Biology subjects

Zeng, Q.

Publications and source records attributed to Zeng, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

The deacetylase dependent and independent role of HDAC3 in cardiomyopathy

BackgroundCardiomyopathy is a common disease of cardiac muscle that negatively affects cardiac function. HDAC3 commonly functions as co-repressor by removing acetyl moieties from histone tails. However, a deacetylase-independent role of HDAC3 has also been described. Cardiac deletion of HDAC3 causes reduced cardiac contractility accompanied by lipid accumulation. The molecular function of HDAC3 in cardiomyopathy remains unknown. We have used the powerful genetic tools in Drosophila to investigate the enzymatic and non-enzymatic roles of HDAC3 in cardiomyopathy. Methods and ResultsUsing the Drosophila heart model, we showed that cardiac-specific HDAC3 knockdown leads to prolonged systoles and reduced cardiac contractility. Immunohistochemistry revealed structural abnormalities characterized by myofiber disruption in HDAC3 knock down hearts. Cardiac-specific HDAC3 knockdown showed increased levels of whole body triglycerides and increased fibrosis. The introduction of deacetylase-dead HDAC3 mutant in HDAC3 KD background showed comparable results with wild type HDAC3 in aspects of contractility and Pericardin deposition. However, deacetylase-dead HDAC3 mutants failed to improve triglyceride accumulation. ConclusionsOur data indicate that HDAC3 plays a deacetylase-independent role in maintaining cardiac contractility and preventing Pericardin deposition as well as a deacetylase-dependent role to maintain triglyceride homestasis.

physiology↗

bioRxiv2022

Epigenomic complexity of the human brain revealed by single-cell DNA methylomes and 3D genome structures

Delineating the gene regulatory programs underlying complex cell types is fundamental for understanding brain functions in health and disease. Here, we comprehensively examine human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in over 500,000 cells from 46 brain regions. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. With these resources, we developed scMCodes that reliably predict brain cell types using their methylation status at select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell type-specific gene regulation in the adult human brain.

neuroscience↗

bioRxiv2022

Calpain-2 mediates SARS-CoV-2 entry and represents a therapeutic target

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, much effort has been dedicated to identifying effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A number of calpain inhibitors show excellent antiviral activities against SARS-CoV-2 by targeting the viral main protease (Mpro), which plays an essential role in processing viral polyproteins. In this study, we found that calpain inhibitors potently inhibited the infection of a chimeric vesicular stomatitis virus (VSV) encoding the SARS-CoV-2 spike protein, but not Mpro. In contrast, calpain inhibitors did not exhibit antiviral activities towards the wild-type VSV with its native glycoprotein. Genetic knockout of calpain-2 by CRISPR/Cas9 conferred resistance of the host cells to the chimeric VSV-SARS-CoV-2 virus and a clinical isolate of wild-type SARS-CoV-2. Mechanistically, calpain-2 facilitates SARS-CoV-2 spike protein-mediated cell attachment by positively regulating the cell surface levels of ACE2. These results highlight an Mpro-independent pathway targeted by calpain inhibitors for efficient viral inhibition. We also identify calpain-2 as a novel host factor and a potential therapeutic target responsible for SARS-CoV-2 infection at the entry step.

microbiology↗

bioRxiv2022

Type 17 Follicular Helper T (Tfh17) Cells are Superior for Memory Maintenance

A defining feature of successful vaccination is the ability to induce long-lived antigen- specific memory cells. Follicular helper T (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2 and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17 respectively. Here, we developed a new method to induce Tfh1, Tfh2 and Tfh17-like (iTfh1, iTfh2 and iTfh17) cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh (TfhCM) with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.

immunology↗

bioRxiv2022

Distinct Single-cell Immune Ecosystems Distinguish True and De Novo HBV-related Hepatocellular Carcinoma Recurrences

Revealing differential tumor immune microenvironment (TIME) characteristics between true versus de novo hepatocellular carcinoma (HCC) recurrence could help optimal development and use of immunotherapies. Here, we studied the TIME of recurrent HBV-related HCCs by 5and VDJ single-cell and bulk RNA-sequencing, flow cytometry, and multiplexed immunofluorescence. Analyses of mutational profiles, evolutionary trajectories, and clonal architecture using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The TIME of truly recurrent HCCs was characterized by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed an upregulated GDF15 expression level on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited anti-tumor immunity in the TIME of truly recurrent lesions. In contrast, we found that myeloid cells crosstalk with T cells mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCC. In conclusion, our results support genomic diagnosis and immune profiling for guiding immunotherapy implementation based on the type of HCC recurrence and TIME. HighlightsO_LITruly recurrent lesions are seeded before primary tumor diagnosis, and that de novo cancer can occur earlier than the clinically used 2-year limit. C_LIO_LIScRNA-seq unravels distinct immune ecosystems in true versus de novo HCC recurrences, highlighting the need for different immunotherapy strategies for two types of HCC recurrence. C_LIO_LICD8+ T cells in de novo recurrence displayed cytotoxic and exhausted phenotypes while those in truly recurrent lesions showed a memory phenotype with weak cytotoxicity. C_LIO_LIHCC cells expressing the inhibitory molecule GDF15 were in the proximity of DCs only in truly recurrent lesions. C_LIO_LIHigh GDF15 expression level was associated with truly recurrent HCC and worse prognosis. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/494526v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1b76bf0org.highwire.dtl.DTLVardef@10f889aorg.highwire.dtl.DTLVardef@d16b52org.highwire.dtl.DTLVardef@dceb7a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Immunological findings in a group of individuals who were non-responders to standard two-dose SARS-CoV-2 vaccines

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic. The virus has infected more than 505 million people and caused more than 6 million deaths. However, data on non-responders to SARS-CoV-2 vaccines in the general population are limited. The objective of the study is to comprehensively compare the immunological characteristics of non-responders to SARS-CoV-2 vaccines in the 18-59 years with that in the 60 years and older using internationally recognized cutoff values. Participants included 627 individuals who received physical examinations and volunteered to participate in COVID-19 vaccination from the general population. The main outcome was an effective seroconversion characterized by anti-SARS-CoV-2 spike IgG level of at least 4-fold increase from baseline. Profiling of naive immune cells was analyzed prior to vaccination to demonstrate baseline immunity. Outcomes of effective seroconversion in the 18-59 years with that in the 60 years and older were compared. The quantitative level of the anti-spike IgG was significantly lower in the 60 years and older and in men among the 18-59 years. There were 7.5% of non-responders among the 18-59 years and 11.7% of non-responders in the 60 years and older using the 4-fold increase parameter. The effective seroconversion rate was significantly related to the level of certain immune cells before vaccination, such as CD4 cells, CD8 cells and B cells and the age. An individual with a titer of anti-SARS-CoV-2 spike IgG that is below 50 BAU/mL might be considered a non-responder between 14-90 days after the last vaccine dose. Booster vaccination or additional protective measures should be recommended for non-responders as soon as possible to reduce disease severity and mortality.

immunology↗

bioRxiv2022

SARS-CoV-2 Omicron BA.1 variant infection of human colon epithelial cells

Omicron B.1.1.529 became the predominant SARS-CoV-2 variant in early 2022, causing a new wave of public anxiety. Compared to the ancestral strain, Omicron has 50 mutations, with over 30 mutations in the spike protein. These differences likely underlie the changes in Omicron biology noted in other studies, including an attenuation in the lung parenchyma, compared to the ancestral SARS-CoV-2 strain and other variants, as well as a preference for endosomal entry, in place of the TMPRSS2-mediated membrane fusion pathway. This raises questions on Omicron tropism and infectivity in various target organ systems, including the gastrointestinal (GI) tract. Up to 70% of COVID-19 patients report GI symptoms, including nausea, vomiting, and diarrhea. Here, we show that in the context of donor intrinsic genetic heterogeneity, the SARS-CoV-2 Omicron variant infects human colonoids similarly, if not less effectively, than the ancestral WT (WA1) strain or the Delta variant. Additionally, we note a higher ratio of viral RNA to infectious virus titer, which may suggest that Omicron is potentially less infectious in the intestine. This study lays the foundation for further work defining mechanisms mediating intestinal infection and pathogenesis by Omicron.

microbiology↗

bioRxiv2022

Profiling the size-dependent heterogeneity of membrane proteins in a mixed population of small extracellular vesicle for potential cancer diagnosis

The heterogeneity in small extracellular vesicles (small EVs) introduces an extra level of complexity in small EV-based liquid biopsy for cancer diagnosis. Heterogeneous membrane protein expression is correlated with sizes of small EVs, but accessing this correlative information is limited by the precise isolation of size-dependent subpopulations. Herein, we present a single EV enumeration (SEVEN) approach to profile protein heterogeneity in size-dependent subpopulations, and demonstrate its potential in improving the accuracy of cancer diagnosis. The interferometric plasmonic microscopy (iPM) capable of imaging single biological nanoparticles with the diameter down to 30 nm is employed to detect small EVs at the single-particle level. Small EVs population with mixed sizes are directly imaged, individually sized and digitally counted during their binding onto different aptamer-coated iPM sensor surfaces. The protein expression levels and binding kinetics of three size-dependent subpopulations are analyzed, forming a multidimensional data matrix for cancer diagnosis. Using small EVs derived from different cancer cell lines, highly heterogeneous protein profiles are recorded in the three subpopulations. We further demonstrate that the cancer classification accuracy could be greatly improved by including the subpopulation level heterogeneous protein profiles as compared with conventional ensemble measurement.

biochemistry↗

bioRxiv2022

Near telomere-to-telomere nuclear phased chromosomes of the dikaryotic wheat fungus Rhizoctonia cerealis

Rhizoctonia cerealis (Rce), which causes sharp eyespot, is one of the most destructive wheat pathogens. However, the genetic and molecular virulence mechanisms of Rce have not been elucidated. As a dikaryotic organism, the haplotype phasing of this fungus has not been completed so far. We applied a haplotype phasing algorithm to generate a high-quality near telomere-to-telomere nuclear-phased genome sequence of Rce strain R0301. Sixteen pairs of chromosomes were assigned to the A and B genomes with a total size of 83 Mb. Based on a dual-time course RNA-seq, 25308 genes were predicted. Genes for steroid biosynthesis and starch and sucrose metabolism were significantly enriched, together with many genes encoding carbohydrate-active enzymes (CAZymes) and secreted effector proteins, which should be involved in infection of wheat plants. Population genomic analysis of 31 isolates collected in China during the last forty years suggests that this population has not undergone substantial differentiation over time. ImportanceThe finished genome reference is the basis of revealing pathogens biology base. Many efforts have been made to produce the chromosome-scale assembly of fungi. However, the reference of many pathogenic fungi is highly fragmented, which prevents the analysis of genome structure variation, evolution and import pathogenicity genes. Here, we assembly the only chromosome-scale haplotype-phased reference of dikaryotic fungus so far. This assembly achieves the gold standard based on many evaluation software, which indicates that the pipeline developed in this study can be applied to assemble references for other dikaryotic organisms. This work can also promote the research on the globes destructive wheat pathogens, sharp eyespot, caused by R. cerealis.

genomics↗

bioRxiv2022

More or less deadly? A mathematical model that predicts SARS-CoV-2 evolutionary direction.

SARS-CoV-2 has caused tremendous deaths world wild. It is of great value to predict the evolutionary direction of SARS-CoV-2. In this paper, we proposed a novel mathematical model that could predict the evolutionary trend of SARS-CoV-2. We focus on the mutational effects on viral assembly capacity. A robust coarse-grained mathematical model is constructed to simulate the virus dynamics in the host body. Both virulence and transmissibility can be quantified in this model. The relationship between virulence and transmissibility can be simulated. A delicate equilibrium point that optimizing the transmissibility can be numerically obtained. Based on this model, we predict the virulence of SARS-CoV-2 might further decrease, accompanied by an enhancement of transmissibility. However, this trend is not continuous; its virulence will not disappear but remains at a relatively stable range. We can also explain the cross-species transmission phenomenon of certain RNA virus based on this model. A small-scale model which simulates the virus packing process is also proposed. It can be explained why a small number of mutations would lead to a significant divergence in clinical performance, both in the overall particle formation quantity and virulence. This research provides a mathematical attempt to elucidate the evolutionary driving force in RNA virus evolution.

evolutionary biology↗

bioRxiv2022

CHDbase: A Comprehensive Knowledgebase for Congenital Heart Disease-related Genes and Clinical Manifestations

Congenital heart disease (CHD) is the most common cause of major birth defects, with a prevalence of 1%. Although an increasing number of studies reporting the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase with CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124 susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of study were integrated with each item of research record. We also integrated functional annotations through parsing ~50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach, and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibility, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org/.

genetics↗

bioRxiv2022

Superficial white matter microstructure affects processing speed in cerebral small vessel disease

White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD). This condition contributes to about 50% of dementias worldwide, a massive health burden in aging. Microstructural alterations in the deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in the superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In this paper, 141 patients with CSVD were studied. Processing speed was assessed by the completion time of the Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (lesion volume on T2-FLAIR) and diffusion MRI, including DTI and free-water (FW) imaging microstructure measures. The results of our study indicate that the superficial white matter may play a particularly important role in cognitive decline in CSVD. SWM imaging measures resulted in a large contribution to processing speed, despite a relatively small WMH burden in the SWM. SWM FW had the strongest association with processing speed among all imaging markers and, unlike the other diffusion MRI measures, significantly increased between two patient subgroups with the lowest WMH burdens (possibly representing early stages of disease). When comparing two patient subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Given significant effects of WMH volume and regional FW on processing speed, we performed a mediation analysis. SWM FW was found to fully mediate the association between WMH volume and processing speed, while no mediation effect of DWM FW was observed. Overall, our findings identify SWM abnormalities in CSVD and suggest that the SWM has an important contribution to processing speed. Results indicate that FW in the SWM is a sensitive marker of microstructural changes associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes in future research.

neuroscience↗

bioRxiv2021

Accurate Name Entity Recognition for Biomedical Literatures: A Combined High-quality Manual Annotation and Deep-learning Natural Language Processing Study

A combined high-quality manual annotation and deep-learning natural language processing study is reported to make accurate name entity recognition (NER) for biomedical literatures. A home-made version of entity annotation guidelines on biomedical literatures was constructed. Our manual annotations have an overall over 92% consistency for all the four entity types -- gene, variant, disease and species --with the same publicly available annotated corpora from other experts previously. A total of 400 full biomedical articles from PubMed are annotated based on our home-made entity annotation guidelines. Both a BERT-based large model and a DistilBERT-based simplified model were constructed, trained and optimized for offline and online inference, respectively. The F1-scores of NER of gene, variant, disease and species for the BERT-based model are 97.28%, 93.52%, 92.54% and 95.76%, respectively, while those for the DistilBERT-based model are 95.14%, 86.26%, 91.37% and 89.92%, respectively. The F1 scores of the DistilBERT-based NER model retains 97.8%, 92.2%, 98.7% and 93.9% of those of BERT-based NER for gene, variant, disease and species, respectively. Moreover, the performance for both our BERT-based NER model and DistilBERT-based NER model outperforms that of the state-of-art model--BioBERT, indicating the significance to train an NER model on biomedical-domain literatures jointly with high-quality annotated datasets.

bioinformatics↗

bioRxiv2021

Th1/17 Cells Infiltrate Murine Cytomegalovirus-Infected Renal Allografts via Virus-Induced CCL20 and Promote Th1 Cells through IL-17A.

Cytomegalovirus (CMV) infection is associated with renal allograft failure by unknown mechanisms. In a murine renal transplant model, murine CMV (MCMV) induces intragraft infiltration of Th17 cells co-expressing Th1 cytokines, IFN-{gamma} and TNF-, but only a minority of intragraft Th17 cells are specific for MCMV antigens. Instead, MCMV promotes viral antigen-independent Th17 cell recruitment via CCL20-CCR6 and CXCL10-CXCR3 interactions. Th17 cells correlate directly with Th1 cell frequencies and inversely with Tregs in MCMV infected grafts. Pharmacologic inhibition of IL-17A reduces intragraft Th17 cells and neutrophils, increases Tregs, and reduces total but not MCMV-specific Th1 cells. Among a clinical renal transplant cohort with acute rejection, patients with CMV DNAemia had significantly higher serum IL-17A quantities compared to those without CMV DNAemia. Together, these findings indicate that CMV infection upregulates Th17 cell activity during acute rejection and suggests that inhibition of IL-17A may ameliorate CMV-associated allograft injury without impairing antiviral Th1 cells.

immunology↗

bioRxiv2021

Integration of the cyanophage-encoded phosphate binding protein into the cyanobacterial phosphate uptake system

To acquire phosphorus, cyanobacteria use the typical bacterial ABC-type phosphate transporter, which is composed of a periplasmic high-affinity phosphate-binding protein PstS and a channel formed by two transmembrane proteins PstC and PstA. The pstS gene has been identified in the genomes of cyanophages that infect the unicellular cyanobacteria Prochlorococcus and Synechococcus. However, it is unknown how the cyanophage PstS interplays with the host PstC and PstA to function as a chimeric ABC transporter. Here we showed that the cyanophage P-SSM2 PstS protein was abundant in the infected Prochlorococcus NATL2A cells and the host phosphate uptake rate was enhanced after infection. This is consistent with our biochemical and structural analyses showing that the phage PstS protein is indeed a high-affinity phosphate-binding protein. We further modeled the complex structure of phage PstS with host PstCA and revealed three putative interfaces that may facilitate the formation of the chimeric ABC transporter. Our results provide insights into the molecular mechanism by which cyanophages enhance the phosphate uptake rate of cyanobacteria. Phosphate acquisition by infected bacteria can increase the phosphorus contents of released cellular debris and virus particles, which together constitute a significant proportion of the marine dissolved organic phosphorus pool.

microbiology↗

bioRxiv2021

Rotavirus NSP1 contributes to intestinal viral replication, pathogenesis, and transmission

Rotavirus (RV)-encoded non-structural protein 1 (NSP1), the product of gene segment 5, effectively antagonizes host interferon (IFN) signaling via multiple mechanisms. Recent studies with the newly established RV reverse genetics system indicate that NSP1 is not essential for the replication of simian RV SA11 strain in cell culture. However, the role of NSP1 in RV infection in vivo remains poorly characterized due to the limited replication of heterologous simian RVs in the suckling mouse model. Here, we used an optimized reverse genetics system and successfully recovered recombinant murine RVs with or without NSP1 expression. While the NSP1-null virus replicated comparably with the parental murine RV in IFN-deficient and IFN-competent cell lines in vitro, it was highly attenuated in 5-day-old wild-type suckling pups. In the absence of NSP1 expression, murine RV had significantly reduced replication in the ileum, systemic spread to mesenteric lymph nodes, fecal shedding, diarrhea occurrence, and transmission to uninoculated littermates. Of interest, the replication and pathogenesis defects of NSP1-null RV were only minimally rescued in Stat1 knockout pups, suggesting that NSP1 facilitates RV replication in an IFN-independent manner. Our findings highlight a pivotal function of NSP1 during homologous RV infections in vivo and identify NSP1 as an ideal viral protein for targeted attenuation for future vaccine development. IMPORTANCERotavirus remains one of the most important causes of severe diarrhea and dehydration in young children worldwide. Although NSP1 is dispensable for rotavirus replication in cell culture, its exact role in virus infection in vivo remains unclear. In this study, we demonstrate that in the context of a fully replication-competent, pathogenic, and transmissible murine rotavirus, loss of NSP1 expression substantially attenuated virus replication in the gastrointestinal tract, diarrheal disease, and virus transmission in suckling mice. Notably, the NSP1-deficient murine rotavirus also replicated poorly in mice lacking host interferon signaling. Our data provide the first piece of evidence that NSP1 is essential for murine rotavirus replication in vivo, making it an attractable target for developing improved next-generation rotavirus vaccines better suited for socioeconomically disadvantaged and immunocompromised individuals.

microbiology↗

bioRxiv2021

The genetic architecture of phenotypic diversity in the betta fish (Betta splendens)

The Betta fish displays a remarkable variety of phenotypes selected during domestication. However, the genetic basis underlying these traits remain largely unexplored. Here, we report a high-quality genome assembly and re-sequencing of 727 individuals representing diverse morphologies of the betta fish. We show that current breeds have a complex domestication history with extensive introgression with wild species. Using GWAS, we identify the genetic basis of multiple traits, including several coloration phenotypes, sex-determination which we map to DMRT1, and the long-fin phenotype which maps to KCNJ15. We identify a polygenic signal related to aggression with many similarities to human psychiatric traits, involving genes such as CACNB2 and DISC1. Our study provides a resource for developing the Betta fish as a genetic model for morphology and behavior in vertebrates.

genetics↗

bioRxiv2021

VCFCons: a versatile VCF-based consensus sequence generator for small genomes

We had developed VCFCons to address urgent need for a robust consensus sequence generator for SARS-CoV-2 viral surveillance, which presented several unique requirements, including: (a) low coverage areas should be noted with Ns, (b) low frequency or suspicious variant calls need to be filtered. We have found that, while some existing tools such as bcftools can generate the desired consensus sequence, it required multiple filtering steps and additional scripting. VCFCons can generate consensus sequences based on variant calls in a VCF format with versatile filtering criteria based on coverage and estimated variant frequency. We applied VCFCons to the Labcorp SARS-CoV-2 sequencing data and showed that it generated correct consensus sequences that were successfully submitted to GISAID and NCBI. We hope the community will find value in this tool and aim to continue developing VCFCons to handle more complex viral data in the future.

bioinformatics↗