Biology subjects

Shi, Y.

Publications and source records attributed to Shi, Y..

At least 361 records · Page 20Linked to original sources

bioRxiv2021

A natural marmoset model of genetic generalized epilepsy.

As a common neurological disease, epilepsy has been extensively studied. Efforts have been made on rodent and other animal models to reveal the pathogenic mechanisms of epilepsy and develop new drugs as treatment. However, the features of current epilepsy models cannot fully mimic different kinds of epilepsy in human, asking for non-human primates models of epilepsy. The common marmoset (Callithrix jacchus) is a New World monkey that is widely used to study brain function. Here, we show a natural marmoset model of generalized epilepsy. In this unique marmoset family, generalized epilepsy was successfully induced by handling operation in some individuals. We mapped the marmoset family with handling-sensitive epilepsy and found that epileptic marmoset had an autosomal dominant genetic predisposition. Those marmosets were more sensitive to epilepsy inducers pentylenetetrazol (PTZ). By electrocorticogram (ECoG) recording, we detected epileptic discharge in marmoset with history of seizures. However, there was no significant change in the overall structure of epileptic marmoset brain. In summary, we report a family of marmosets with generalized seizures induced by handling operation. This epileptic marmoset family provides insights to better understand the mechanism of generalized epilepsy and helps to develop new therapeutic methods. Short summaryDespite the rodent and other animal models on epilepsy, a common neurological disease, the understanding of the pathogenic mechanisms of epilepsy and treatment are yet to be advanced., Non-human primates are good experimental animals for modelling neurological disease. Here we report a common marmoset family with generalized epilepsy induced by handling stimulation. We mapped the epileptic marmoset family and found that epilepsy had a genetic predisposition. The present report deals in detail with the phenotypes and characteristics of epileptic marmosets. This natural marmoset reflect epilepsy model will help to better understand the mechanism of epilepsy and develop new therapeutic methods.

neuroscience↗

bioRxiv2021

Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

BackgroundInterferon (IFN) pathway activation in tumors can have dual, sometimes opposing, influences on immune responses. Therapeutic inhibition of programmed cell death ligand (PD-L1) - a treatment that reverses PD-1-mediated suppression of tumor-killing T-cells - is linked to alterations in IFN signaling; however, less is known about the role of IFNs after treatment resistance. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined the consequences of PD-L1 blockade on IFN-related secretory changes in preclinical models of acquired resistance. MethodsTherapy-resistant cell variants were derived from orthotopically grown mouse tumors initially sensitive or insensitive to PD-L1 antibody treatment. Cells representing acquired resistance were analyzed for changes to IFN-regulated secretory machinery that could impact tumor progression. ResultsWe identified a PD-L1 treatment-induced secretome (PTIS) that was enriched for several IFN-stimulated genes (ISGs) and significantly enhanced when stimulated by type I IFNs (IFN or IFN{beta}). Secretory changes were specific to treatment-sensitive tumor models and found to suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing a tumor-intrinsic treatment adaptation with potentially broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth was slowed by the blockade of individual secreted PTIS components (such as IL6) and stopped altogether by a more generalized disruption of type I IFN signaling. In vitro, genetic or therapeutic methods to target PD-L1 could only partially recapitulate the IFN-enhanced PTIS phenotype, showing that in vivo-based systems with intact tumor:immune cell interactions are needed to faithfully mimic acquired resistance as it occurs in patients. ConclusionsThese results suggest that prolonged in vivo PD-L1 inhibition can rewire type I IFN signaling to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.

cancer biology↗

bioRxiv2021

Thiol-based mucolytics exhibit antiviral activity against SARS-CoV-2 through allosteric disulfide disruption in the spike glycoprotein

Small molecule therapeutics targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lagged far behind the development of vaccines in the fight to control the COVID-19 pandemic. Here, we show that thiol-based mucolytic agents, P2119 and P2165, potently inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity of repurposed mucolytic agents to the reduction of key disulfides, specifically, by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif (RBM) in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol warhead pointed directly towards Cys432. These collective findings establish the vulnerability of human coronaviruses to repurposed thiol-based mucolytics and lay the groundwork for developing these compounds as a potential treatment, preventative and/or adjuvant against infection.

microbiology↗

bioRxiv2021

Parallel Evaluation of Nucleophilic and Electrophilic Chemical Probes for Sulfenic Acid: Reactivity, Selectivity and Biocompatibility

S-sulfenylation of cysteine thiols (Cys-SOH) is a regulatory posttranslational modification in redox signaling and an important intermediate to other cysteine chemotypes. Owing to the dual chemical nature of the sulfur in sulfenic acid, both nucleophilic and electrophilic chemical probes have been developed to react with and detect Cys-SOH; however, the efficiency of existing probes has not been evaluated in a side-by-side comparison. Here, we employ small-molecule and protein models of Cys-SOH and compare the chemical probe reactivity. These data clearly show that 1,3-diketone-based nucleophilic probes react more efficiently with sulfenic acid as compared to strained alkene/alkyne electrophilic probes. Kinetic experiments that rigorously address the selectivity of the 1,3-diketone-based probes are also reported. Consideration of these data alongside relative cellular abundance, indicates that biological electrophiles, including cyclic sulfenamides, aldehydes, disulfides and hydrogen peroxide, are not meaningful targets of 1,3-diketone-based nucleophilic probes, which still remain the most viable tools for the bioorthogonal detection of Cys-SOH.

biochemistry↗

bioRxiv2021

Quantifying concordant genetic effects of de novo mutations on multiple disorders

Exome sequencing on tens of thousands of parent-proband trios has identified numerous deleterious de novo mutations (DNMs) and implicated risk genes for many disorders. Recent studies have suggested shared genes and pathways are enriched for DNMs across multiple disorders. However, existing analytic strategies only focus on genes that reach statistical significance for multiple disorders and require large trio samples in each study. As a result, these methods are not able to characterize the full landscape of genetic sharing due to polygenicity and incomplete penetrance. In this work, we introduce EncoreDNM, a novel statistical framework to quantify shared genetic effects between two disorders characterized by concordant enrichment of DNMs in the exome. EncoreDNM makes use of exome-wide, summary-level DNM data, including genes that do not reach statistical significance in single-disorder analysis, to evaluate the overall and annotation-partitioned genetic sharing between two disorders. Applying EncoreDNM to DNM data of nine disorders, we identified abundant pairwise enrichment correlations, especially in genes intolerant to pathogenic mutations and genes highly expressed in fetal tissues. These results suggest that EncoreDNM improves current analytic approaches and may have broad applications in DNM studies.

genetics↗

bioRxiv2021

Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimers disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-{gamma} with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and {beta}-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R=-0.874, p<0.0001) but not in vehicle controls (R=-0.356, p=0.081). Reduced TSPO-PET signal upon treatment was associated with better spatial learning and higher fibrillar {beta}-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R=0.952, p<0.0001). TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Pre-therapeutic assessment of baseline microglial activation and sex are strong predictors of individual immunomodulation effects and could serve for responder stratification.

neuroscience↗

bioRxiv2021

Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition

BackgroundWe undertook longitudinal {beta}-amyloid positron emission tomography (A{beta}-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist pioglitazone in A{beta} model mice. We thus tested the hypothesis this treatment would rescue from increases of the A{beta}-PET signal while promoting spatial learning and preservation of synaptic density. MethodsPS2APP mice (N=23; baseline age: 8 months) and AppNL-G-F mice (N=37; baseline age: 5 months) were investigated longitudinally for five months using A{beta}-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. ResultsSurprisingly, A{beta}-PET and immunohistochemistry revealed a shift towards higher fibrillary composition of A{beta}-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. ConclusionThese translational data suggest that a shift towards higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the A{beta}-PET signal upon immunomodulatory treatments targeting A{beta} aggregation can thus be protective.

neuroscience↗

bioRxiv2021

Structure-based Classification of Tauopathies

Ordered assembly of the tau protein into filaments characterizes multiple neurodegenerative diseases, which are called tauopathies. We previously reported that by electron cryo-microscopy (cryo-EM), tau filament structures from Alzheimers disease (1,2), chronic traumatic encephalopathy (CTE) (3), Picks disease (4) and corticobasal degeneration (CBD) (5) are distinct. Here we show that the structures of tau filaments from typical and atypical progressive supranuclear palsy (PSP), the most common tauopathy after Alzheimers disease, define a previously unknown, three-layered fold. Moreover, the tau filament structures from globular glial tauopathy (GGT, Types I and II) are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs from the above and resembles the four-layered CBD fold. The majority of tau filaments from aging-related tau astrogliopathy (ARTAG) also have the AGD fold. Surprisingly, tau protofilament structures from inherited cases with mutations +3/+16 in intron 10 of MAPT, the microtubule-associated protein tau gene, are identical to those from AGD, suggesting that a relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, tau filament structures from cases of familial British dementia (FBD) and familial Danish dementia (FDD) are the same as those from Alzheimers disease and primary age-related tauopathy (PART). These structures provide the basis for a classification of tauopathies that also allows identification of new entities, as we show here for a case diagnosed as PSP, but with abundant spherical 4R tau inclusions in limbic and other brain areas. The structures of the tau fold of this new disease (Limbic-predominant Neuronal inclusion body 4R Tauopathy, LNT) were intermediate between those of GGT and PSP.

neuroscience↗

bioRxiv2021

Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing

The RNA recognition motif (RRM) binds to nucleic acids as well as proteins. More than one such domain is found in the pre-mRNA processing hnRNP proteins. While the mode of RNA recognition by RRMs is known, the molecular basis of their protein interaction remains obscure. Here we describe the mode of interaction between hnRNP L and LL with the methyltransferase SETD2. We demonstrate that for the interaction to occur, a leucine pair within a highly conserved stretch of SETD2 insert their side chains in hydrophobic pockets formed by hnRNP L RRM2. Notably, the structure also highlights that RRM2 can form a ternary complex with SETD2 and RNA. Remarkably, mutating the leucine pair in SETD2 also results in its reduced interaction with other hnRNPs. Importantly, the similarity that the mode of SETD2-hnRNP L interaction shares with other related protein-protein interactions reveals a conserved design by which splicing regulators interact with one another.

biochemistry↗

bioRxiv2021

Gene flow influences the genomic architecture of local adaptation in six riverine fish species

Understanding how gene flow influences adaptive divergence is important for predicting adaptive responses. Theoretical studies suggest that when gene flow is high, clustering of adaptive genes in fewer genomic regions would protect adaptive alleles from among-population recombination and thus be selected for, but few studies have tested this hypothesis with empirical data. Here, we used RADseq to generate genomic data for six fish species with contrasting life histories from six reaches of the Upper Mississippi River System, USA. We then conducted genome scans for genomic islands of divergence to examine the distribution of adaptive loci and investigated whether these loci were found in inversions. We found that gene flow varied among species, and adaptive loci were clustered more tightly in species with higher gene flow. For example, the two species with the highest overall FST (0.03 - 0.07) and therefore lowest gene flow showed little evidence of clusters of adaptive loci, with adaptive loci spread uniformly across the genome. In contrast, nearly all adaptive loci in the species with the lowest FST (0.0004) were found in a single large putative inversion. Two other species with intermediate gene flow (FST ~ 0.004) also showed clustered genomic architectures, with most islands of divergence clustered on a few chromosomes. These results provide important empirical evidence to support the hypothesis that increasingly clustered architectures of local adaptation are associated with high gene flow. Our study utilized a unique system with species spanning a large gradient of life histories to highlight the importance of gene flow in shaping adaptive divergence.

evolutionary biology↗

bioRxiv2021

CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 variants

SARS-CoV-2 and its variants are raging worldwide. Unfortunately, the global vaccination is not efficient enough to attain a vaccine-based herd-immunity and yet no special and effective drug is developed to contain the spread of the disease. Previously we have identified CD147 as a novel receptor for SARS-CoV-2 infection. Here, we demonstrated that CD147 antibody effectively inhibits infection and cytokine storm caused by SARS-CoV-2 variants. In CD147KO VeroE6 cells, infections of SARS-CoV-2, its variants (B.1.1.7, B.1.351) and pseudovirus mutants (B.1.1.7, B.1.351, B.1.525, B.1.526 (S477N), B.1.526 (E484K), P.1, P.2, B.1.617.1, B.1.617.2) were decreased. Meanwhile, CD147 antibody effectively blocked the entry of variants and pseudomutants in VeroE6 cells, and inhibited the expression of cytokines. A model of SARS-CoV-2-infected hCD147 transgenic mice was constructed, which recapitulated the features of exudative diffuse alveolar damage and dynamic immune responses of COVID-19. CD147 antibody could effectively clear the virus and alveolar exudation, resolving the pneumonia. We found the elevated level of cyclophilin A (CyPA) in plasma of severe/critical cases, and identified CyPA as the most important proinflammatory intermediate causing cytokine storm. Mechanistically, spike protein of SARS-CoV-2 bound to CD147 and initiated the JAK-STAT pathway, which induced expression of CyPA. CyPA reciprocally bound to CD147, triggered MAPK pathway and consequently mediated the expression of cytokine and chemokine. In conclusion, CD147 is a critical target for SARS-CoV-2 variants and CD147 antibody is a promising drug to control the new wave of COVID-19 epidemic.

immunology↗

bioRxiv2021

Chromatin state barriers enforce an irreversible mammalian cell fate decision

Stem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase this output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogated determinants of this point of no return in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how the chromatin state enforces and perpetuates cell fate and identifies potential avenues for manipulating cell identity. HighlightsO_LIThere exists a point of irreversible commitment in granulocytic differentiation C_LIO_LIChromatin state dynamics establish the transition from self-renewal to differentiation commitment C_LIO_LIReduced chromatin accessibility underlies an irreversible loss of regulatory site access C_LIO_LIRestoration of a transcription factor feedback loop alters the differentiation commitment point C_LI

molecular biology↗

bioRxiv2021

Elevated Neuropeptide Y1 Receptor Signaling Contributes to β-cell Dysfunction and Failure in Type 2 Diabetes

Loss of functional {beta}-cell mass is a key factor contributing to the poor glycaemic control in type 2 diabetes. However, therapies that directly target these underlying processes remains lacking. Here we demonstrate that gene expression of neuropeptide Y1 receptor and its ligand, neuropeptide Y, was significantly upregulated in human islets from subjects with type 2 diabetes. Importantly, the reduced insulin secretion in type 2 diabetes was associated with increased neuropeptide Y and Y1 receptor expression in human islets. Consistently, pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected {beta}-cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, Y1 receptor antagonist BIBO3304 treatment improved {beta}-cell function and preserved functional {beta}-cell mass, thereby resulting in better glycaemic control in both high-fat-diet/multiple low-dose streptozotocin- and db/db type 2 diabetic mice. Collectively, our results uncovered a novel causal link of increased islet NPY-Y1 receptor signaling to {beta}-cell dysfunction and failure in human type 2 diabetes. These results further demonstrate that inhibition of Y1 receptor by BIBO3304 represents a novel and effective {beta}-cell protective therapy for improving functional {beta}-cell mass and glycaemic control in type 2 diabetes.

cell biology↗

bioRxiv2021

Vaccination-induced rapid protection against bacterial pneumonia via training alveolar macrophage in mice

Vaccination strategies for rapid protection against multidrug-resistant bacterial infection are very important, especially for hospitalized patients who have high risk of exposure to these bacteria. However, few such vaccination strategies exist due to a shortage of knowledge supporting their rapid effect. Here we demonstrated a single intranasal immunization of inactivated whole cell (IWC) of Acinetobacter baumannii elicits rapid protection against A. baumannii-infected pneumonia via training of innate immune response in Rag1-/- mice. Immunization-trained alveolar macrophages (AMs) showed enhanced TNF- production upon restimulation. Adoptive transfer of immunization-trained AMs into naive mice mediated rapid protection against infection. Elevated TLR4 expression on vaccination-trained AMs contributed to rapid protection. Moreover, immunization-induced rapid protection was also seen in Pseudomonas aeruginosa and Klebsiella pneumoniae pneumonia models, but not in Staphylococcus aureus and Streptococcus pneumoniae model. Our data reveal that a single intranasal immunization induces rapid and efficient protection against certain Gram-negative bacterial pneumonia via training AMs response, which highlights the importance and the possibility of harnessing trained immunity of AMs to design rapid-effecting vaccine.

immunology↗

bioRxiv2021

Blood vessels regulate primary motor neuronal pathfinding in zebrafish via exosome contained microRNA-22

A precise neuro-vascular communication is crucial to orchestrate directional migration and patterning of the complex vascular network and neural system. However, how blood vessels are involved in shaping the proper neuronal formation has not been fully understood. So far, limited studies have reported the discovery and functions of microRNAs (miRNAs) in guiding vascular and neural pathfinding. Currently, we showed that the deficiency of miRNA-22a, an endothelial-enriched miRNA, caused dramatic pathfinding defects both in intersegmental vessels (ISVs) and primary motor neurons (PMNs) in zebrafish embryos. Furthermore, we found the specific inhibition of miR-22a in ECs resulted in the patterning defects of both ISVs and PMNs. However, neuronal block of miR-22a mainly led to the axonal defects of PMN. Then we demonstrated that endothelial miR-22a regulates PMNs axonal navigation via exosome pathway. Sema4c was identified as a potential target of miR-22a through transcriptomic analysis and in silico analysis. Furthermore, luciferase assay and EGFP sensor assay in vivo confirmed the binding of miR-22a with 3-UTR of sema4c. In addition, Down-regulation of sema4c in the miR-22a morphants significantly neutralized the aberrant patterning of vascular and neural networks. Our study revealed that miR-22a acted as a dual guidance cue coordinating vascular and neuronal patterning and expanded the repertoire of guidance molecules, which might be of use therapeutically to guide vessels and nerves in the relevant diseases that affect both systems.

developmental biology↗

bioRxiv2021

Endothelial SIRPα signaling controls thymic progenitor homing for T cell regeneration and antitumor immunity

Thymic homing of hematopoietic progenitor cells (HPCs) is an essential step for the subsequent T cell development. Previously we have identified a subset of specialized thymic portal endothelial cells (TPECs), which is important for thymic HPC homing. However, the underlying molecular mechanism remains still unknown. Here we found that signal regulatory protein alpha (SIRP) is preferentially expressed on TPECs. Disruption of CD47-SIRP signaling in mice resulted in reduced number of thymic early T cell progenitors (ETPs) and impaired thymic HPC homing. Mechanistically, SIRP-deficient ECs and CD47-deficient lymphocytes demonstrated impaired transendothelial migration (TEM). Specifically, SIRP intracellular ITIM motif-initiated downstream signaling in ECs was found to be required for TEM in a SHP2- and Src-dependent manner. Furthermore, CD47-signaling from migrating cells and SIRP intracellular signaling were found to be required for VE-cadherin endocytosis in ECs. Functionally, SIRP signaling is required for T cell regeneration upon sub-lethal total body irradiation (SL-TBI); CD47-SIRP signaling blockade post SL-TBI diminishes antitumor immunity. Thus, our study reveals a novel role of endothelial SIRP signaling for thymic HPC homing for T cell regeneration and antitumor immunity. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/440464v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d53edorg.highwire.dtl.DTLVardef@100f2c9org.highwire.dtl.DTLVardef@1438a6forg.highwire.dtl.DTLVardef@135aa2b_HPS_FORMAT_FIGEXP M_FIG C_FIG Thymic homing of hematopoietic progenitor cells is fundamental to the T cell-based adaptive immunity, yet the molecular basis of this process is less clear. We discovered that endothelial SIRP signaling, engaged by migrating cell derived CD47 ligand, regulates thymic homing of hematopoietic progenitor cells for T cell regeneration and antitumor immunity. O_LISIRP is preferentially expressed on thymic portal endothelial cells. C_LIO_LIEndothelial SIRP regulates thymic homing of hematopoietic progenitor cells. C_LIO_LICD47-SIRP downstream signaling induces VE-cadherin endocytosis. C_LIO_LICD47-SIRP signaling blockade impairs thymic T cell regeneration and antitumor immunity. C_LI

immunology↗

bioRxiv2021

Performance Determinants of Unsupervised Clustering Methods for Microbiome Data

BackgroundIn microbiome data analysis, unsupervised clustering is often used to identify naturally occurring clusters, which can then be assessed for associations with characteristics of interest. In this work, we systematically compared beta diversity and clustering methods commonly used in microbiome analyses. We applied these to four published datasets where highly distinct microbiome profiles could be seen between sample groups. ResultsAlthough no single method outperformed the others consistently, we did identify key scenarios where certain methods can underperform. Specifically, the Bray Curtis metric resulted in poor clustering in a dataset where high-abundance OTUs were relatively rare. In contrast, the unweighted UniFrac metric clustered poorly when used on a dataset with a high prevalence of low-abundance OTUs. To test our proposition, we systematically modified properties of the poorly performing datasets and found that this approach resulted in improved Bray Curtis and unweighted UniFrac performance. Based on these observations, we rationally combined the Bray Curtis metric and the unweighted UniFrac metrics and found that this new beta diversity metric showed high performance across all datasets. We also evaluated our findings by examining a clinical dataset where clusters are less separated. ConclusionsOur systematic evaluation of clustering performance in these five datasets demonstrates that there is no existing clustering method that universally performs best across all datasets. We propose a combined metric of Bray Curtis and unweighted UniFrac that capitalizes on the complementary strengths of the two metrics.

microbiology↗

bioRxiv2021

HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of CNV, CNVR and ROH

Here we present an R package for summarizing, annotating, converting, comparing and visualizing CNV (copy number variants) and ROH (runs of homozygosity) detected from SNP (single nucleotide polymorphism) genotyping data. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving and user friendly for research in humans and most diploid livestock species. Availability and ImplementationThe source code, demo data and vignettes can be found at https://github.com/JH-Zhou/HandyCNV

bioinformatics↗