Biology subjects

Lee, S.

Publications and source records attributed to Lee, S..

At least 397 records · Page 22Linked to original sources

bioRxiv2023

A large sensory and multi-omics evaluation unraveled chemical and genetic basis of orange flavor

Sweet orange (Citrus sinensis) exhibits limited genetic diversity and high susceptibility to Huanglongbing (HLB). New HLB-tolerant orange-like hybrids are promising alternatives. However, the genetic control of key flavor compounds in oranges remains unknown. Evaluating 179 juice samples, including oranges, mandarins, Poncirus trifoliata and hybrids, distinct volatile compositions were found. A random forest model predicted untrained samples with 78% accuracy and identified 26 compounds crucial for orange flavor. Notably, seven esters--methyl hexanoate, ethyl hexanoate, ethyl 3-hydroxyhexanoate, ethyl octanoate, methyl butanoate, ethyl butanoate, and ethyl 2-methylbutanoate--differentiated orange from mandarin. Cluster analysis showed six esters with shared genetic control. Differential gene expression analysis identified CsAAT1, an alcohol acyltransferase responsible for ester production in orange. Its activity was validated through overexpression assays. A SNP-based DNA marker in the CDS region accurately predicted phenotypes. This study enhances our understanding of orange flavor compounds, their biosynthetic pathways, and expands breeding options for orange-like cultivars.

genetics↗

bioRxiv2023

Interindividual differences in pain can be explained by fMRI, sociodemographic, and psychological factors

In a recent article, Hoeppli et al. (2022) reported that sociodemographic and psychological factors were not associated with interindividual differences in reported pain intensity. In addition, the interindividual differences in pain could not be detected by thermal pain-evoked brain activities measured by functional Magnetic Resonance Imaging (fMRI). Their comprehensive analyses provided convincing evidence for these null findings, but here we provide another look at their conclusions by analyzing their behavioral data and a large-scale fMRI dataset involving thermal pain (N = 124). Our main findings are as follows: First, a multiple regression model incorporating all available sociodemographic and psychological measures could significantly predict the interindividual differences in reported pain intensity. The key to achieving a significant prediction was including multiple individual difference measures in a single model. Second, with fMRI data from a relatively homogeneous group of 124 participants, we could identify brain regions and a multivariate pattern-based predictive model significantly correlated with the interindividual differences in reported pain intensity. Our results, along with the findings of Hoeppli et al., highlight the challenge of predicting interindividual differences in pain, but also suggest that it is not an impossible task.

neuroscience↗

bioRxiv2023

Sex-Specific Effects of Anxiety on Cognition and Activity-Dependent Neural Networks: Insights from (Female) Mice and (Wo)Men

INTRODUCTIONNeuropsychiatric symptoms (NPS), such as depression and anxiety, are observed in 90% of Alzheimers disease (AD) patients, two-thirds of whom are women. NPS usually manifest long before AD onset creating a therapeutic opportunity. Here, we examined the impact of anxiety on AD progression and the underlying brain-wide neuronal mechanisms. METHODSTo gain mechanistic insight into how anxiety impacts AD progression, we performed a cross-sectional analysis on mood, cognition, and neural activity utilizing the ArcCreERT2 x enhanced yellow fluorescent protein (eYFP) x APP/PS1 (AD) mice. The ADNI dataset was used to determine the impact of anxiety on AD progression in human subjects. RESULTSFemale AD mice exhibited anxiety-like behavior and cognitive decline at an earlier age than control (Ctrl) mice and male mice. Brain-wide analysis of c-Fos+ revealed changes in regional correlations and overall network connectivity in AD mice. Sex-specific memory trace changes were observed; female AD mice exhibited impaired memory traces in dorsal CA3 (dCA3), while male AD mice exhibited impaired memory traces in the dorsal dentate gyrus (dDG). In the ADNI dataset, anxiety predicted transition to dementia. Female subjects positive for anxiety and amyloid transitioned more quickly to dementia than male subjects. CONCLUSIONSWhile future studies are needed to understand whether anxiety is a predictor, a neuropsychiatric biomarker, or a comorbid symptom that occurs during disease onset, these results suggest that AD network dysfunction is sexually dimorphic, and that personalized medicine may benefit male and female AD patients rather than a one size fits all approach.

neuroscience↗

bioRxiv2023

Design of four component T=4 tetrahedral, octahedral, and icosahedral protein nanocages through programmed symmetry breaking

Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral (T-sym), octahedral (O-sym) or icosahedral (I-sym) point group symmetry to generate closed cage-like structures1,2. Generating more complex closed structures requires breaking perfect point group symmetry. Viruses do this in the icosahedral case using quasi-symmetry or pseudo-symmetry to access higher triangulation number architectures3-9, but nature appears not to have explored higher triangulation number tetrahedral or octahedral symmetries. Here, we describe a general design strategy for building T = 4 architectures starting from simpler T = 1 structures through pseudo-symmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (T-sym), 96 (O-sym), and 240 (I-sym) subunits, each with four distinct chains and six different protein-protein interfaces, and diameters of 33nm, 43nm, and 75nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen displaying vaccine candidates10,11 and targeted delivery vehicles12,13.

biochemistry↗

bioRxiv2023

TRAIL agonists rescue mice from radiation-induced lung injury

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. One Sentence SummaryPrevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-{psi}-irradiation by short- term treatment with innate immune TRAIL pathway agonists

pathology↗

bioRxiv2023

Multi-scale models reveal hypertrophic cardiomyopathy MYH7 G256E mutation drives hypercontractility and elevated mitochondrial respiration

RationaleOver 200 mutations in the sarcomeric protein {beta}-myosin heavy chain (MYH7) have been linked to hypertrophic cardiomyopathy (HCM). However, different mutations in MYH7 lead to variable penetrance and clinical severity, and alter myosin function to varying degrees, making it difficult to determine genotype-phenotype relationships, especially when caused by rare gene variants such as the G256E mutation. ObjectiveThis study aims to determine the effects of low penetrant MYH7 G256E mutation on myosin function. We hypothesize that the G256E mutation would alter myosin function, precipitating compensatory responses in cellular functions. MethodsWe developed a collaborative pipeline to characterize myosin function at multiple scales (protein to myofibril to cell to tissue). We also used our previously published data on other mutations to compare the degree to which myosin function was altered. ResultsAt the protein level, the G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 50.9%, suggesting more myosins available for contraction. Myofibrils isolated from hiPSC-CMs CRISPR-edited with G256E (MYH7WT/G256E) generated greater tension, had faster tension development and slower early phase relaxation, suggesting altered myosin-actin crossbridge cycling kinetics. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. Single-cell transcriptomic and metabolic profiling demonstrated upregulation of mitochondrial genes and increased mitochondrial respiration, suggesting altered bioenergetics as an early feature of HCM. ConclusionsMYH7 G256E mutation causes structural instability in the transducer region, leading to hypercontractility across scales, perhaps from increased myosin recruitment and altered crossbridge cycling. Hypercontractile function of the mutant myosin was accompanied by increased mitochondrial respiration, while cellular hypertrophy was modest in the physiological stiffness environment. We believe that this multi-scale platform will be useful to elucidate genotype-phenotype relationships underlying other genetic cardiovascular diseases.

molecular biology↗

bioRxiv2023

De novo design of modular protein hydrogels with programmable intra- and extracellular viscoelasticity

Relating the macroscopic properties of protein-based materials to their underlying component microstructure is an outstanding challenge. Here, we exploit computational design to specify the size, flexibility, and valency of de novo protein building blocks, as well as the interaction dynamics between them, to investigate how molecular parameters govern the macroscopic viscoelasticity of the resultant protein hydrogels. We construct gel systems from pairs of symmetric protein homo-oligomers, each comprising 2, 5, 24, or 120 individual protein components, that are crosslinked either physically or covalently into idealized step-growth biopolymer networks. Through rheological assessment and molecular dynamics (MD) simulation, we find that the covalent linkage of multifunctional precursors yields hydrogels whose viscoelasticity depends on the crosslink length between the constituent building blocks. In contrast, reversibly crosslinking the homo-oligomeric components with a computationally designed heterodimer results in non-Newtonian biomaterials exhibiting fluid-like properties under rest and low shear, but shear-stiffening solid-like behavior at higher frequencies. Exploiting the unique genetic encodability of these materials, we demonstrate the assembly of protein networks within living mammalian cells and show via fluorescence recovery after photobleaching (FRAP) that mechanical properties can be tuned intracellularly, in correlation with matching formulations formed extracellularly. We anticipate that the ability to modularly construct and systematically program the viscoelastic properties of designer protein-based materials could have broad utility in biomedicine, with applications in tissue engineering, therapeutic delivery, and synthetic biology. SignificanceProtein-based hydrogels have many applications in cellular engineering and medicine. Most genetically encodable protein hydrogels are made from naturally harvested proteins or protein-polymer hybrid constructs. Here we describe de novo protein hydrogels and systematically investigate the impact of microscopic properties of the building blocks (e.g., supramolecular interaction, valencies, geometries, flexibility) on the resultant macroscopic gel mechanics, both intra-and extracellularly. These de novo supramolecular protein assemblies, whose properties can be tuned from solid gels to non-Newtonian fluids, provide expanded opportunities for applications in synthetic biology and medicine.

bioengineering↗

bioRxiv2023

VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes

Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice. Intra-cerebrospinal fluid administration of an adeno-associated virus expressing VEGF-C (AAV-VEGF-C) increases the CNS lymphatic network. Post-contrast T1 mapping of the head and neck showed that deep cervical lymph node size and drainage of CNS-derived fluids were increased. Single nuclei RNA sequencing revealed a neuro-supportive role of VEGF-C via upregulation of calcium and brain-derived neurotrophic factor (BDNF) signaling pathways in brain cells. In a mouse model of ischemic stroke, AAV-VEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage. AAV-VEGF-C thus promotes CNS-derived fluid and solute drainage, confers neuroprotection, and reduces ischemic stroke damage. Short abstractIntrathecal delivery of VEGF-C increases the lymphatic drainage of brain-derived fluids confers neuroprotection, and improves neurological outcomes after ischemic stroke.

neuroscience↗

bioRxiv2023

Impact and role of hypothalamic corticotropin releasing hormone neurons in withdrawal from chronic alcohol consumption in female and male mice.

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths (W.H.O., 2022). The endocrine stress system, initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), is profoundly linked with alcohol use, abuse, and relapse (Blaine & Sinha, 2017). These PVN CRH-releasing (PVNCRH) neurons are essential for peripheral and central stress responses (Rasiah et al., 2023), but little is known about how alcohol affects these neurons. Here, we show that two- bottle choice alcohol consumption blunts the endocrine mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRH neurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. Only male mice show a concurrent increase in GABAergic synaptic transmission. We then tested whether chemogenetic inhibition of PVNCRH neurons would restore stress response in female mice with a history of alcohol drinking in the looming disc test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRH neurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress responsive PVNCRH neurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress (Rodriguez et al., 2020), perhaps pointing to a potential underlying mechanism in alcohol mediated changes to PVNCRH neurons that alter stress response.

neuroscience↗

bioRxiv2023

Distinct brain-wide presynaptic networks underlie the functional identity of individual cortical neurons

Neuronal connections provide the scaffolding for neuronal function. Revealing the connectivity of functionally identified individual neurons is necessary to understand how activity patterns emerge and support behavior. Yet, the brain-wide presynaptic wiring rules that lay the foundation for the functional selectivity of individual neurons remain largely unexplored. Cortical neurons, even in primary sensory cortex, are heterogeneous in their selectivity, not only to sensory stimuli but also to multiple aspects of behavior. Here, to investigate presynaptic connectivity rules underlying the selectivity of pyramidal neurons to behavioral state1-12 in primary somatosensory cortex (S1), we used two-photon calcium imaging, neuropharmacology, single-cell based monosynaptic input tracing, and optogenetics. We show that behavioral state-dependent neuronal activity patterns are stable over time. These are minimally affected by neuromodulatory inputs and are instead driven by glutamatergic inputs. Analysis of brain-wide presynaptic networks of individual neurons with distinct behavioral state-dependent activity profiles revealed characteristic patterns of anatomical input. While both behavioral state-related and unrelated neurons had a similar pattern of local inputs within S1, their long-range glutamatergic inputs differed. Individual cortical neurons, irrespective of their functional properties, received converging inputs from the main S1-projecting areas. Yet, neurons that tracked behavioral state received a smaller proportion of motor cortical inputs and a larger proportion of thalamic inputs. Optogenetic suppression of thalamic inputs reduced behavioral state-dependent activity in S1, but this activity was not externally driven. Our results revealed distinct long-range glutamatergic inputs as a substrate for preconfigured network dynamics associated with behavioral state.

neuroscience↗

bioRxiv2023

Acoustically-Targeted Measurement of Transgene Expression in the Brain

Gene expression is a critical component of brain physiology and activity, but monitoring this expression in the living brain represents a significant challenge. Here, we introduce a new paradigm called Recovery of Markers through InSonation (REMIS) for noninvasive measurement of gene expression in the brain with cell-type, spatial, and temporal specificity. Our approach relies on engineered protein markers that are designed to be expressed in neurons and exit into the interstitium. By applying ultrasound to targeted brain regions, these markers are released into the bloodstream, where they can be readily detected using biochemical techniques. REMIS can noninvasively confirm gene delivery and measure endogenous signaling in specific brain sites through a simple insonation and a subsequent blood test. Using REMIS, we successfully measured chemogenetic induction of neuronal activity in ultrasound-tar-geted brain regions. REMIS recovery of markers is reliable and demonstrated improved recovery of markers from the brain into the blood in every tested animal. Overall, our work establishes a noninvasive, spatially-specific means of monitoring gene delivery outcomes and endogenous signaling in mammalian brains, opening up possibilities for brain research and noninvasive monitoring of gene therapies in the brain.

bioengineering↗

bioRxiv2023

Apposed networks of interacting TCRs and BCRs exhibiting mosaicked CDR3 sequences made of fixed junctional motifs

T and B cells are the two arms of the adaptive immune system that mediate cellular and humoral immunity, respectively, using highly diverse repertoires of antigen receptors. T cells recognize antigens using the T cell receptor (TCR), whereas B cells use the B cell receptor (BCR or surface immunoglobulin). Complementary determining regions (CDR3) of TCRs and BCRs are randomly generated through somatic VDJ recombination and nucleotide deletions and insertions at the V-D and D-J junctions. Contrary to this paradigm, here we describe two networks of millions of TCR{beta} and IGH clonotypes that are made from only two CDR3 sequences and associated with more 63 diseases. The TCR{beta} network members bore either the prototypic signature CDR3 sequence (CASSPGTEAFF), its N-terminal VD motif (CASSPGT) recombined with various J{beta} segments (CASSPGT-J{beta}x) or its DJ{beta} motif recombined with various V{beta} (V{beta}x-PGTEAFF). The BCR network members exhibit one signature CDR3 sequence (CARx1-4DTAMVYYFYDW) made from an invariant DJH motif (DTAMVYYFDYW) combined with various VH genes. The prototypes of the two networks are apparently teleogically related as they were dually expressed on the rare population of dual expresser (DE) lymphocytes and molecular dynamic simulations show that they were interacting partners. We conclude that members of the two networks represent a core set of evolutionary-conserved primordial antigen receptors that play fundamental roles in host defense and autoimmune diseases.

immunology↗

bioRxiv2023

Downregulation of the silent potassium channel Kv8.1 increases ALS motor neuron vulnerability

The Kv8.1 potassium ion channel encoded by the KCNV1 gene is a "silent" subunit whose biological function is unknown. In ALS patient-derived motor neurons carrying SOD1(A4V) and C9orf72 mutations, its expression is highly reduced, yielding increased vulnerability to cell death without a change in motor neuronal firing. Our data suggests that Kv8.1 modulates Kv2 channel function to impact neuronal metabolism and lipid/protein transport pathways, but not excitability.

neuroscience↗

bioRxiv2023

Deciphering the Differential Impact of Thrombopoietin/MPL Signaling on Hematopoietic Stem Cell Function in Bone Marrow and Spleen

Thrombopoietin (TPO) and its receptor MPL play crucial roles in hematopoietic stem cell (HSC) function and platelet production. However, the precise effects of TPO/MPL signaling on HSC regulation in different hematopoietic niches remain unclear. Here, we investigated the effects of TPO/MPL ablation on marrow and splenic hematopoiesis in TPO-/- and MPL-/- mice during aging. Despite severe thrombocytopenia, TPO-/- and MPL-/- mice did not develop marrow failure during a 2-year follow-up. Marrow and splenic HSCs exhibited different responses to TPO/MPL ablation and exogenous TPO treatment. Splenic niche cells compensated for marrow HSC loss in TPO-/- and MPL-/- mice by upregulating CXCL12 levels. These findings provide new insights into the complex regulation of HSCs by TPO/MPL and reveal a previously unknown link between TPO and CXCL12, two key growth factors for HSC maintenance. Understanding the distinct regulatory mechanisms between marrow and spleen hematopoiesis will help develop novel therapeutic approaches for hematopoietic disorders.

cell biology↗

bioRxiv2023

PhIP-Seq uncovers novel autoantibodies and unique endotypes in interstitial lung disease

Interstitial lung diseases (ILDs) are a heterogeneous group of disorders that can develop in patients with connective tissue diseases (CTD). Establishing autoimmunity in ILD impacts prognosis and treatment. ILD patients are screened for autoimmunity by assaying for anti-nuclear autoantibodies, rheumatoid factors and other non-specific tests. However, this approach has not been rigorously validated and may miss autoimmunity that manifests as autoantibodies to tissue antigens not previously defined in ILD. Here, we use Phage Immunoprecipitation-Sequencing (PhIP-Seq) to conduct a large, multi-center unbiased autoantibody discovery screen of ILD patients and controls. PhIP-Seq identified 17 novel autoreactive targets, and machine learning classifiers derived from these targets discriminated ILD serum from controls. Among these 17 candidates, we validated Cadherin Related Family Member 5 (CDHR5) as an autoantigen and found CDHR5 autoantibodies in patients with rheumatologic disorders and importantly, subjects not previously diagnosed with autoimmunity. Lung tissue of CDHR5 autoreactive patients showed transcriptional profiles consistent with activation of NF{kappa}B signaling and upregulation of chitotriosidase (CHIT1), a molecular pathway linked to fibrosis. Our study shows PhIP-Seq uncovers novel autoantibodies in ILD patients not revealed by standard clinical tests. Furthermore, CDHR5 autoantibodies may define a novel molecular endotype of ILD characterized by inflammation and fibrosis.

molecular biology↗

bioRxiv2023

Dysregulated expression of Hoxa1 isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes.

The homeobox gene, Hoxa1, has two different isoforms generated by alternative splicing: a full-length homeodomain-containing Hoxa1 (Hoxa1-FL), and a truncated Hoxa1 (Hoxa1-T), that lacks the homeodomain. The effects of the distinct Hoxa1 isoforms in hematopoiesis have not been investigated. Oncoretroviral studies revealed that Hoxa1-T acts in a dominant negative manner, regulating transcriptionally active Hoxa1. Oncoretroviral overexpression of wildtype Hoxa1 (WT-Hoxa1), which generates both Hoxa1 isoforms, in murine hematopoietic stem and progenitor cells (HSPCs) perturbed hematopoiesis, resulting in transplantable myelodysplastic syndromes (MDS) in mice. Overexpression of a mutated Hoxa1 cDNA (MUT-Hoxa1) that generates Hoxa1-FL, but not Hoxa1-T, led to a more severe MDS that transformed to secondary acute myeloid leukemia (sAML). DNA damage repair pathways were downregulated in Hoxa1-overexpressing hematopoietic progenitor cells, accompanied by increased {gamma}H2AX foci. In silico analyses revealed that CD34+ cells from approximately 50% of patients with MDS had elevated HOXA1-FL expression. Conditional knock-in WT-Hoxa1 and MUT-Hoxa1 mice were generated and had features of pre-MDS, developing altered hematopoiesis within 4 months of Hoxa1 isoform overexpression in HSPCs. HSPCs were significantly reduced in all knock-in mice, accompanied by significantly increased apoptosis in WT-Hoxa1 HSPCs. Healthy wildtype recipients transplanted with bone marrow cells from Hoxa1 knock-in mice developed trilineage MDS, with Hoxa1 isoform and gene dosage dependent phenotypes. Collectively our data identify a role for HOXA1 in the pathogenesis of MDS. Our Hoxa1 mouse models capture different stages of progression of disease from pre-MDS to MDS to sAML and provide novel, clinically relevant tools to study MDS. Key pointsHOXA1 is upregulated in approximately 50% of MDS patient CD34+ BM cells, highlighting a potential role for HOXA1 in the pathogenesis of MDS. Dysregulated expression of Hoxa1 isoforms in murine hematopoietic stem and progenitor cells predisposes mice to pre-MDS and MDS.

cancer biology↗

bioRxiv2023

Dynamic expectations: Behavioral and electrophysiological evidence of sub-second updates in reward predictions

Expectations are often dynamic: any sports fan knows that expectations are rapidly updated as games unfold. Yet expectations have traditionally been studied as static. Here, using slot machines as a case study, we provide parallel behavioral and electrophysiological evidence of sub-second moment-to-moment changes in expectations. In Study 1, we show that the dynamics of the EEG signal before the slot machine stopped differed depending on the nature of the outcome, including not only whether the participant won or lost, but also how close they came to winning. In line with our predictions, Near Win Before outcomes (the slot machine stops one item before a match) were similar to Wins, but different than Near Win After (the machine stops one item after a match) and Full Miss (the machine stops two or three items from a match). In Study 2, we designed a novel behavioral paradigm to measure moment-to-moment changes in expectations via dynamic betting. We found that different outcomes also elicited unique expectation trajectories in the deceleration phase. Notably, these behavioral expectation trajectories paralleled Study 1s EEG activity in the last second prior to the machines stop. In Studies 3 (EEG) and 4 (behavior) we replicated these findings in the loss domain where a match entails a loss. Again, we found a significant correlation between behavioral and EEG results. These four studies provide the first evidence that dynamic sub-second updates in expectations can be behaviorally and electrophysiologically measured. Our findings open up new avenues for studying the ongoing dynamics of reward expectations and their role in healthy and unhealthy cognition.

neuroscience↗

bioRxiv2023

Lepidoptera genomics based on 88 chromosomal reference sequences informs population genetic parameters for conservation

Butterflies and moths (Lepidoptera) are one of the most ecologically diverse and speciose insect orders, with more than 157,000 described species. However, the abundance and diversity of Lepidoptera are declining worldwide at an alarming rate. As few Lepidoptera are explicitly recognised as at risk globally, the need for conservation is neither mandated nor well-evidenced. Large-scale biodiversity genomics projects that take advantage of the latest developments in long-read sequencing technologies offer a valuable source of information. We here present a comprehensive, reference-free, whole-genome, multiple sequence alignment of 88 species of Lepidoptera. We show that the accuracy and quality of the alignment is influenced by the contiguity of the reference genomes analysed. We explored genomic signatures that might indicate conservation concern in these species. In our dataset, which is largely from Britain, many species, in particular moths, display low heterozygosity and a high level of inbreeding, reflected in medium (0.1 - 1 Mb) and long (> 1 Mb) runs of homozygosity. Many species with low inbreeding display a higher masked load, estimated from the sum of rejected substitution scores at heterozygous sites. Our study shows that the analysis of a single diploid genome in a comparative phylogenetic context can provide relevant genetic information to prioritise species for future conservation investigation, particularly for those with an unknown conservation status.

genomics↗