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Scaria, V.

Publications and source records attributed to Scaria, V..

At least 19 recordsLinked to original sources
bioRxiv2024

LncRNA TAAL is a Modulator of Tie1-Mediated Vascular Function in Diabetic Retinopathy

Diabetic retinopathy (DR), a leading cause of vision impairment and blindness, is characterized by abnormal retinal vascular changes due to chronic hyperglycemia. The Tie-1 signaling pathway, essential for vascular growth and remodeling, has emerged as a key therapeutic target, though its molecular mechanisms and interactome remain largely unclear. Through a protein-centric approach, we identified a novel lncRNA and named it Tie1-associated angiogenic lncRNA (TAAL). TAAL lncRNA regulates endothelial cell migration, proliferation, tube formation, and permeability by modulating ER-calcium homeostasis and cytoskeleton dynamics. In zebrafish, taal modulation led to angiogenic defects, which were rescued by human TAAL orthologue. Our molecular studies further revealed that TAAL negatively regulates Tie1 protein via ubiquitin-mediated degradation. Notably, TAAL expression is upregulated in the blood of DR patients and downregulated in endothelial DR cell models. Overexpression of TAAL restored endothelial permeability and VE-cadherin surface expression. These findings establish TAAL as a novel regulator of Tie1 protein turnover, with potential therapeutic implications for diabetic retinopathy.

genetics↗
bioRxiv2024

SCAR-6 elncRNA locus epigenetically regulates PROZ and modulates coagulation and vascular function

Syntenic conservation is an effective strategy to identify evolutionarily conserved lncRNA orthologs. In this study, we identified a novel uncharacterized conserved lncRNA known as Syntenic Cardiovascular Conserved Region-Associated lncRNA-6 (scar-6) and functionally validated its role in coagulation and cardiovascular function. Precise editing of the scar-6 lncRNA locus in zebrafish (scar-6gib007{Delta}12/{Delta}12) resulted in cranial hemorrhage and permeability defects. Further analysis, including overexpression, locus editing, and rescue experiments, provided compelling evidence for the critical role of the scar-6 transcript in the coagulation process of zebrafish. Notably, rescue attempts were unsuccessful in mitigating cranial hemorrhage. Molecular investigation revealed that the scar-6 RNA acts as an enhancer lncRNA (elncRNA), and controls the expression of prozb, an inhibitor of factor Xa, through the enhancer element on its locus. The scar-6 locus actively suppresses the loop formation between prozb and scar-6 sequences, facilitated by methylation of CpG island via the prdm14-PRC2 complex, which is stabilized by the scar-6 elncRNA transcript. Disruption of this mechanism in scar-6gib007{Delta}12/{Delta}12 zebrafish led to impaired vascular function and subsequent hemorrhage. This was triggered by the activation of the PAR2 receptor mediated by upregulation of prozb, which in turn caused NF-{kappa}B-mediated endothelial cell activation. This study presents novel evidence for the multifaceted function of the scar-6 locus, highlighting its crucial role in regulating the coagulation cascade gene prozb and maintaining homeostasis and vascular function. Synopsis O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/604148v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@ea55e4org.highwire.dtl.DTLVardef@ad01beorg.highwire.dtl.DTLVardef@4da1eborg.highwire.dtl.DTLVardef@c153a9_HPS_FORMAT_FIGEXP M_FIG C_FIG ProZ-PZI is a natural inhibitor of activated coagulation factor X (F10) and plays a major role in maintaining hemostasis in-vivo. Here, the novel evolutionary syntenic conserved scar-6 elncRNA locus is shown to regulate prozb expression and control coagulation and vascular integrity in zebrafish. O_LIThe scar-6 acts as an enhancer lncRNA (elncRNA). It controls prozb expression and modulates coagulation and vascular function in zebrafish. C_LIO_LIThe scar-6 elncRNA stabilizes the Prdm14-PRC2 complex binding to scar-6 locus. This inhibits prozb/scar-6 looping via methylating the CpG island under wildtype conditions. C_LIO_LIOverexpressed prozb in scar-6 edited animals activates PAR2 receptor, causing endothelial cell activation and vascular dysfunction. C_LI

genetics↗
bioRxiv2024

Syntenic lncRNAs exhibit DNA regulatory functions with sequence evolution

Syntenic long non-coding RNAs (lncRNAs) often show limited sequence conservation across species, prompting concern in the field. This study delves into functional signatures of syntenic lncRNAs between humans and zebrafish. Syntenic lncRNAs have high expression in zebrafish and [~]90% near protein-coding genes in sense or antisense orientation. During early zebrafish development and human embryonic stem cells (H1-hESC), are enriched with cis-regulatory repressor signatures, influencing development-associated genes. In later zebrafish developmental stages and specific human cell lines, these lncRNAs serve as enhancers or transcription-start-sites(TSS) for protein-coding. Analysis of Transposable Elements (TEs) in syntenic lncRNA sequence divergence unveils intriguing patterns, human lncRNAs show enrichment in simple repeat elements, while zebrafish counterparts exhibit LTR element enrichment. This sequence evolution, possibly stemming from post-rearrangement mutations, enhances DNA elements or cis-regulatory functions. It may also contribute to vertebrate innovation by creating novel TF binding sites within the locus. This study sheds light on the conserved functionality of syntenic lncRNAs through DNA elements, emphasizing their role across species despite sequence divergence.

genetics↗
bioRxiv2023

DystoGen Compendium: A comprehensive resource of ACMG annotated movement disorder associated genetic variants

PurposeIn recent years, the advent of high throughput sequencing techniques has led to the identification of a number of genetic variants across different genes that are associated with movement disorders. However, the under-appreciation of the variant spectrum in movement disorders and the lack of consolidated and systematic evidence-based annotation of these variants has long undermined the true potential of genomic approaches to expedite precision medicine. MethodsWe manually curated the genetic variants from a panel of 118 genes that have been associated with monogenic causes of movement disorders and systematically annotated them according to ACMG & AMP (American College of Medical Genetics and the Association of Molecular Pathologists) guidelines. ResultsData integration after systematic classification of variants according to ACMG & AMP guidelines showed 5118 pathogenic/likely pathogenic variants accounting for 18.03% of the total unique variants being annotated. This data and annotations are available in a comprehensive online compendium DystoGen. ConclusionTo the best of our knowledge, this is the most comprehensive compendium of genetic variants in movement disorders annotated as per the ACMG & AMP guidelines for pathogenicity. The compendium indexes 28377 variants along with a wide array of information including the geographical origin of the variant, global distribution, and population allele frequency. The resource has been made available in the URL https://clingen.igib.res.in/dystogen/.

bioinformatics↗
bioRxiv2022

Genetic variants of human platelet antigens in the Indian population from 1029 whole genomes

BackgroundGenetic variants in human platelet antigens (HPAs) considered as allo- or auto antigens are associated with various disorders including neonatal alloimmune thrombocytopenia, platelet transfusion refractoriness and post-transfusion purpura. While global differences in genotype frequencies were observed, the distribution of HPA variants in the Indian population are largely unknown. This study aims to explore the landscape of HPA variants in India to provide a basis for risk assessment and management of related complications. Materials and methodsPopulation specific frequencies of genetic variants associated with the 35 classes of HPAs (HPA-1 to HPA-35) were estimated by systematically analyzing genomic variations of 1029 healthy Indian individuals as well as from global population genome datasets.. ResultsAllele frequencies of the most clinically relevant HPA systems in the Indian population were found as follows, HPA-1a - 0.89, HPA-1b - 0.15, HPA-2a - 0.94, HPA-2b - 0.05, HPA-3a - 0.66, HPA-3b - 0.36, HPA-4a - 1.00, HPA-4b - 0, HPA-5a - 0.92, HPA-5b - 0.08, HPA-6a - 1.00, HPA-6b - 0, HPA-15a - 0.58 and HPA-15b - 0.42. In addition, HPA-4b allele frequencies were found to be significantly higher in India in comparison to global populations. ConclusionThis study provides the first comprehensive analysis of HPA allele and genotype frequencies using large scale representative whole genome sequencing data of the Indian population.

genomics↗
bioRxiv2022

The genome sequence of the Lumpy Skin Disease virus from the outbreak in India suggests a distinct lineage of the virus

Although previously confined to regions within Africa, Lumpy Skin Disease Virus (LSDV) infections have caused significantly large outbreaks in several regions of the world in very recent years. In 2019, an outbreak of the disease was reported from India with low rates of morbidity and no reported mortality. However, in 2022, an ongoing outbreak of LSDV spanning over 7 states in India resulted in a reported mortality of over 80,000 cattle over a short period of three months. Here, we report complete genome sequences of 6 viral isolates of LSDV collected from affected cattle during an ongoing outbreak of the disease in Rajasthan, India. Analysis of the viral sequences suggests the genomes from the 2022 outbreak harbour a large number of genetic variations compared to the reference genome and form a distinct lineage. This report also highlights the importance of genome sequencing and surveillance of transboundary infectious agents and genomic characterisation of outbreaks.

genomics↗
bioRxiv2022

A distinct phylogenetic cluster of Monkeypox genomes suggests an early and cryptic spread of the virus

Since its first reports in humans in 1970, monkeypox has been predominantly restricted to countries in Africa where the disease is endemic. Early in 2022, a large number of cases of the disease were reported from Europe and other countries in patients with no history of travel to regions where monkeypox is endemic. Amid a rise in cases, the availability of genome sequences of monkeypox virus isolates in the public domain provides an opportunity to understand the transmission and evolution of the virus. Here, we describe a distinct phylogenetic cluster of monkeypox virus (lineage A.2) using genome sequences available on GISAID. Lineage A.2 currently encompasses 9 genome sequences from 6 viral isolates collected from 3 countries and is distinctly different from the predominant lineage B.1 which is linked to the large European outbreak.

genomics↗
bioRxiv2022

Genetic landscape of Human neutrophil antigen variants in India from population-scale genomes

BackgroundAntibodies against human neutrophil antigens (HNAs) play a significant role in various clinical conditions such as neonatal alloimmune neutropenia (NAIN). Transfusion-related acute lung injury (TRALI) and other non-hemolytic transfusion reactions. This study aims to identify the genotype and allele frequencies of HNAs in the healthy Indian population. MethodsGenetic variants from whole genomes of 1029 healthy Indian individuals were retrieved to accurately perform frequency estimation of HNA-1, HNA-3, HNA-4 and HNA-5 alleles using in-house computational pipeline. ResultsIn HNA class I, the genotype frequencies of FCGR3B*01 (HNA1a/a), FCGR3B*02 (HNA1b/b) and FCGR3B*03 (HNA1c/c) were 0.29%, 27.31% and 1.75% respectively. In HNA-3 the frequencies of HNA3a/a (SLC44A2*01), HNA3a/b and HNA3b/b (SLC44A2*02) were found to be 62.0%, 31.7% and 5.8% respectively. Frequency of ITGAM*01 encoding HNA4a/a was 90.1% and that of ITGAM*02 encoding HNA4b/b was 0.3%. Furthermore, HNA5a/a (ITGAL*01) and HNA5b/b (ITGAL*02) were found to have 12.9% and 48.6% genotype frequencies in the Indian population respectively. It was also found that the allele frequency HNA-5 variant, rs2230433 (ITGAL_chr16:30506720G>C) encoding 5b allele was highly prevalent (78.2%) in the Indian population which was comparable to South Asians (65.6%) but differed greatly from East Asians (14.3%), Latino Americans (25.7%), African-Americans (42.2%), European-Finnish (25.4%), European-non-Finnish (29.4%), Greater Middle Easterners (34.5%), Amish (30.2%) and Ashkenazi Jewish (31.4%). ConclusionThis study presents the first comprehensive report of HNA variant and genotype frequencies using large scale representative whole genome sequencing data of the Indian population. Significant difference was observed in the prevalence of HNA5a and HNA5b in India in comparison to other global populations.

genomics↗
bioRxiv2022

Anti-COVID-19 Activity of FDA Approved Drugs through RNA G-quadruplex Binding

The COVID-19 pandemic caused by SARS-CoV-2 has caused millions of infections and deaths worldwide. Limited treatment options and the threat from emerging variants underline the need for novel and widely accessible therapeutics. G-quadruplexes (G4s) are nucleic acid secondary structures known to affect many cellular processes including viral replication and transcription. We identified heretofore not reported G4s with remarkably low mutation frequency across >5 million SARS-CoV-2 genomes. The G4 structure was targeted using FDA-approved drugs that can bind G4s - Chlorpromazine (CPZ) and Prochlorperazine (PCZ). We found significant inhibition in lung pathology and lung viral load of SARS-CoV-2 challenged hamsters when treated with CPZ, PCZ that was comparable to the widely used antiviral drug Remdesivir. In support, in vitro G4 binding, inhibition of reverse transcription from RNA isolated from COVID-infected humans, and attenuated viral replication and infectivity in Vero cell cultures were clear in case of both CPZ/PCZ. Apart from the wide accessibility of CPZ/PCZ, targeting relatively invariant nucleic acid structures poses an attractive strategy against fast mutating viruses like SARS-CoV-2.

molecular biology↗
bioRxiv2022

Genetic epidemiology of human neutrophil antigen variants suggest significant global variability

Human neutrophil antigens possess significant clinical implications especially in the fields of transfusion and transplantation medicine. Efforts to estimate the prevalence of genetic variations underpinning the antigenic expression are emerging. However, there lacks a precise capture of the global frequency profiles. Our article emphasizes the potential utility of maintaining an organized online repository of evidence on neutrophil antigen associated genetic variants from published literature and reports. This in our opinion, is an emerging area and would significantly benefit from the awareness and understanding of population-level diversities.

genomics↗
bioRxiv2021

Comprehensive assessment of Indian variations in the druggable kinome landscape highlights distinct insights at the sequence, structure and pharmacogenomic stratum

India confines more than 17% of the worlds population and has a diverse genetic makeup with several clinically relevant rare mutations belonging to many sub-group which are undervalued in global sequencing datasets like the 1000 Genome data (1KG) containing limited samples for Indian ethnicity. Such databases are critical for the pharmaceutical and drug development industry where the diversity plays a crucial role in identifying genetic disposition towards adverse drug reactions. A qualitative and comparative sequence and structural study utilizing variant information present in the recently published, largest curated Indian genome database (IndiGen) and the 1000 Genome data was performed for variants belonging to the kinase coding genes,the second most targeted group of drug targets. The sequence level analysis identified similarities and differences among different populations based on the nsSNVs and amino acid exchange frequencies whereas comparative structural analysis of IndiGen variants was performed with pathogenic variants reported in UniProtKB Humsavar data. The influence of these variations on structural features of the protein, such as structural stability, solvent accessibility, hydrophobicity, and the hydrogen-bond network were investigated. In-silico screening of the known drugs to these Indian variation-containing proteins reveal critical differences imparted in the strength of binding due to the variations present in the Indian population. In conclusion, this study constitutes a comprehensive investigation into the understanding of common variations present in the second largest population in the world, and investigating its implications in the sequence, structural and pharmacogenomic landscape. The preliminary investigation reported in this paper, supporting the screening and detection of ADRs specific to the Indian population could aid in the development of techniques for pre-clinical and post-market screening of drug-related adverse events in the Indian population.

genomics↗
bioRxiv2021

A genome-wide circular RNA transcriptome in Rat

BackgroundCircular RNAs are a novel class of non-coding RNAs that backsplice from 5 donor site and 3 acceptor site to form a circular structure. A number of circRNAs have been discovered in model organisms including human, mouse, Drosophila, among other organisms. There are a few candidate-based studies on circular RNAs in rat, a well studied model organism. The availability of a recent dataset of transcriptomes encompassing 11 tissues, 4 developmental stages and 2 genders motivated us to explore the landscape of circular RNAs in the organism. MethodologyIn order to understand the difference among different pipelines, we have used the same bodymap RNA sequencing dataset. A number of pipelines have been published to identify the backsplice junctions for the discovery of circRNAs but studies comparing these tools have suggested that a combination of tools would be a better approach to identify high-confidence circular RNAs. We employed 5 different combinations of tools including tophat_CIRCexplorer2, segemehl_CIRCexplorer2, star_CIRCexplorer, Bowtie2_findcirc and Bowtie2_findcirc (noHisat2) to identify circular RNAs from the dataset. ResultsOur analysis identified a number of tissue-specific, developmental stage specific and gender specific circular RNAs. We further independently validated 16 circRNA junctions out of 24 selected candidates in 5 tissue samples. We additionally estimated the quantitative expression of 5 circRNA candidates using real-time PCR and our analysis suggests 3 candidates as tissue-enriched ConclusionThis study is one of the most comprehensive studies that provides a circular RNA transcriptome as well as to understand the difference among different computational pipelines in Rat.

molecular biology↗
bioRxiv2021

ESC - a comprehensive resource for SARS-CoV-2 immune escape variants

Ever since the breakout of COVID-19 disease, ceaseless genomic research to inspect the epidemiology and evolution of the pathogen has been undertaken globally. Large scale viral genome sequencing and analysis have uncovered the functional impact of numerous genetic variants in disease pathogenesis and transmission. Emerging evidence of mutations in spike protein domains escaping antibody neutralization is reported. We have built a database with precise collation of manually curated variants in SARS-CoV-2 from literature with potential escape mechanisms from a range of neutralizing antibodies. This comprehensive repository encompasses a total of 5258 variants accounting for 2068 unique variants tested against 230 antibodies, patient convalescent plasma and vaccine breakthrough events. This resource enables the user to gain access to an extensive annotation of SARS-CoV-2 escape variants which would contribute to exploring and understanding the underlying mechanisms of immune response against the pathogen. The resource is available at http://clingen.igib.res.in/esc/ GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/431922v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@12bd86forg.highwire.dtl.DTLVardef@18e7279org.highwire.dtl.DTLVardef@fd97f8org.highwire.dtl.DTLVardef@104434b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗
bioRxiv2021

BGvar - a comprehensive resource for blood group immunogenetics

BackgroundBlood groups form the basis of effective and safe blood transfusion. There are about 41 well recognized human blood group systems presently known. Blood groups are molecularly determined by the presence of specific antigens on the red blood cells and are genetically determined and inherited following Mendelian principles. The lack of a comprehensive, relevant, manually compiled and genome-ready dataset of red cell antigens limited the widespread application of genomic technologies to characterise and interpret the blood group complement of an individual from genomic datasets. Materials and MethodsA range of public datasets were used to systematically annotate the variation compendium for its functionality and allele frequencies across global populations. Details on phenotype or relevant clinical importance were collated from reported literature evidence. ResultsWe have compiled the Blood Group Associated Genomic Variant Resource (BGvar), a manually curated online resource comprising all known human blood group related allelic variants including a total of 1672 ISBT approved alleles and 1552 alleles predicted and curated from literature reports. This repository includes 1606 Single Nucleotide Variations (SNVs), 270 Insertions, Deletions (InDels) and Duplications and about 1310 combination mutations corresponding to 41 human blood group systems and 2 transcription factors. This compendium also encompasses gene fusion and rearrangement events occurring in human blood group genes. ConclusionTo the best of our knowledge, BGvar is a comprehensive and a user friendly resource with most relevant collation of blood group alleles in humans. BGvar is accessible online at URL: http://clingen.igib.res.in/bgvar/

genomics↗
bioRxiv2021

Insights from Genomes and Genetic Epidemiology of SARS-CoV-2 isolates from the state of Andhra Pradesh

Coronavirus disease (COVID-19) emerged from a city in China and has now spread as a global pandemic affecting millions of individuals. The causative agent, SARS-CoV-2 is being extensively studied in terms of its genetic epidemiology using genomic approaches. Andhra Pradesh is one of the major states of India with the third-largest number of COVID-19 cases with limited understanding of its genetic epidemiology. In this study, we have sequenced 293 SARS-CoV-2 genome isolates from Andhra Pradesh with a mean coverage of 13,324X. We identified 564 high-quality SARS-CoV-2 variants, out of which 15 are novel. A total of 18 variants mapped to RT-PCR primer/probe sites, and 4 variants are known to be associated with an increase in infectivity. Phylogenetic analysis of the genomes revealed the circulating SARS-CoV-2 in Andhra Pradesh majorly clustered under the clade A2a (94%), while 6% fall under the I/A3i clade, a clade previously defined to be present in large numbers in India. To the best of our knowledge, this is the most comprehensive genetic epidemiological analysis performed for the state of Andhra Pradesh.

genomics↗
bioRxiv2020

Initial insights into the genetic epidemiology of SARS-CoV-2 isolates from Kerala suggest local spread from limited introductions

Coronavirus disease 2019 (COVID-19) rapidly spread from a city in China to almost every country in the world, affecting millions of individuals. Genomic approaches have been extensively used to understand the evolution and epidemiology of SARS-CoV-2 across the world. Kerala is a unique state in India well connected with the rest of the world through a large number of expatriates, trade, and tourism. The first case of COVID-19 in India was reported in Kerala in January 2020, during the initial days of the pandemic. The rapid increase in the COVID-19 cases in the state of Kerala has necessitated the understanding of the genetic epidemiology of circulating virus, evolution, and mutations in SARS-CoV-2. We sequenced a total of 200 samples from patients at a tertiary hospital in Kerala using COVIDSeq protocol at a mean coverage of 7,755X. The analysis identified 166 unique high-quality variants encompassing 4 novel variants and 89 new variants identified for the first time in SARS-CoV-2 samples isolated from India. Phylogenetic and haplotype analysis revealed that the circulating population of the virus was dominated (94.6% of genomes) by three distinct introductions followed by local spread, apart from identifying polytomies suggesting recent outbreaks. The genomes formed a monophyletic distribution exclusively mapping to the A2a clade. Further analysis of the functional variants revealed two variants in the S gene of the virus reportedly associated with increased infectivity and 5 variants that mapped to five primer/probe binding sites that could potentially compromise the efficacy of RT-PCR detection. To the best of our knowledge, this is the first and most comprehensive report of genetic epidemiology and evolution of SARS-CoV-2 isolates from Kerala.

genomics↗
bioRxiv2020

Analysis of the potential impact of genomic variants in SARS-CoV-2 genomes from India on molecular diagnostic assays

An isolated epidemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus Diseases (COVID-19) originating in Wuhan, China has now rapidly emerged into a global pandemic affecting millions of people worldwide. Molecular detection of SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) forms the mainstay in screening, diagnosis and epidemiology of disease. The virus has been evolving through base substitutions. The recent availability of genomes of SARS-CoV-2 isolates from different countries including India motivated us to assess the presence and potential impact of variations in target sites for the oligonucleotide primers and probes used in molecular diagnosis. We catalogued a total of 132 primers or probes sequences from the literature and the public domain. Our analysis revealed a total of 125 unique genetic variants in 80 either primers or probes binding sites. A total of 13 unique variants had allele frequency of [≥] 1% in Indian SARS-CoV-2 genomes mapped to the primers or probes binding sites. A total of 15 primers or probes binding sites had cumulative variant frequency of [≥] 1% in the SARS-CoV-2 genomes. These included primers or probes sites which are widely used in India and across the world for molecular diagnosis as well as approved by national and international agencies. This highlights the need for sequencing genomes of emerging pathogens to make evidence based policies for development and approval of diagnostics. To the best of our knowledge, ours is the most comprehensive analysis of genomic variants in genomes of SARS-CoV-2 isolates from India and their potential impact on efficacy of molecular diagnostics.

genomics↗