Biology subjects

Kumar, K.

Publications and source records attributed to Kumar, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Polygenic hierarchies of macroscale brain structural organisation

Different Magnetic Resonance Imaging-derived cortical, subcortical, and white matter measures are presumed to reflect different developmental and cellular processes, but how their genetic architecture is organised and the underlying cellular and developmental processes is unclear. We conducted genome-wide association studies of 2,326 imaging-derived phenotypes (IDPs) spanning twelve structural measures across the cortex, subcortex, ventricles, and white matter tracts in the UK Biobank (Nmax = 53,751), replicated in ABCD (Nmax = 5,119), identifying 14,176 experiment-wide significant loci and prioritizing 848 genes. We found that IDPs primarily cluster by measure into six families: brain size, cortical thickness, curvature, microstructural coherence, microstructural diffusivity, and orientation dispersion. This structure was preserved across prioritized genes, cell types, and developmental timing; brain size implicates first-trimester radial glia programs, while white matter coherence implicates adolescent astrocyte and oligodendrocyte lineages. Within individual measures, genetic effects were further organised along broad spatial gradients, with a principal gradient reflecting allometric scaling for most measures and secondary gradients showing correspondence with the sensory-association topographic axis across several measures. We identified 79 genes with spatially restricted effects along the cortex, with many aligning with these dominant gradients while a substantial subset showed additional spatial patterns. Together, these findings reveal a hierarchical organisation of the genetic architecture of macroscale human brain structure, spanning phenotype families, broad spatial gradients, and regionally restricted developmental programmes.

genomics↗

bioRxiv2026

Genetic mapping of Citrullus amarus for resistance to gummy stem blight in watermelon

Gummy stem blight affects several cucurbit crops and has emerged as a serious production constraint of watermelon cultivation globally. However, no commercial varieties are available possessing resistance against this disease. Identification of genetic determinants and underlying QTLs are prerequisites for resistant variety development. In this direction, an attempt was made to understand genetics and identify responsible loci using two resistant accessions viz., PI 482276 and IIHR 82. Inheritance analysis indicated that resistance to GSB is governed by polygenes in both accessions. Four QTLs were identified for the population derived from PI 482276 x Arka Manik, while six were observed in the cross IIHR 82 x Arka Manik employing QTL-seq approach. The QTL regions contained important genes putatively involved in resistance reaction such as NAC domain-containing protein 17-like, chitinase 2- like, Pectinesterase, Coiled-coil domain-containing protein 18, Kinase family protein expansin-like B1 protein etc. Our results offer further insight into the disease resistance genetics and its utilization in resistance breeding for gummy stem blight in watermelon.

genomics↗

bioRxiv2026

gVCF2CNV: a scalable pipeline for CNV detection from whole-genome sequencing data

Motivation: Copy-number variants (CNVs) contribute to human disease and population trait variation. CNV detection from large whole-genome sequencing cohorts remains computationally demanding, as most methods require BAM or CRAM files. Genomic VCF (gVCF) files are smaller, routinely generated by standard variant-calling workflows, and contain the read depth and allelic information needed for CNV detection. However, gVCF files are not directly compatible with established CNV callers that rely on Log R Ratio (LRR) and B Allele Frequency (BAF) signals. Results: We present gVCF2CNV, a Nextflow pipeline that converts gVCF files into Log R Ratio and B Allele Frequency signals compatible with established CNV callers. Applied to 12,509 individuals from the SPARK cohort, gVCF2CNV generated signals at an average of 2.7 million SNV positions per individual and completed signal extraction in 4 hours using 192 CPUs. CNV calling with PennCNV and QuantiSNP identified candidate CNVs across a broad size range, with trio-based Mendelian precision reaching approximately 80% or higher for deletions of at least 30 kb and duplications of at least 5 kb. Application to 414,824 individuals from the All of Us cohort was completed in 96 hours, demonstrating feasibility at biobank scale. These results show that gVCF files can serve as a scalable input for CNV detection in large WGS cohorts. Availability and Implementation: gVCF2CNV is available at https://github.com/JacquemontLab/gVCF2CNV, implemented as a Nextflow pipeline with Perl and Python components, supported on Linux. Contact: mame.seynabou.diop@umontreal.ca

bioinformatics↗

bioRxiv2026

State-dependent aperiodic EEG dynamics track cortical network reorganization in chronic epilepsy

Aperiodic (1/f-like) EEG activity has rapidly become a popular noninvasive marker of cortical network state, proposed to index excitation-inhibition (E/I) balance and increasingly applied across neurological and psychiatric disorders. However, whether this approach remains reliable in the pathological brain, where disease progressively reorganizes neural networks, alters signal morphology, and drives continuous transitions between cortical states has yet to be systematically established.Using a medication-free genetic model of chronic epilepsy (Lafora disease; Epm2a-- mice), we tracked the aperiodic component of the cortical EEG across resting wakefulness, isoflurane anesthesia, and PTZ-induced seizures of graded severity, asking how a single spectral marker behaves as the brain moves between states. Epileptic mice exhibited systematically steeper aperiodic exponents than controls, an effect that persisted after removal of interictal epileptiform discharges and was replicated using independent time-resolved spectral parameterization. Slopes steepened predictably under GABAergic anesthesia, supporting the interpretation that aperiodic activity captures biologically meaningful state transitions beyond simple contamination by pathological waveforms. Across seizure phases, the aperiodic exponent varied systematically, however, the exponent flattened during ictal activity in step with the dominant discharge morphology, revealing that pathological waveform shape itself is a substantial contributor to seizure-state exponent changes. Together, these findings indicate that aperiodic EEG dynamics reflect a combination of chronic network-state reorganization and waveform-shape-driven spectral distortion, with their relative contributions varying across brain states. These results support spectral parameterization as a sensitive approach for tracking pathological neural activity in chronic epilepsy while delineating its interpretive boundaries in the presence of pathological waveforms.

neuroscience↗

bioRxiv2026

Integrative genomics reveals shared and stress-specific adaptive pathways underlying acidic soil-associated metal toxicity in rice

Soil acidity-associated toxicities of aluminum (Al), cadmium (Cd), and manganese (Mn) severely constrain rice productivity in upland ecosystems. To investigate the genomic basis of adaptation to acidic soil-related metal stress, we conducted an integrated meta-QTL (M-QTL) and functional genomics analysis in rice. Meta-analysis of 681 QTLs and MTAs from 53 QTL mapping and GWAS studies identified 79 robust M-QTLs, including ten overlapping regions associated with Al-, Cd-, and Mn-responsive traits. A multi-criteria prioritization framework identified 98 candidate genes supported by positional overlap, transcriptomic recurrence, and functional annotation, enriched for ion transport, detoxification, and redox regulation pathways. M-QTL10.9 emerged as a major hotspot enriched for glutathione-S-transferase genes, whereas M-QTL9.5 contained the highest density of prioritized candidates linked to Al and Cd responses. Comparative physiological & biochemical analyses of the contrasting rice genotypes Sahasarang and IR64 revealed genotype-dependent differences in antioxidant responses, metal partitioning, metabolic regulation, and cell wall remodeling under individual and combined metal stresses. Expression profiling of prioritized candidate genes, including OsACO family genes, OsZIP10, and OsGSTU10, further revealed genotype-dependent transcriptional divergence under combined stress. The identification of overlapping M-QTLs across Al, Cd, and Mn datasets suggests both shared and stress-specific adaptive responses to acidic soil-associated metal stress in rice.

genomics↗

bioRxiv2026

Non-equilibrium vibrational dynamics govern ultrafast electron transfer in avian cryptochrome

Photoactivated intermolecular electron transfer (ET) in cryptochromes proceeds along chains of aromatic residues and creates a spatially separated pair of radical electrons. Ultrafast time-dependent spectroscopy can provide experimental insight into this process and theoretical estimates of charge transfer rates are commonly obtained via Marcus theory. Here, we present a new perspective on the ET in European robin cryptochrome 4a (ErCry4a) that synthesizes insights from real-time ET calculations, ultrafast spectroscopic measurements and analytical derivations. The simulations exemplify that molecular vibrations play an essential role in enabling the ET dynamics, which was further rationalized through analytical derivations. Ultrafast pump-probe spectroscopy provided experimental access to the first 1.5 ns of the ET cascade, where multiple radical pair recombination rates arise due to the dynamic equilibrium along the ET chain. We show that the motions of the protein environment and the ET dynamics are inseparably coupled, violating the timescale separation required for Marcus theory. The presented results highlight that non-equilibrium coupling between electronic and nuclear motion dominates ET kinetics in ErCry4a during the first nanosecond after photo-excitation. The findings exemplify the limits of Marcus theory and refine the interpretation of ultrafast spectroscopic signatures in cryptochromes.

biophysics↗

bioRxiv2026

Primate Hippocampus Reveals Distinct Rules for Associative Synaptic Plasticity

Long-term potentiation (LTP) is a key cellular mechanism underlying learning and memory, but its conservation across species remains unclear. Using nonhuman primates (NHPs), we examined hippocampal synaptic plasticity at Schaffer collateral- CA1 synapses. Theta-burst stimulation (TBS) reliably induced LTP in NHPs, comparable to rodents. However, unlike rodents, TBS in NHPs readily engaged synaptic tagging and capture (STC), indicating a lower threshold for associative plasticity. This was accompanied by increased expression of plasticity-related proteins, including PKM{zeta} and BDNF, suggesting enhanced recruitment of protein synthesisdependent stabilization mechanisms. These findings reveal a species-specific divergence in the molecular regulation of persistent synaptic plasticity and identify an evolutionary specialization in mechanisms supporting associative memory. Together, our results highlight limitations of rodent models in fully capturing human-relevant memory processes and underscore the importance of primate systems for translational neuroscience.

neuroscience↗

bioRxiv2026

Secreted phospholipase A2α generates a pathogen-derived lysophospholipid to signal local immunity

In plants, effector-triggered immunity (ETI) is initiated when NLR receptors recognize pathogen effectors, yet the molecular signals linking this recognition to downstream defense activation remain poorly defined, in contrast to the well-characterized immunogenic signals of pattern-triggered immunity. Here, we show that a lysophospholipid is a previously unidentified ETI-mediating immune signal generated through host enzymatic conversion of pathogen membrane lipids. Upon recognition of avirulent Pseudomonas syringae, secretory phospholipase A2 (PLA2) is rapidly induced and secreted into the apoplast, where it hydrolyzes bacterial phosphatidylethanolamine to produce lysophosphatidylethanolamines (LPEs), predominantly LPE18:1. Genetic ablation of PLA2 compromises local immunity, hypersensitive response confinement, and defense gene activation, all of which are largely rescued by exogenous LPE18:1. Mechanistically, LPE18:1 promotes ICS1-dependent salicylic acid biosynthesis and NPR1-mediated transcriptional reprogramming. Together, these findings support pathogen-derived LPE18:1 as a newly identified lipid-based immune signal that links NLR activation to spatially confined defense responses. The evolutionary conservation of secretory PLA2 enzymes and lysophospholipid signaling from plants to mammals suggests that host-directed enzymatic remodeling of pathogen membranes into immune-activating lipid signals may constitute a conserved strategy of innate immunity.

plant biology↗

bioRxiv2026

Wunen(s) help navigate Primordial Germ Cells by attenuating Hedgehog signaling

Directed cell migration is a vital process that depends on the combined activities of attractive and repulsive cues. As it is essential for normal development, the precise identity of guidance signals and the underlying molecular and cellular mechanisms is being rigorously investigated. In a Drosophila embryo, PGC migration is orchestrated by non-cell autonomous repulsive and attractive cues, controlled by Wunen(s) - Wunen and Wunen2 and, HMGCoA-reductase (Hmgcr), respectively. Hedgehog (Hh), a PGC attractant, is potentiated by Hmgcr. We demonstrate that Wunen(s) employ both nonautonomous and autonomous modes to inhibit Hh signaling. Consistently, in embryos maternally compromised for wunen, mesodermal cells and PGCs accumulate excess Hh, leading to precocious clumping of the PGCs. This behaviour is reminiscent of PGC-specific loss of patched (ptc) - the Hh receptor and an antagonist of Smoothened (Smo), a G protein-coupled receptor (GPCR), involved in Hh signal transduction. Consistently, Wunen(s) inhibit membrane localization of Smo. Conversely, simultaneous overexpression of wunen mitigates PGC scattering induced by ectopic hmgcr expression. Finally, unbiased lipidomics of embryonic extracts after maternal knockdown of wunen confirms disruptions in lipid metabolism. We discuss the mechanistic underpinnings of Wunen(s) involvement in repressing Hh signalling to engineer PGC migration.

developmental biology↗

bioRxiv2026

MCNV2 (Mendelian CNV Validation): Mendelian Precision for CNV quality assessment

SummaryDetection of copy number variations from genomic sequencing and array data is prone to high false-positive rates. Distinguishing true variation from false positives remains challenging as quality metrics depend on technologies used, the quality of the data, and the calling algorithm. Mendelian inheritance in parent-offspring trios offers a powerful method to detect false positives, yet no tool exists to systematically compute, explore, optimize, and interpret the precision of CNV calls accordingly. Here we present Mendelian CNV Validation (MCNV2), an R package implementing Mendelian Precision (MP), as a reproducible metric for standardized CNV quality assessment. MCNV2 provides a command-line interface for pipeline integration and an interactive Shiny application for real-time exploration of MP across CNV types, size categories, and quality metrics. Availability and ImplementationMCNV2 is available at https://github.com/JacquemontLab/MCNV2-Mendelian-CNV-Validation. Contactmame.seynabou.diop@umontreal.ca Supplementary InformationSupplementary information are available at https://mcnv2-mendelian-cnv-validation.readthedocs.io/en/latest/

genetics↗

bioRxiv2026

Optimal Reference Panel Design in Ancient DNA Imputation from Coalescent Theory, Simulation, and Real Data Application with an Ancient Reference Panel

Imputation is widely used in the ancient DNA (aDNA) field to determine which phenotypically important alleles ancient individuals carried, to study natural selection, and to detect segments of the genome that are shared between individuals identical by descent. However, rare variant imputation is less accurate, and rare variants tend to be excluded from downstream analyses. State-of-the-art imputation methods leverage large reference panels, improving rare variant accuracy in modern targets. However, it is unclear how to identify optimal panels for aDNA targets. It seems plausible that aDNA reference panels would improve imputation of aDNA, but no such panels have been assembled or tested. We leveraged analytical results from coalescent theory and complementary simulations to evaluate both performance of large modern panels, and ancient panels impact on aDNA imputation. For modern panels, sample sizes as small as 5,000 saturate imputation performance and model misspecifications in standard imputation algorithms increase imputation error for rare and intermediate frequency variants. For instance, for European hunter-gatherers, non-reference imputed variants with derived allele frequency less than at least 2% should be removed. Including ancient genomes in a modern reference panel substantially improved imputation accuracy in analytical modelling and simulations, particularly, for rare variants and older samples from groups with low effective population size. We assembled a joint reference panel with 1000 Genomes and 95 ancient samples and used it to impute 95 downsampled genomes, finding modest gains in imputation performance. This approach can rescue rare variants typically discarded from current imputation pipelines and may prove useful as the number of ancient samples increases.

genomics↗

bioRxiv2026

Protein without farms: What comparative genomics reveals about ''Power-to-Food'' microbes

Conventional agriculture is increasingly incompatible with planetary boundaries, such as land and water demand, greenhouse-gas emissions, and disruption of the nitrogen cycle. Hydrogen-oxidizing bacteria (HOB) enable a scalable "power-to-food" approach in which aerobic gas fermentation turns CO2 and renewable H2, along with N2 in some strains, into protein-rich biomass, largely decoupling protein production from arable land and climate variability. The same chemistry is attractive for closed-loop space life support, where crew CO2 and electrolysis-derived H2 can be recycled into edible biomass. Here, we compare two leading HOB chassis strains, Cupriavidus necator H16 and Xanthobacter sp. SoF1, using standardized re-annotation, orthology-based comparison, pathway reconstruction, and safety-oriented genome screening. Importantly, SoF1 is the production strain for Solar Foods Solein(R), a dried microbial biomass ingredient, which is approved as a novel food in Singapore and has a self-affirmed GRAS status in the United States. H16 has a larger, multipartite genome of 7.41 Mb split across two chromosomes and the pHG1 megaplasmid, whereas SoF1 is more compact at 4.91 Mb and encoded on a single replicon. Both encode Calvin-Benson-Bassham CO2 fixation and multiple [NiFe]-hydrogenase systems supporting growth on CO2/H2, but nitrogen economy differentiates the hosts. SoF1 encodes a complete nitrogen-fixation module (nifHDK) and nitrate-assimilation genes, whereas H16 lacks nif and instead encodes nitrate/nitrite respiration for oxygen-limited flexibility. Safety screening revealed no evidence of canonical virulence determinants, integron or plasmid-linked antimicrobial resistant (AMR) cassettes, or high-confidence foodborne exotoxins under strict thresholds. These results convert genome-level features into actionable design constraints for selecting and engineering food-grade HOB, strengthening robust air-to-protein bioprocesses on Earth and informing a blueprint for closed-loop, space-compatible protein production. HighlightsO_LIHydrogen-oxidizing bacteria enable power-to-protein from CO2, H2 with minimal land use. C_LIO_LIHead-to-head genomics defines design rules for food-grade "air-to-protein" bioprocesses. C_LIO_LIContrasting nitrogen routes guide media design, nutrient inputs, and closed-loop operation. C_LIO_LICO2 fixation and hydrogenase gene sets reveal complementary robustness and control features. C_LIO_LIGenome architecture and COG shifts inform safety, stability, and regulatory-ready strain choice. C_LI

genomics↗

bioRxiv2026

Prime editing of an evolutionarily informed PEPC residue enhances photosynthesis and grain nutrition in C₃ rice

C4 photosynthesis evolved through adaptive changes in key metabolic enzymes that enhance carbon fixation efficiency, yet transferring such traits into C3 crops has met limited success. Using precision prime editing, we introduced an evolutionarily conserved single amino acid substitution (Arg[->]Gly) into phosphoenolpyruvate carboxylase (PEPC) in rice. Edited plants exhibited enhanced PEPC activity in the presence of the feedback inhibitor malate, increased chlorophyll content, elevated photosynthetic rates under ambient CO2, and increased seed size and weight. Remarkably, seeds from the edited lines showed simultaneous enrichment of zinc (Zn), iron (Fe), and protein, hereafter referred to as ZiP rice. This work demonstrates that a single, evolutionarily guided residue change can reprogram core carbon metabolism in a C3 crop, enabling concurrent improvements in photosynthesis and grain nutritional quality.

plant biology↗

bioRxiv2025

Harmine Selectively Drives Human Beta Cell Differentiation and Function Via Protein Kinase A Pathways

Harmine and other small molecule inhibitors of the kinase DYRK1A induce human beta cells to replicate and regenerate in vitro and in vivo, and are effective at reversing diabetes in animal models. In addition to its beta cell proliferative and regenerative effects, harmine also induces expression of transcription factors and other genes involved in beta cell differentiation and function, exemplified by PDX1, MAFA, NKX6.1, GLP1R, PCSK1 and many others. Harmine also rapidly enhances glucose-stimulated insulin secretion in vitro and in vivo, reversing diabetes within days in diabetic mice transplanted with a marginal mass of human islets. We had assumed that this pro-differentiation or pro-function effect was a common feature of all DYRK1A inhibitors, and was mediated by DYRK1A inhibition. Thus, DYRK1A is a primary target (we refer to it as Target 1) for harmine. Here, to our surprise, we report that the pro-differentiation effect is not a generalized action for all small molecule DYRK1A inhibitors and does not result from DYRK1A interference or genetic silencing. Instead, the prodifferentiation effect is restricted to a small select subset of DYRK1A inhibitors (harmine, 2-2c and 5-IT). Remarkably, the pro-differentiation effect results from the unique ability of these drugs to activate protein kinase A (PKA), a dual mechanism that distinguishes this class from other DYRK1A inhibitors. The beneficial effects of harmine on PKA appear to be indirect, driven by an as yet unidentified, Target 2 in the PKA pathway. These findings make it clear that all DYRK1A inhibitors are not interchangeable, and that those that drive both proliferation and differentiation/function will likely be preferable in human clinical therapeutic settings. They also provide a novel target or roadmap for enhancing human beta cell differentiation in Type 1 and Type 2 diabetes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/692818v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@bd015corg.highwire.dtl.DTLVardef@a46f9borg.highwire.dtl.DTLVardef@19b4f65org.highwire.dtl.DTLVardef@179aa28_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Active geometrodynamics predicts the emergence of cytokinesis

Cell division accomplishes the segregation of genetic material and involves remarkable changes in the cellular geometry culminating in cytokinesis: the cleavage of a mother cell giving rise to two daughter cells. Cytokinesis in animal cells is driven by flows resulting from cortical tension gradients in the actomyosin cortex. Here, we combine a theory for the active geometrodynamics of the cortical surface and quantitative measurements in the C. elegans zygote to reveal the physical principles of cytokinesis. At high activity, we observe the spontaneous emergence of ring-like patterns of myosin concentration and cell shape in the theory. The constriction dynamics of this self-organized pattern agrees with the ingression of the cytokinetic furrow and concomitant myosin accumulation during the first division in the C. elegans embryo. Through RNAi perturbations, we quantitatively test our theoretical predictions of myosin accumulation rates linearly varying with the ingression rate, and the emergence of asymmetric ingression. Our work suggests that the self-organised geometrodynamics of active fluid surfaces underlies cytokinesis.

biophysics↗

bioRxiv2025

sCentInDB: A database of essential oil chemical profiles of Indian medicinal plants

Essential oils are complex mixtures of volatile compounds produced by aromatic plants. Due to their odor and therapeutic properties, essential oils are used in personal care, food flavoring and pharmaceutical industries. As a high-value and low-volume organic product, optimizing plant yield and modifying composition by leveraging knowledge on chemical profiles of essential oils can lead to enhanced bioproducts. To this end, we present sCentInDB, a manually curated DataBase of Essential oil Chemical profiles of Medicinal plants of India, which has been built based on information in published literature. sCentInDB is a FAIR-compliant database which compiles information on 554 Indian medicinal plants at the plant part level, encompassing 2170 essential oil profiles, 3420 chemicals, 471 plant-part-therapeutic use associations, 120 plant-part-odor associations, and 218 plant-part-color associations. For the documented essential oils, sCentInDB also compiles extensive metadata including sample location, isolation and analysis methods. Subsequently, an extensive analysis of the chemical space of essential oils documented in sCentInDB was performed. By constructing a chemical similarity network, the chemical space was found to be structurally diverse with terpenoids distributed across the network. Moreover, a comparison of the scaffold diversity in sCentInDB was performed against three other aroma libraries using cyclic system retrieval curves. Altogether, sCentInDB will serve as a valuable resource for researchers working on plant volatiles and employing genetic engineering to enhance oil yield and composition. Further, sCentInDB will aid in establishment of quality standards for essential oils and provide vital insights for therapeutic and perfumery applications. sCentInDB is accessible at https://cb.imsc.res.in/scentindb/.

pharmacology and toxicology↗

bioRxiv2025

Bioinformatics analysis identifies sequence determinants of enzymatic activity for the PHARC associated lipase ABHD12

In humans, PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) is an early onset autosomal recessive neurological disorder caused by deleterious mutations to ABHD12 (/{beta}-hydrolase domain protein # 12). Biochemically, ABHD12 functions as a lipase, and catalyzes the hydrolysis of lysophosphatidylserine (lyso-PS) (lyso-PS lipase). By doing so, it controls the concentrations and signaling pathways regulated by this potent signaling lysophospholipid in the mammalian brain. While genetic mapping efforts have identified over 30 mutations in ABHD12 from human PHARC subjects, the biochemical activity of these pathogenic mutants remains unknown. To understand this, here, we performed an exhaustive bioinformatics survey, and collated ABHD12 protein sequences from various organisms across evolution. Next, based on sequence alignments and structural modeling, we identified functionally relevant conserved residues in the ABHD12 protein sequence that are potentially important for its enzymatic activity. To validate these in silico findings, we generated numerous mutants of murine ABHD12, including those associated with human PHARC subjects, and assayed them for their enzymatic activity. Taken together, these complementary in silico and biochemical studies provide the first thorough sequence-function relationship for mammalian ABHD12, especially relevant in the context of PHARC. Finally, our evolutionary analysis identified CG15111 as an ABHD12 ortholog in the fruit fly (Drosophila melanogaster), and enzymatic assays indeed confirmed that recombinant CG15111 has robust lyso-PS lipase activity. Flies serve as an excellent animal system to model various human neurological diseases, and the identification of CG15111 as a Drosophila melanogaster ABHD12 ortholog opens new avenues to study PHARC in fly models.

biochemistry↗

bioRxiv2025

Mirror effect of genomic deletions and duplications on cognitive ability across the human cerebral cortex

Cognitive deficits are common across many neurodevelopmental and psychiatric conditions, including those studied in the current set of PGC-CNV papers. How changes in regional gene expression across the cerebral cortex influence cognitive ability remains unknown. Population variation in gene dosage--which significantly impacts gene expression--represents a unique paradigm to address this question. We developed a cerebral-cortex gene-set burden analysis (CC-GSBA) to associate a trait with genomic deletions and duplications that disrupt genes with similar expression profiles across 180 cortical regions. We performed CC-GSBA across 180 cortical regions to test associations with cognitive ability in 260,000 individuals from general population cohorts. Most cortical gene sets were associated with a decrease in cognitive ability when deleted or duplicated, and this novel approach revealed opposing cortical patterns for the effect sizes of deletions and duplications. These cortical patterns of effect sizes followed the cortical gradient previously characterized at the molecular, cellular, and functional levels. We show that genes with preferential expression in sensorimotor regions demonstrated the largest effect on cognition when deleted. At the opposing end of the cortical gradient, genes with preferential expression in multimodal association regions affected cognition the most when duplicated. These two gene dosage cortical patterns could not be explained by particular cell types, developmental epochs, or genetic constraints, highlighting the fact that the macroscopic network organization of the cerebral cortex is key to understanding the effects of gene dosage on cognitive traits.

neuroscience↗