Occupational exposure further increased total and high-risk ARG burdens among farm workers. Together, these findings indicate that TSP can serve as an important route of occupational AMR exposure, with high-risk ARGs and Staphylococcus contributing to connectivity between airborne and nasal resistomes. Incorporating the host microbiome may therefore provide a more complete assessment of human-associated AMR exposure within a One Health framework.

Airborneresistome↗
PubMed2026

Genomic epidemiology and ceftazidime-avibactam resistance mechanism of KPC-3-producing Pseudomonas aeruginosa: A decade retrospective study in China.

OBJECTIVES: Carbapenem-resistant Pseudomonas aeruginosa (CRPA), especially KPC-producing P. aeruginosa, is rapidly expanding and posing a serious public health threat. Here, we aim to characterise the epidemiology of KPC-3-producing P. aeruginosa in a tertiary hospital over a 10-year period and elucidate the mechanism of ceftazidime-avibactam (CZA) resistance driven by blaKPC-3 to blaKPC-267 mutations in CRPA, along with conducting a global phylogeographic analysis of KPC-3-producing P. aeruginosa. METHODS: 11 non-duplicate KPC-3-producing CRPA isolates collected over a 10-year period were characterized by antimicrobial susceptibility testing and whole-genome sequencing (WGS). The genetic context and transferability of blaKPC-3/267 and the mechanism of KPC-267-mediated CZA resistance were investigated. Global phylogenomic analysis was performed to characterize the geographic distribution and population structure of blaKPC-3-carrying P. aeruginosa. RESULTS: All 11 KPC-3-producing CRPA strains in this study belonged to ST1076 and exhibited multidrug resistance. The blaKPC-267-positive CZA-resistant strain SRMPA3523 was isolated from patient 1 after blaKPC-3-positive P. aeruginosa SRMPA1139 and SRMPA1630 were treated with CZA. WGS indicated that blaKPC-3/267 was located on the Tn6296 transposon contained in the transferable IncP-2 plasmid. KPC-267 mediates resistance to CZA by reducing the inhibitory effect of avibactam and increasing affinity for ceftazidime. Global analysis indicated that blaKPC-3-carrying P. aeruginosa were predominantly in China, America, and Colombia, with ST1076 and ST111 as dominant clones. CONCLUSIONS: This study characterised the global phylogeography of blaKPC-3-carrying P. aeruginosa and identified KPC-267 as a KPC-3-derived variant associated with CZA resistance. This finding highlighted the risk of developing CZA resistance in KPC-producing P. aeruginosa strains under therapeutic pressure.

CRPA↗
PubMed2026

Genomic insights into the first blaKPC-2-carrying Klebsiella pneumoniae isolate reported in Chile: limited local dissemination of the globally distributed ST101 lineage.

OBJECTIVE: To genomically characterize Kpn-KPC-1, the first blaKPC-2-carrying Klebsiella pneumoniae isolate reported in Chile, and contextualize it within the global ST101 lineage. METHODS: Kpn-KPC-1 was analyzed by whole-genome sequencing. Its resistome, virulome, plasmid content, and blaKPC-2 genetic context were characterized, and 537 publicly available ST101 genomes were used for comparative phylogenomics. RESULTS: Kpn-KPC-1 belonged to ST101 and carried blaKPC-2 within the conventional Tn4401a transposon on a mosaic plasmid encoding multiple replication initiators and conjugation-associated genes. The isolate also harbored an OmpK36 porin alteration and accessory resistance- and virulence-associated determinants, including ICEKp3/ybt-9, K17, and O1&#x3b1;&#x3b2;,2&#x3b1;. Phylogenomic analysis placed Kpn-KPC-1 within a predominantly European clade, closest to Italian isolates recovered between 2012 and 2018. The absence of additional Chilean ST101 isolates related to Kpn-KPC-1 supports limited local dissemination of this lineage. Globally, ST101 was enriched in carbapenemase genes, particularly blaOXA-48-like and blaKPC variants. CONCLUSIONS: Kpn-KPC-1 represents a transient introduction of a carbapenemase-prone, high-risk ST101 lineage rather than the founder of a locally disseminated clone in Chile. Genome-level analysis resolved the blaKPC-2 context in this historical isolate, linking the carbapenemase gene to Tn4401a on a mosaic multidrug-resistance plasmid within an imported ST101 background. These findings underscore the value of retrospective genomics for reconstructing early antimicrobial-resistance introduction events.

Carbapenem-resistant enterobacterales↗
PubMed2026

hPSC models in cancer mechanisms and therapeutic discovery.

Despite major advances in cancer genomics and immunotherapy, the field remains limited by experimental models that fail to faithfully recapitulate human tumor initiation, genetic context, and immune-tumor interactions. Traditional animal and immortalized cell models often lack predictive power for therapeutic response and toxicity. Recent advances in human pluripotent stem cell (hPSC) technology have transformed this landscape, enabling the generation of patient-specific cancer models, multicellular organoids and assembloids, and scalable immune effector cells. These platforms now permit mechanistic dissection of tumorigenesis, reconstruction of human tumor microenvironments, and development of off-the-shelf immunotherapies. This review will synthesize these emerging findings, define key technological and biological gaps, and outline future directions for integrating hPSC-based modeling into precision oncology and translational cancer research.

cancer immunotherapy↗
PubMed2025

Co-existence of the oxazolidinone resistance genes cfr and optrA on a novel multiresistance plasmid from a methicillin-resistant Macrococcoides bohemicum strain.

OBJECTIVES: To identify and characterize the oxazolidinone resistance genes cfr and optrA from a methicillin-resistant Macrococcoides bohemicum strain of chicken origin. METHODS: The presence of mobile oxazolidinone resistance genes was detected by PCR. Antimicrobial susceptibility testing was conducted by broth microdilution. Transfer experiments were carried out to evaluate horizontal transferability of the plasmid. WGS was performed using a combination of Illumina NovaSeq/Oxford Nanopore PromethION platforms. RESULTS: The M. bohemicum strain HLJ23 exhibited an MDR phenotype and was positive for both cfr and optrA genes. WGS revealed that the genes cfr and optrA co-exist on the novel MDR plasmid pHLJ23-71kb. Although conjugation experiments were unsuccessful, plasmid pHLJ23-71kb could be transferred to Staphylococcus aureus RN4220 by electrotransformation. Genetic context analysis showed that the cfr and optrA together with another four antimicrobial resistance genes are located in an MDR region on plasmid pHLJ23-71kb. Sequence analysis suggested that this MDR region possibly originated from Mammaliicoccus or Staphylococcus spp. CONCLUSIONS: To the best of our knowledge, this study represents the first report of the oxazolidinone resistance genes cfr and optrA in the genus Macrococcoides. Furthermore, attention should be paid to the exchange of resistance determinants between members of the genera Staphylococcus, Mammaliicoccus and Macrococcoides.

Plasmids↗
PubMed1992

The effects of retinoic acid on the expression of alpha-fetoprotein and albumin genes in rat hepatoma cell lines.

Many transcriptional regulators can stimulate or repress gene expression depending on the cellular or genetic contexts. Thus dexamethasone increases the amount of alpha-fetoprotein mRNA in Morris rat hepatoma derived cell line McA-RH 8994 cells, but decreases it in McA-RH 7777 cells. In the present study, we demonstrated that retinoic acid, whose receptors belong to the steroid/thyroid hormone receptor gene family, also enhanced the expression of alpha-fetoprotein and albumin gene in McA-RH 8994 cells, but had no effect on alpha-fetoprotein gene expression in McA-RH 7777 cells. In contrast to the effect of dexamethasone on the alpha-fetoprotein gene expression, which requires ongoing protein synthesis, cycloheximide, a protein synthesis inhibitor, enhanced the effect of retinoic acid. Actinomycin D inhibited the retinoic acid mediated increase in alpha-fetoprotein and albumin mRNA expression. Since the McA-RH 8994 cells did not express retinoic acid receptor beta mRNA, the observed regulatory effects of retinoic acid on alpha-fetoprotein and albumin gene expression were not mediated through retinoic acid receptor beta. We also conclude that the regulation was at the level of transcription and that retinoic acid and dexamethasone probably regulate the expression of liver specific genes through different mechanisms.

Albumins↗
PubMed2026

Emergence of Acinetobacter soli harboring three carbapenemase-encoding genes (blaNDM-1, blaIMP-14, and blaOXA-58) on a single plasmid in an ICU patient.

Acinetobacter soli is an environmentally adaptable species increasingly recognized as an emerging pathogen in hospital settings, particularly in intensive care units (ICUs). In this study, we report the first A. soli isolate from an ICU patient that co-harbors three carbapenemase-encoding genes (blaNDM-1, blaIMP-14, and blaOXA-58) on a single plasmid. Whole-genome sequencing revealed that multidrug resistance in this strain is mediated by a 294,790 bp plasmid, pSLAB-A, carrying 16 antimicrobial resistance genes, including all three carbapenemases. Comparative plasmid analysis showed a highly conserved backbone but identified a unique ~40 kb multidrug-resistance region containing blaNDM-1, blaIMP-14, and eight additional resistance genes. Genetic context analysis indicated that insertion sequences (ISAba125 and ISAba3) and class 1 integrons contribute to the mobilization and accumulation of carbapenemase-encoding genes. Plasmid stability assays demonstrated that pSLAB-A remained stably maintained for more than 90 generations without antibiotic selection. A global survey of the NCBI database identified 15 A. soli strains carrying carbapenemase-encoding genes, most of which were isolated from China, with clinical specimens representing the predominant source. Seven carbapenemase-encoding genes were detected, with blaNDM-1 being the most prevalent. Among eight isolates with complete genomes, all carried carbapenemase-encoding genes on plasmids. Phylogenetic analysis revealed regional dissemination of a clonal lineage across hospitals in Zhejiang Province and sustained nosocomial transmission within a hospital in Taiwan. These findings suggest that the spread of carbapenem resistance in A. soli is largely driven by multidrug-resistance plasmids, facilitating clonal expansion in hospital environments and posing a growing challenge for antimicrobial therapy and infection control in ICUs.IMPORTANCECarbapenem-resistant A. soli is an emerging clinical concern, capable of causing severe invasive infections, including bacteremia, in intensive care unit settings, and its emergence poses substantial challenges to antimicrobial therapy. In this study, we demonstrate that carbapenem resistance in A. soli is predominantly mediated by the acquisition of multidrug-resistance plasmids carrying carbapenemase-encoding genes. Owing to its strong environmental persistence, A. soli can readily undergo nosocomial clonal dissemination once carbapenem resistance is acquired. Moreover, the spread of multidrug plasmids co-harboring multiple carbapenemase-encoding genes may accelerate the evolutionary trajectory of resistance in A. soli, further exacerbating the threat to clinical management. Given its demonstrated capacity to cause hospital-associated infections and to rapidly acquire multidrug resistance, A. soli warrants heightened vigilance from both clinical and public health perspectives.

beta-Lactamases↗
PubMed1975

Immunologic benefits and hazards of milk in maternal-perinatal relationship.

Aside from nutritional significance, milk affords infant mammals immunologic benefits. However, it is not without immunologically based hazards. These stem from its antigenicity and the fact that in certain species that receive their maternal immunologic endowment postpartum, hemolytic disease of the newborn may be mediated by colostral antibodies. Awareness that viable leukocytes are ingredients of colostrum and milk has stimulated interest in the significance of these cells. Skin grafting tests on foster-nursed rats and mice have given circumstantial evidence that, in these species, leukocytes may be transmitted naturally from the mother's blood stream to the suckling's blood stream through the milk, and that these cells may be beneficial (adoptive immunization) or, in some genetic contexts, harmful (initiating graft-versus-host disease). In man, too, studies on necrotizing enteritis and other disease provide increasing support for the thesis that leukocytes in milk fulfill a protective function, possibly as a consequence of their "natural" transplantation.

Animals↗
PubMed1979

[The concept of mental deficiency. Evolution of theories, attitudes and practices].

In the last twenty years a deep renewal of the conceptions about and the treatments of the mentally deficients has taken place. In an attempt to clarify somehow the confusion in the communication between specialists, the author reminds the classical position on this subject, which relies upon the definition of the idiocy: a state of a severe mental defect, set up early in life, with an organic cause and being incurable for this reason. In spite of the later considerable differenciation at different levels and types, the classical position maintains this definition as the ground of the nosographic class of the mental retardations (debility is considered then as a light idiocy), divided in two sub-classes of either "polygenic heredity" or accidents causing early brain damages. From a clinical point of view, such a theoretical position is difficult to apply, especially in cases of middle and light mental defects. From a theoretical point of view, this classical position has been often attacked: by the evidence of the socio-cultural factors of the intellectual development, by the analysis of the so-called instrumental troubles, by the studies about the early lack of mother-care and the child-psychoses with a defect, by the more recent works on dysharmonic evolvements, etc. All this has lead to major theoretical changes which force to give up the illusion of a "single class" of mental retardations and study therefore each case in the trajectory of its development, not only of the cognitive patterns but also of the whole personality structure. This clinical approach forces to admit organic, environmental (sociological and psycho-sociological) and relational, dynamic factors as well; and, to accept that their combination, replaced in a genetic context of the functioning patterns, establishes a new, properly psychological level of causality. So, even the idea of a "defectology" is non-sense; the factors and the problems in question are the same as in any other psychogenesis. Nevertheless, the study of cases, in which this psychogenesis is caracterized by a mental deficit, is very important.

Adolescent↗
PubMed2025

Investigating the interplay between prematurity and genetic variation in the context of rare developmental disorders.

BACKGROUND: Rare damaging genetic variation accounts for a substantial proportion of the risk of rare developmental disorders (DDs), but common genetic variants as well as environmental factors, including prematurity, also contribute. Little is known about the interplay between prematurity and genetic variation in influencing phenotypic outcomes in DDs, nor about how genetic factors may contribute to risk of preterm birth in DDs. METHODS: We leveraged phenotypic and genetic data from 21,712 patients with DDs recruited for clinical sequencing, 16% of whom were born prematurely. Using multivariable regression models, we compared phenotypic features and the prevalence of diagnostic genetic variation in specific genes between preterm and term individuals with DDs. We tested whether the fraction of cases attributable to de novo mutations differed between term and preterm probands. Additionally, we assessed whether associations between common variant contributions to education-related traits and prematurity are explained by direct genetic effects. RESULTS: Prematurity was associated with more severe clinical phenotypes among these DD patients, including more affected organ systems and more delayed developmental milestones. Prematurity and the presence of a monogenic diagnosis contributed additively to severity. We found that genes associated with fetal anomalies were enriched for diagnostic mutations among preterm individuals (p&#x2009;=&#x2009;7.83&#x2009;&#xd7;&#x2009;10-5). We also demonstrated an exome-wide enrichment of de novo mutations (DNMs) in both term and preterm probands; the fraction of cases explained by DNMs in known DD-associated genes was higher in term than preterm cases (25% versus 20%) but DNMs in as-yet-undiscovered genes likely contribute approximately equally to both groups (14% versus 13%). Finally, we showed that the positive association between polygenic predisposition to education-related traits and gestational duration is likely to be the result of genetically influenced parental traits or confounders, rather than direct genetic effects in the child, and that a monogenic diagnosis modifies this association. CONCLUSIONS: Our findings emphasise the importance of considering environmental factors like prematurity in understanding outcomes in DDs suspected to have a genetic component, and motivate further exploration of the role that genetic variation plays in influencing prematurity.

Humans↗
PubMed2025

A Balanced Inversion Polymorphism Exhibits a Dominance Reversal at the Gene Expression Level that Depends on Developmental Context.

How genetic variance for fitness is maintained is incompletely understood. Mutation-selection balance and single-locus overdominance cannot account for the large variance observed. Recent work suggests that antagonistic balancing selection, favoring different alleles in different contexts and involving beneficial dominance reversals, might contribute to maintaining fitness variance. However, while this mechanism is plausible, evidence for dominance reversals remains scarce. Here, we study how In(3R)Payne, a balanced inversion polymorphism in Drosophila melanogaster, affects gene expression and chromatin accessibility by using RNA-seq and ATAC-seq (assay for transposase-accessible chromatin with sequencing). We find that, in embryos, the inverted (INV) arrangement tends to have dominant effects, while the standard (STD) arrangement behaves like a recessive Mendelian allele. Yet, in wing discs, this pattern is reversed: STD has mostly dominant effects, whereas INV behaves recessively. Since this shift in the dominance of the INV "allele" between developmental contexts affects the expression of suites of genes in a concerted manner, it might be mediated by a dominance modifier, for example, a transcription factor. In favor of this idea, 25% of the differentially expressed genes between INV and STD encode transcription factors. Interestingly, while only four differentially expressed genes are shared between embryos and wing discs, one of them is HP1c, a chromatin-binding protein and major transcriptional regulator, and thus a promising candidate for mediating the context-dependent change in dominance. Although the relationship between these patterns and fitness is presently unknown, our observations are consistent with a potential role of reversals (or, more generally, shifts) of dominance in maintaining inversion polymorphism.

Animals↗