Biology subjects

Long, L.

Publications and source records attributed to Long, L..

At least 19 recordsLinked to original sources

bioRxiv2026

The fusion gene occurrence spectrum predicts the spatial structure of chromosomes

Chromosome was "self-assembled" into a complex three-dimensional topology in the nucleus, which provided the structural basis for important biological processes such as gene expression regulation and cell differentiation. The current understanding of the three-dimensional organization of the genome is based on high-throughput sequencing and imaging technologies to visualize the conformation of chromatin in its native environment. This study proposes a new research perspective and technical means to use fusion genes to determine the interaction information and three-dimensional structure of chromosomes. This three-dimensional information provided by the fusion gene spectrum not only shows the universality of the spatial layout of chromosomes, but also increases the interpretability of the occurrence of fusion genes. The chromatin conformation capture data of multiple tissues and periods is significantly correlated with the strength of fusion genes. For example, the frequency of trans-interaction between chromosomes 11 and 17 was the highest, and the frequency of fusion gene occurrence corresponding to KMT2A on chromosome 11 was the highest. Therefore, we infer that this structural universality is a common feature of the human genome, which provides a theoretical basis and data for predicting chromosome fusion events.

cancer biology↗

bioRxiv2026

RNA-guided transcriptional repression by TIGR-Tas systems

Tandem interspaced guide RNA (TIGR)-TIGR-associated protein (Tas) systems are a widespread family of RNA-guided DNA-targeting proteins whose diversity has remained uncharacterized because their arrays, unlike CRISPR arrays, lack the sequence conservation required by existing annotation tools. We developed TIGRFinder, a motif-based pipeline that identified 6,685 TIGR arrays from genomic and metagenomic data. Phylogenetic and structural analysis of Tas proteins revealed clade-specific insertions in stem-loop binding Tas proteins that co-vary with features of their cognate tigRNAs. Cryo-electron microscopy structures of two stem-loop binding TasR ribonucleoprotein complexes demonstrate how these protein insertions directly accommodate extended tigRNA stems while maintaining DNA binding through catalytically inactive RuvC domains. We also show that these catalytically dead TasR proteins, along with the nuclease-lacking TasA, function as RNA-guided transcriptional repressors. These findings establish TIGR-Tas as a functionally diverse family of RNA-guided effectors, with comprehensive annotations available through TIGRSafari (https://tigr.bio) to support further exploration and engineering.

molecular biology↗

bioRxiv2026

Dynamic resource allocation orchestrates physical simulation in the human brain

Humans can flexibly predict physical events by internally simulating object dynamics in the brain--a capacity lacking in current AI systems. Using a ball collision paradigm with visual occlusion combined with multimodal neuroimaging (fMRI/MEG), we uncover a spatiotemporally organized neural architecture for physical simulation. fMRI reveals hierarchical spatial segregation: higher-order cortical regions encode relational physical variables, distinct from object-specific features encoded in the lower-order sensorimotor regions. MEG uncovers two temporally distinct neural processes: a real-time simulation tracking the evolving state of the object, in alignment with collision dynamics, and an early predictive signal anticipating collision occurrence ([~]700 ms before contact). We propose that this early predictive control mechanism dynamically allocates cognitive resources during simulation. This is formalized by a Dynamic Resource Intuitive Physics Engine (IPE) model, which captures both behavioral data and the dual neural timescales by optimizing accuracy-cost tradeoffs. Crucially, this framework predicts early encoding of another adaptive control variable separate from collision occurrence, as evidenced by both MEG and pupillary responses. These findings reveal how the brain achieves efficient physical inference through hierarchically organized predictive control that dynamically allocates cognitive resources.

neuroscience↗

bioRxiv2025

Diverse haplotypes at a complex Solanum americanum locus confer resistance to Phytophthora infestans and P. capsici

Plants encounter diverse pathogens and have evolved a two-layered innate immune system to detect pathogen molecules and activate defense mechanisms that restrict infection. Most cloned plant Resistance (R) genes encode NLR immune receptors. NLR genes are often found in clusters of paralogs with sequence and copy number variation; whether these NLR clusters evolve in response to single or multiple pathogens has been unclear. We report here the isolation of a Phytophthora capsici resistance gene, Rpc2, along with a novel P. infestans resistance gene, Rpi-amr5, from two Solanum americanum accessions. These orthologous genes reside in the Rpi-amr1 cluster, which has previously been associated with resistance to P. infestans. By screening RXLR effector libraries of P. infestans and P. capsici, we identified multiple effectors recognized by both NLRs. Our findings highlight the complexity of NLR clusters and evolution driven by interactions with multiple pathogens. This work will underpin efforts to elevate resistance against Phytophthora pathogens and enhances our understanding of NLR evolution.

plant biology↗

bioRxiv2025

Novel single-domain AA12 pyrroloquinoline quinone-dependent oxidoreductases directly and co-operatively drive lytic polysaccharide monooxygenase activity with AA8 module

The single-domain auxiliary activity family 12 (AA12) pyrroloquinoline quinone-dependent oxidoreductases and free AA8 modules are prevalent in cellulolytic fungi, however, their function in polysaccharide biodegradation is still confused. Here, we characterized three single-domain AA12 oxidoreductases and one free AA8 module from Thermothelomyces thermophilus and Thermothielavioides terrestris. All three single-domain AA12 oxidoreductases are restrict dehydrogenases with trace oxidase activity. All three single-domain AA12 enzymes could directly transfer electrons to lytic polysaccharide monooxygenase (LPMO) and drive NcLPMO9C activity. Furthermore, inter-protein electron transfer between single-domain AA12 enzymes and the AA8 module was observed. The AA12 enzyme-driven NcLPMO9C efficiency could be significantly enhanced by the addition of free AA8 module TthAA8B, probably attributing to the acceleration of electron transfer from AA12 enzymes to NcLPMO9C and the attenuation of H2O2 accumulation mediated by TthAA8B. Our findings highlight the potential role of single-domain AA12 enzyme and free AA8 modules in the biodegradation system of LPMOs. IMPORTANCEThis study reveals the directly electron transferring and driving capability of single-domain AA12 PQQ-dependent enzyme for the oxidative reaction of lytic polysaccharide monooxygenase (LPMO). This funding is quite distinct from the AA8 cytochrome domain-dependent driving pattern of the previous characterized multi-domain CcPDH. We also demonstrated that this priming capability could be facilitated by the free AA8 cytochrome module, providing new insight on the interactions and functions of single-domain AA12 enzymes and free AA8 modules in fueling LPMO activity during fungal lignocellulose biodegradation process. These findings collectively provide evidence for the potential function of widespread single-domain AA12 PQQ-dependent enzymes and free AA8 cytochrome modules as unique enzyme redox partners in cellulolytic fungi.

biochemistry↗

bioRxiv2025

PERRC: Protease Engineering with Reactant Residence Time Control

Proteases with engineered specificity hold great potential for targeted therapeutics, protein circuit construction, and biotechnology applications. However, many proteases exhibit broad substrate specificity, limiting their applications. Engineering protease specificity remains challenging because evolving a protease to recognize a new substrate, without counterselecting against its native substrate, often results in high residual activity on the original substrate. To address this, we developed Protease Engineering with Reactant Residence Time Control (PERRC), a platform that exploits the correlation between endoplasmic reticulum (ER) retention sequence strength and ER residence time. PERRC allows precise control over the stringency of protease evolution by adjusting counterselection to selection substrate ratios. Using PERRC, we evolved an orthogonal tobacco etch virus protease variant, TEVESNp, that selectively cleaves a substrate (ENLYFES) that differs by only one amino acid from its parent sequence (ENLYFQS). TEVESNp exhibits a remarkable 65-fold preference for the evolved substrate, marking the first example of an engineered orthogonal protease driven by such a slight difference in substrate recognition. Furthermore, TEVESNp functions as a competent protease for constructing orthogonal protein circuits in bacteria, and molecular dynamic simulations analysis reveals subtle yet functionally significant active site rearrangements. PERRC is a modular dual-substrate display system that facilitates precise engineering of protease specificity.

synthetic biology↗

bioRxiv2024

Uncovering the signaling networks of disseminated glioblastoma cells in vivo with INSIGHT

Dysregulation of intracellular signaling networks underpins cancer. However, a systems-level elucidation of how signaling networks within distinct cell subpopulations drive cancer progression in vivo has been unattainable due to technical limitations. We developed INSIGHT (INvestigating SIGnaling network of specific cell subpopulation in Heterogeneous Tissue), a new platform technology combining fluorescence-activated cell sorting with ultra-sensitive mass spectrometry to enable phosphoproteomic characterization of rare and discrete cell subpopulations from fixed tissues. We demonstrated the broad utility of INSIGHT by analyzing the oligodendroglial cell-specific signaling network in the mouse brain. We then applied INSIGHT to investigate the rare, disseminated tumor cell subpopulation in glioblastoma patient-derived xenograft models. INSIGHT uncovered a global rewiring of signaling networks with tumor cell dissemination, marked by a transition from proliferation-associated signaling in the primary tumor cells to signaling associated with postsynapse, neuronal migration, and ion homeostasis in disseminated tumor cells. We reveal interconnections between signaling circuitries within the networks, with numerous proteins, including GluA2, exhibiting altered phosphorylation without protein expression changes, emphasizing the role of post-translational modifications in glioblastoma dissemination. We validated key phosphorylation changes and inferred differentially active kinases with tumor spread to offer new systems-level insights into glioblastoma dissemination mechanisms in vivo. INSIGHT is generally applicable to a wide range of biological systems without genetic engineering and provides quantitative phosphorylation and protein expression data for selected cell subpopulations from heterogeneous tissues.

systems biology↗

bioRxiv2024

MOZ and HBO1 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML) and drive leukemogenesis through liquid-liquid phase separation-mediated nuclear condensate formation. However, the composition and consequences of NUP98 FO-associated condensates are incompletely understood. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including MOZ/KAT6A, HBO1/KAT7, and the common MOZ/HBO1 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Moz and Hbo1 impairs NUP98-r cell fitness. MOZ/HBO1 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, MOZ/HBO1 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML. SIGNIFICANCE STATEMENTMOZ and HBO1 associate with NUP98 fusion oncoprotein condensates to drive leukemogenesis. Inhibition of their histone acetyltransferase activity is an effective therapeutic strategy in NUP98-rearranged leukemias, including those resistant to Menin inhibition. Moreover, combined MOZ/HBO1 and Menin inhibition is synergistic, supporting clinical translation to improve outcomes of NUP98 FO-driven leukemias.

cancer biology↗

bioRxiv2023

Closed-loop control of functional electrical stimulation using a selectively recording and bidirectional nerve cuff interface

BackgroundDiscriminating recorded afferent neural information can provide sensory feedback for closed-loop control of functional electrical stimulation, which restores movement to paralyzed limbs. Previous work achieved state-of-the-art off-line classification of electrical activity in different neural pathways recorded by a multi-contact nerve cuff electrode, by applying deep learning to spatiotemporal neural patterns. ObjectiveTo incorporate this approach into closed-loop stimulation. MethodsAcute in vivo experiments were conducted on 11 Long Evans rats to demonstrate closed-loop stimulation. A 64-channel (8 x 8) nerve cuff electrode was implanted on each rats sciatic nerve for recording and stimulation. A convolutional neural network (CNN) was trained with spatiotemporal signal recordings associated with 3 different states of the hindpaw (dorsiflexion, plantarflexion, and pricking of the heel). After training, firing rates were reconstructed from the classifier outputs for each of the three target classes. A rule-based closed-loop controller was implemented to produce ankle movement trajectories using neural stimulation, based on the classified nerve recordings. Closed-loop stimulation was initiated by the detection of a heel prick, and induced dorsiflexion. The detection of dorsiflexion triggered stimulation to induce plantarflexion, and vice versa. A single trial began with a heel prick and ended when an incorrect state transition occurred or when a second heel prick was detected. ResultsClosed-loop stimulation was successfully demonstrated in 6 subjects. Number of successful trials per subject ranged from 1-17 and number of correct state transitions per trial ranged from 3-53. ConclusionThis work demonstrates that a CNN applied to multi-contact nerve cuff recordings can be used for closed-loop control of functional electrical stimulation.

neuroscience↗

bioRxiv2023

Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles

Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor microRNAs, such as miR-99b-3p. Furthermore, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.

cancer biology↗

bioRxiv2023

Pathology of natural infection with highly pathogenic avian influenza virus (H5N1) clade 2.3.4.4b in wild terrestrial mammals in the United States in 2022

This article describes the first detections of disease due to natural infection with highly pathogenic avian influenza virus (HPAIv) H5N1 of the Eurasian lineage goose/Guangdong clade 2.3.4.4b in wild terrestrial mammals throughout the United States during 2021-2022. Affected mammalian species include 50 red foxes (Vulpes vulpes), 6 striped skunks (Mephitis mephitis), 4 raccoons (Procyon lotor), 2 bobcats (Lynx rufus), 2 Virginia opossums (Didelphis virginiana), 1 coyote (Canis latrans), 1 fisher (Pekania pennanti), and 1 gray fox (Urocyon cinereoargenteus). Infected mammals primarily exhibited neurological signs. Necrotizing meningoencephalitis, interstitial pneumonia, and myocardial necrosis were the most common lesions; however, species variations in lesion distribution were observed. Genotype analysis of sequences from 48 animals indicates that these cases represent spillover infections from wild birds.

pathology↗

bioRxiv2022

A Toxin-Antidote Selfish Element Increases Fitness of its Host

Selfish genetic elements can promote their transmission at the expense of individual survival, creating conflict between the element and the rest of the genome. Recently, a large number of toxin-antidote (TA) post-segregation distorters have been identified in non-obligate outcrossing nematodes. Their origin and the evolutionary forces that keep them at intermediate population frequencies are poorly understood. Here, we study a TA element in C. elegans called peel-1/zeel-1. Two major haplotypes of this locus, with and without the selfish element, segregate in C. elegans. Here we study the fitness consequences of the peel-1/zeel-1 element outside of its role in gene drive in non-outcrossing animals. We demonstrate that loss of the toxin peel-1 decreased fitness of hermaphrodites and resulted in reductions in fecundity and body size. This fitness advantage is independent of the antidote zeel-1, suggesting that a distinct peel-1 pathway plays a biological role. This work demonstrates that a TA element can provide a fitness benefit to its hosts, either during their initial evolution or by being co-opted by the animals following their selfish spread. These findings guide our understanding on how TA elements can remain in a population where gene drive is minimized, helping resolve the mystery of prevalent TA elements in selfing animals.

evolutionary biology↗

bioRxiv2021

Direct photoresponsive inhibition of a p53-like transcription activation domain in PIF3 by Arabidopsis phytochrome B

Phytochrome B (PHYB) triggers diverse light responses in Arabidopsis by binding to a group of antagonistically acting PHYTOCHROME-INTERACTING transcription FACTORs (PIFs) to promote PIF degradation, consequently downregulating PIF target genes. However, whether PHYB directly controls the transactivation activity of PIFs remains ambiguous. Here we show that the prototypic PIF, PIF3, possesses a p53-like transcription activation domain (TAD) consisting of a sequence-specific, hydrophobic activator motif surrounded by acidic residues. A PIF3mTAD mutant in which the activator motif is replaced with alanines fails to activate PIF3 target genes in Arabidopsis in dark, light, and shade conditions, validating the in vivo functions of the PIF3 TAD. Intriguingly, binding of PHYBs N-terminal photosensory module to the PHYB-binding site adjacent to the TAD inhibits its transactivation activity. These results unveil a photoresponsive transcriptional switching mechanism in which photoactivated PHYB directly masks the transactivation activity of PIF3. Our study also suggests the unexpected conservation of sequence-specific TADs between the animal and plant kingdoms.

plant biology↗

bioRxiv2020

A secreted endoribonuclease ENDU-2 from the soma protects germline immortality in C. elegans

Multicellular organisms coordinate tissue specific response to environmental information via both cell-autonomous and non-autonomous mechanisms. In addition to secreted ligands, secreted small RNAs have recently been reported to regulate gene expression across tissue boundaries. Here we show that the conserved poly-U specific endoribonuclease ENDU-2 is secreted from the soma and taken-up by the germline to ensure germline immortality at elevated temperature in C. elegans. ENDU-2 binds to mature mRNAs and negatively regulates mRNA abundance both in the soma and the germline. While ENDU-2 promotes RNA decay in the soma directly via its endoribonuclease activity, ENDU-2 prevents misexpression of soma-specific genes in the germline and preserves germline immortality independent of its RNA-cleavage activity. In summary, our results suggest that the secreted RNase ENDU-2 transmits environmental information across tissue boundaries and contributes to maintenance of stem cell immortality probably via retaining a stem cell specific program of gene expression.

molecular biology↗

bioRxiv2020

Increased light availability enhances tolerance against ocean acidification stress in Halimeda opuntia

Although the adverse impacts of ocean acidification (OA) on marine calcifiers have been investigated substantially, the anti-stress abilities regulated by increased light availability are unclear. Herein, the interactive effects of three light levels combined with two pCO2 concentrations on the physiological acclimation of the calcifying macroalga Halimeda opuntia were investigated using a pCO2-light coupling experiment. The results indicate that OA exhibits an adverse role in influencing algal growth, calcification, photosynthesis and other physiological performances in H. opuntia. The relative growth rate in elevated pCO2 significantly declined by 13.14%-41.29%, while net calcification rates decreased by nearly three-fold under OA. Notably, increased light availability could enhance stress resistance by the accumulation of soluble organic molecules, especially soluble carbohydrate, soluble protein and free amino acids, and in combination with metabolic enzyme-driven activities alleviated OA stress. Carotenoid content in low light conditions accumulated remarkably and rapid light curves for relative electron transport rate was significantly enhanced by increasing light intensities, indicating that this new organization of the photosynthetic machinery in H. opuntia accommodated light variations and elevated pCO2 conditions. Taken together, the results describe stress resistance by the enhancement of metabolic performance in marine calcifiers to mitigate OA stress. One sentence summaryIncreased light availability enhances stress resistance in Halimeda opuntia by the accumulation of soluble organic molecules and enzyme-driven activities to alleviate ocean acidification stress. Credit authorship contribution statementFangfang Yang and Lijuan Long conceived and designed the experiments. Zhangliang Wei performed the experiments and wrote the paper. Yuanzi Huo analyzed the data, while Chao Long and Yating Zhang contributed materials and analysis tools. Lijuan Long agrees to serve as the author responsible for contact and communication. HighlightsO_LIElevated pCO2 adversely affects the physiological performance of Halimeda. C_LIO_LIModerately high light increases soluble organic molecules and enzymatic-driven activities. C_LIO_LIIncreased light availability enables H. opuntia to alleviate the negative effects of ocean acidification. C_LI

plant biology↗

bioRxiv2020

Circulating BMP9 protects the pulmonary endothelium during inflammation-induced lung injury in mice

RationalePulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome (ARDS), which carries a high mortality. Circulating bone morphogeneic protein 9 (BMP9) is emerging as an important regulator of pulmonary vascular homeostasis. ObjectiveTo determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity, and whether loss of endogenous BMP9 occurs during lipopolysacharride (LPS)-induced lung inflammation and permeability. MethodsA BMP9-neutralizing antibody was administrated to healthy adult mice and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human primary lung endothelial cells. Impact of BMP9 was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and endotoxemic mice. Main ResultsSubacute neutralization of endogenous BMP9 in mice resulted in increased lung vascular permeability, interstitial edema and neutrophil extravasation. In lung endothelial cells, BMP9 regulated a programme of gene expression and pathways controlling vascular permeability and cell membrane integrity. Augmentation of BMP9 signalling in mice with exogenous BMP9 prevented inhaled LPS-caused lung injury and edema. In endotoxemic mice, endogenous BMP9 levels were markedly reduced, due to a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human sepsis patients, circulating levels of BMP9 were also markedly reduced. ConclusionsEndogenous circulating BMP9 is a pulmonary endothelial protective factor, down-regulated during inflammation. Supplementation with exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in the setting of lung injury. Short summaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSIncreased pulmonary endothelial permeability is a major factor in the development of acute respiratory distress syndrome (ARDS). Evidence is emerging that circulating BMP9, secreted from the liver, might protect the pulmonary endothelium from injury. For example, loss of BMP9 levels or signalling receptor contributes to the development of pulmonary arterial hypertension. The role of endogenous BMP9 in endothelial permeability remains unclear. What This Study Adds to the FieldHere we show that subacute neutralization of endogenous BMP9 leads to lung vascular injury, including enhanced permeability and neutrophil extravasation. BMP9 levels were markedly reduced in the setting of inflammation in mice and humans. Conversely, exogenous supplementation of BMP9 protected the lung from LPS-induced injury. This study suggests that exogenous BMP9 could offer a novel approach to prevent increased pulmonary endothelial permeability in the setting of lung injury and ARDS.

physiology↗

bioRxiv2020

Automated measurement of long-term bower behaviors in Lake Malawi cichlids using depth sensing and action recognition

Measuring naturalistic behaviors in laboratory settings is difficult, and this hinders progress in understanding decision-making in response to ecologically-relevant stimuli. In the wild, many animals manipulate their environment to create architectural constructions, which represent a type of extended phenotype affecting survival and/or reproduction, and these behaviors are excellent models of goal-directed decision-making. Here, we describe an automated system for measuring bower construction in Lake Malawi cichlid fishes, whereby males construct sand structures to attract mates through the accumulated actions of thousands of individual sand manipulation decisions over the course of many days. The system integrates two orthogonal methods, depth sensing and action recognition, to simultaneously measure the developing bower structure and classify the sand manipulation decisions through which it is constructed. We show that action recognition accurately (>85%) classifies ten sand manipulation behaviors across three different species and distinguishes between scooping and spitting events that occur during bower construction versus feeding. Registration of depth and video data streams enables topographical mapping of these behaviors onto a dynamic 3D sand surface. The hardware required for this setup is inexpensive (<$250 per setup), allowing for the simultaneous recording from many independent aquariums. We further show that bower construction behaviors are non-uniform in time, non-uniform in space, and spatially repeatable across trials. We also quantify a unique behavioral phenotype in interspecies hybrids, wherein males sequentially express both phenotypes of behaviorally-divergent parental species. Our work demonstrates that simultaneously tracking both structure and behavior provides an integrated picture of long-term goal-directed decision-making in a naturalistic, dynamic, and social environment.

animal behavior and cognition↗

bioRxiv2019

Evolution of Yin and Yang isoforms of a chromatin remodeling subunit results in the creation of two genes

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show that de novo, beneficial alleles in the nurf-1 gene fixed in two laboratory strains of C. elegans after isolation from the wild in 1951, before methods of cryopreservation were developed. nurf-1 encodes an ortholog of BPTF, a large (>300kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that in C. elegans, nurf-1 has split into two, largely non-overlapping isoforms (NURF-1.B and NURF-1.D, which we call Yin and Yang) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade of Caenorhabditis nematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additional nurf-1 transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional biproducts necessary to transcribe the Yin and Yang transcripts in the same cells. Our work suggests that evolution of nurf-1 isoforms in nematodes creates adaptive conflict that can be resolved by the creation of new, independent genes.

evolutionary biology↗