Publications by authors named "Vinod Scaria"

176 Publications

A genome-wide circular RNA transcriptome in rat.

Biol Methods Protoc 2021 7;6(1):bpab016. Epub 2021 Sep 7.

GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), Mathura Road, Delhi 110025, India.

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that back-splice from 5' donor site and 3' acceptor sites to form a circular structure. A number of circRNAs have been discovered in model organisms including human, mouse, , among other organisms. There are a few candidate-based studies on circRNAs in rat, a well-studied model organism as well. A number of pipelines have been published to identify the back splice 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 circRNAs. The availability of a recent dataset of transcriptomes encompassing 11 tissues, 4 developmental stages, and 2 genders motivated us to explore the landscape of circRNAs in the organism in this context. In order to understand the difference among different pipelines, we employed five different combinations of tools to identify circular RNAs from the dataset. We compared the results of the different combination of tools/pipelines with respect to alignment, total number of circRNAs identified and read-coverage. In addition, we identified tissue-specific, development-stage specific and gender-specific circRNAs and further independently validated 16 circRNA junctions out of 24 selected candidates in 5 tissue samples and estimated the quantitative expression of five circRNA candidates using real-time polymerase chain reaction and our analysis suggests three candidates as tissue-enriched. This study is one of the most comprehensive studies which provides a map of circRNAs transcriptome as well as to understand the difference among different computational pipelines in rat.
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http://dx.doi.org/10.1093/biomethods/bpab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435660PMC
September 2021

X-Linked Agammaglobulinemia and COVID-19: Two Case Reports and Review of Literature.

Pediatr Allergy Immunol Pulmonol 2021 09;34(3):115-118

Department of Pediatrics, FPID Regional Diagnostic Centre, Government Medical College Kozhikode, Kozhikode, India.

The Centers for Disease Control and Prevention (CDC) has listed primary immunodeficiency disorders as being predisposed to severe coronavirus disease 2019 (COVID-19). However, patients affected with X-linked agammaglobulinemia (XLA) have shown contrary results. In this study, we present 2 boys in late adolescence from south India with XLA who were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as a review of cases reported in the literature. Two patients with XLA had been diagnosed late and were started on regular immunoglobulin prophylaxis only during adolescence. Both of them had developed bronchiectasis, an irreversible suppurative lung disease. However, both patients made an uneventful recovery without the need for artificial ventilation or convalescent plasma. Successful outcomes of patients with XLA and COVID-19, except for delayed recovery, from our experience and from global reports are intriguing and the role of B cell depletion is being studied as well. Further research and clinical experience are necessary to fully elucidate the reasons for these observations.
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http://dx.doi.org/10.1089/ped.2021.0002DOI Listing
September 2021

An optimized, amplicon-based approach for sequencing of SARS-CoV-2 from patient samples using COVIDSeq assay on Illumina MiSeq sequencing platforms.

STAR Protoc 2021 Sep 2;2(3):100755. Epub 2021 Aug 2.

CSIR- Institute of Genomics and Integrative Biology (CSIR-IGIB), Mathura Road, Delhi, 110025, India.

Sequencing of SARS-CoV-2 genomes is crucial for understanding the genetic epidemiology of the COVID-19 pandemic. It is also critical for understanding the evolution of the virus and also for the rapid development of diagnostic tools. The present protocol is a modification of the Illumina COVIDSeq test. We describe an amplicon-based next-generation sequencing approach with short turnaround time, adapted for bench-top sequencers like MiSeq, iSeq, and MiniSeq. For complete details on the use and execution of this protocol, please refer to Bhoyar et al. (2021).
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http://dx.doi.org/10.1016/j.xpro.2021.100755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326003PMC
September 2021

MUSTARD-a comprehensive resource of mutation-specific therapies in cancer.

Database (Oxford) 2021 07;2021

Department of Genome Informatics, CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), Mathura Road, Delhi 110025, India.

The steady increase in global cancer burden has fuelled the development of several modes of treatment for the disease. In the presence of an actionable mutation, targeted therapies offer a method to selectively attack cancer cells, increasing overall efficacy and reducing harmful side effects. However, different drug molecules are in different stages of development, with new molecules obtaining approvals from regulatory agencies each year. To augment clinical impact, it is important that this information reaches clinicians, patients and researchers swiftly and in a structured, well-annotated manner. To this end, we have developed Mutation-Specific Therapies Resource and Database in Cancer (MUSTARD), a database that is designed to be a centralized resource with diverse information such as cancer subtype, associated mutations, therapy offered and its effect observed, along with links to external resources for a more comprehensive annotation. In its current version, MUSTARD comprises over 2105 unique entries, including associations between 418 unique drug therapies, 189 cancer subtypes and 167 genes curated and annotated from over 862 different publications. To the best of our knowledge, it is the only resource that offers comprehensive information on mutation-specific, gene fusions and overexpressed gene-targeted therapies for cancer. Database URL: http://clingen.igib.res.in/mustard/.
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http://dx.doi.org/10.1093/database/baab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312254PMC
July 2021

Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia.

PLoS One 2021 12;16(7):e0254407. Epub 2021 Jul 12.

CSIR-Institute of Genomics and Integrative Biology, New Delhi, Delhi, India.

X-linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals. We performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed. All patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. We could not identify any single nucleotide variants or small insertion/ deletions from the WES dataset that correlates with the clinical feature of the patient. Structural variant analysis through WGS data identifies a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed a South Asian ancestry. WGS led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling genetic counselling and prenatal diagnosis in the family.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254407PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274882PMC
July 2021

RNA sequencing reveals potential interacting networks between the altered transcriptome and ncRNome in the skeletal muscle of diabetic mice.

Biosci Rep 2021 Jul;41(7)

CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India.

For a global epidemic like Type 2 diabetes mellitus (T2DM), while impaired gene regulation is identified as a primary cause of aberrant cellular physiology; in the past few years, non-coding RNAs (ncRNAs) have emerged as important regulators of cellular metabolism. However, there are no reports of comprehensive in-depth cross-talk between these regulatory elements and the potential consequences in the skeletal muscle during diabetes. Here, using RNA sequencing, we identified 465 mRNAs and 12 long non-coding RNAs (lncRNAs), to be differentially regulated in the skeletal muscle of diabetic mice and pathway enrichment analysis of these altered transcripts revealed pathways of insulin, FOXO and AMP-activated protein kinase (AMPK) signaling to be majorly over-represented. Construction of networks showed that these pathways significantly interact with each other that might underlie aberrant skeletal muscle metabolism during diabetes. Gene-gene interaction network depicted strong interactions among several differentially expressed genes (DEGs) namely, Prkab2, Irs1, Pfkfb3, Socs2 etc. Seven altered lncRNAs depicted multiple interactions with the altered transcripts, suggesting possible regulatory roles of these lncRNAs. Inverse patterns of expression were observed between several of the deregulated microRNAs (miRNAs) and the differentially expressed transcripts in the tissues. Towards validation, overexpression of miR-381-3p and miR-539-5p in skeletal muscle C2C12 cells significantly decreased the transcript levels of their targets, Nfkbia, Pik3r1 and Pi3kr1, Cdkn2d, respectively. Collectively, the findings provide a comprehensive understanding of the interactions and cross-talk between the ncRNome and transcriptome in the skeletal muscle during diabetes and put forth potential therapeutic options for improving insulin sensitivity.
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http://dx.doi.org/10.1042/BSR20210495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276098PMC
July 2021

LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy.

EMBO J 2021 Aug 28;40(15):e107134. Epub 2021 Jun 28.

CSIR-Institute of Genomics and Integrative Biology, Delhi, India.

Long non-coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial-associated lncRNA (VEAL2) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish (veal2 ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta-b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2. Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2-mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA-mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability.
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http://dx.doi.org/10.15252/embj.2020107134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327952PMC
August 2021

Pharmacogenomic landscape of COVID-19 therapies from Indian population genomes.

Pharmacogenomics 2021 07 18;22(10):603-618. Epub 2021 Jun 18.

TVMC, Tirunelveli Medical College, Tirunelveli, Tamil Nadu, 627011, India.

Numerous drugs are being widely prescribed for COVID-19 treatment without any direct evidence for the drug safety/efficacy in patients across diverse ethnic populations. We analyzed whole genomes of 1029 Indian individuals (IndiGen) to understand the extent of drug-gene (pharmacogenetic), drug-drug and drug-drug-gene interactions associated with COVID-19 therapy in the Indian population. We identified 30 clinically significant pharmacogenetic variants and 73 predicted deleterious pharmacogenetic variants. COVID-19-associated pharmacogenes were substantially overlapped with those of metabolic disorder therapeutics. , and are the most shared pharmacogenes. Fifteen COVID-19 therapeutics were predicted as likely drug-drug interaction candidates when used with four inhibitor drugs. Our findings provide actionable insights for future validation studies and improved clinical decisions for COVID-19 therapy in Indians.
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http://dx.doi.org/10.2217/pgs-2021-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216321PMC
July 2021

Computational Analysis and Phylogenetic Clustering of SARS-CoV-2 Genomes.

Bio Protoc 2021 Apr 20;11(8):e3999. Epub 2021 Apr 20.

CSIR Institute of Genomics and Integrative Biology, Mathura Road, Delhi, India.

COVID-19, the disease caused by the novel SARS-CoV-2 coronavirus, originated as an isolated outbreak in the Hubei province of China but soon created a global pandemic and is now a major threat to healthcare systems worldwide. Following the rapid human-to-human transmission of the infection, institutes around the world have made efforts to generate genome sequence data for the virus. With thousands of genome sequences for SARS-CoV-2 now available in the public domain, it is possible to analyze the sequences and gain a deeper understanding of the disease, its origin, and its epidemiology. Phylogenetic analysis is a potentially powerful tool for tracking the transmission pattern of the virus with a view to aiding identification of potential interventions. Toward this goal, we have created a comprehensive protocol for the analysis and phylogenetic clustering of SARS-CoV-2 genomes using Nextstrain, a powerful open-source tool for the real-time interactive visualization of genome sequencing data. Approaches to focus the phylogenetic clustering analysis on a particular region of interest are detailed in this protocol.
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http://dx.doi.org/10.21769/BioProtoc.3999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160537PMC
April 2021

Do monogenic inborn errors of immunity cause susceptibility to severe COVID-19?

J Clin Invest 2021 07;131(14)

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

The SARS-CoV-2 virus, which causes COVID-19, has been associated globally with substantial morbidity and mortality. Numerous reports over the past year have described the clinical and immunological profiles of COVID-19 patients, and while some trends have emerged for risk stratification, they do not provide a complete picture. Therefore, efforts are ongoing to identify genetic susceptibility factors of severe disease. In this issue of the JCI, Povysil et al. performed a large, multiple-country study, sequencing genomes from patients with mild and severe COVID-19, along with population controls. Contrary to previous reports, the authors observed no enrichment of predicted loss-of-function variants in genes in the type I interferon pathway, which might predispose to severe disease. These studies suggest that more evidence is needed to substantiate the hypothesis for a genetic immune predisposition to severe COVID-19, and highlights the importance of considering experimental design when implicating a monogenic basis for severe disease.
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http://dx.doi.org/10.1172/JCI149459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279660PMC
July 2021

Genetic Landscape of Rare Autoinflammatory Disease Variants in Qatar and Middle Eastern Populations Through the Integration of Whole-Genome and Exome Datasets.

Front Genet 2021 13;12:631340. Epub 2021 May 13.

Center for Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Rare monogenic autoinflammatory diseases are a group of recurrent inflammatory genetic disorders caused due to genetic variants in over 37 genes. While a number of these disorders have been identified and reported in Middle Eastern populations, the carrier frequency of these genetic variants in the Middle Eastern population is not known. The availability of whole-genome and exome datasets of over 1,000 individuals from Qatar persuaded us to explore the genetic epidemiology of rare autoinflammatory genetic variants. We have systematically analyzed genetic variants in genome-scale datasets from Qatar with a compendium of variants associated with autoinflammatory diseases. The variants were systematically reclassified according to the American College of Medical Genetics and Genomics guidelines for interpretation of variant pathogenicity. Our analysis identified seven pathogenic and likely pathogenic variants with significant differences in their allele frequencies compared to the global population. The cumulative carrier frequency of these variants was found to be 2.58%. Furthermore, our analysis revealed that five genes, implicated in rare autoinflammatory diseases, were under natural selection. To the best of our knowledge, this is the first and most comprehensive study on the population-scale analysis and genetic epidemiology of genetic variants that cause rare autoinflammatory disease in Middle Eastern populations.
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http://dx.doi.org/10.3389/fgene.2021.631340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155677PMC
May 2021

Genome and transcriptome analysis of the mealybug Maconellicoccus hirsutus: Correlation with its unique phenotypes.

Genomics 2021 Jul 20;113(4):2483-2494. Epub 2021 May 20.

Dr.B.R.Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India. Electronic address:

Mealybugs are aggressive pests with world-wide distribution and are suitable for the study of different phenomena like genomic imprinting and epigenetics. Genomic approaches facilitate these studies in absence of robust genetics in this system. We sequenced, de novo assembled, annotated Maconellicoccus hirsutus genome. We carried out comparative genomics it with four mealybug and eight other insect species, to identify expanded, specific and contracted gene classes that relate to pesticide and desiccation resistance. We identified horizontally transferred genes adding to the mutualism between the mealybug and its endosymbionts. Male and female transcriptome analysis indicates differential expression of metabolic pathway genes correlating with their physiology and the genes for sexual dimorphism. The significantly lower expression of endosymbiont genes in males relates to the depletion of endosymbionts in males during development.
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http://dx.doi.org/10.1016/j.ygeno.2021.05.014DOI Listing
July 2021

Initial Insights Into the Genetic Epidemiology of SARS-CoV-2 Isolates From Kerala Suggest Local Spread From Limited Introductions.

Front Genet 2021 17;12:630542. Epub 2021 Mar 17.

Council of Scientific and Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, New Delhi, India.

Coronavirus disease 2019 (COVID-19) rapidly spread from a city in China to almost every country in the world, affecting millions of individuals. The rapid increase in the COVID-19 cases in the state of Kerala in India has necessitated the understanding of SARS-CoV-2 genetic epidemiology. We sequenced 200 samples from patients in Kerala using COVIDSeq protocol amplicon-based sequencing. The analysis identified 166 high-quality single-nucleotide variants encompassing four novel variants and 89 new variants in the Indian isolated SARS-CoV-2. Phylogenetic and haplotype analysis revealed that the virus was dominated by three distinct introductions followed by local spread suggesting recent outbreaks and that it belongs to the A2a clade. Further analysis of the functional variants revealed that two variants in the gene associated with increased infectivity and five variants mapped in primer binding sites affect the efficacy of RT-PCR. To the best of our knowledge, this is the first and most comprehensive report of SARS-CoV-2 genetic epidemiology from Kerala.
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http://dx.doi.org/10.3389/fgene.2021.630542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010186PMC
March 2021

Functional long non-coding and circular RNAs in zebrafish.

Brief Funct Genomics 2021 Mar 23. Epub 2021 Mar 23.

The utility of model organisms to understand the function of a novel transcript/genes has allowed us to delineate their molecular mechanisms in maintaining cellular homeostasis. Organisms such as zebrafish have contributed a lot in the field of developmental and disease biology. Attributable to advancement and deep transcriptomics, many new transcript isoforms and non-coding RNAs such as long noncoding RNA (lncRNA) and circular RNAs (circRNAs) have been identified and cataloged in multiple databases and many more are yet to be identified. Various methods and tools have been utilized to identify lncRNAs/circRNAs in zebrafish using deep sequencing of transcriptomes as templates. Functional analysis of a few candidates such as tie1-AS, ECAL1 and CDR1as in zebrafish provides a prospective outline to approach other known or novel lncRNA/circRNA. New genetic alteration tools like TALENS and CRISPRs have helped in probing for the molecular function of lncRNA/circRNA in zebrafish. Further latest improvements in experimental and computational techniques offer the identification of lncRNA/circRNA counterparts in humans and zebrafish thereby allowing easy modeling and analysis of function at cellular level.
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http://dx.doi.org/10.1093/bfgp/elab014DOI Listing
March 2021

Founder variants and population genomes-Toward precision medicine.

Adv Genet 2021 18;107:121-152. Epub 2021 Feb 18.

CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India. Electronic address:

Human migration and community specific cultural practices have contributed to founder events and enrichment of the variants associated with genetic diseases. While many founder events in isolated populations have remained uncharacterized, the application of genomics in clinical settings as well as for population scale studies in the recent years have provided an unprecedented push towards identification of founder variants associated with human health and disease. The discovery and characterization of founder variants could have far reaching implications not only in understanding the history or genealogy of the disease, but also in implementing evidence based policies and genetic testing frameworks. This further enables precise diagnosis and prevention in an attempt towards precision medicine. This review provides an overview of founder variants along with methods and resources cataloging them. We have also discussed the public health implications and examples of prevalent disease associated founder variants in specific populations.
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http://dx.doi.org/10.1016/bs.adgen.2020.11.004DOI Listing
August 2021

Hematopoietic Stem Cell Transplantation for Children With Inborn Errors of Immunity.

Indian Pediatr 2021 02;58(2):179-180

CSIR Institute of Genomics and Integragative Biology (CSIR-IGIB), Delhi, India.

This is a retrospective analysis of clinical characteristics of children with inborn errors of immunity who underwent hematopoietic stem cell transplant (HSCT). Although the mean age at diagnosis was 24.4 months, it was 51.9 months at HSCT. There is an urgent need to improve awareness, expand donor registries and initiate newborn screening for inborn errors or immunity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926070PMC
February 2021

High throughput detection and genetic epidemiology of SARS-CoV-2 using COVIDSeq next-generation sequencing.

PLoS One 2021 17;16(2):e0247115. Epub 2021 Feb 17.

Center for Advanced Research in Imaging, Neuroscience & Genomics, New Delhi, Delhi, India.

The rapid emergence of coronavirus disease 2019 (COVID-19) as a global pandemic affecting millions of individuals globally has necessitated sensitive and high-throughput approaches for the diagnosis, surveillance, and determining the genetic epidemiology of SARS-CoV-2. In the present study, we used the COVIDSeq protocol, which involves multiplex-PCR, barcoding, and sequencing of samples for high-throughput detection and deciphering the genetic epidemiology of SARS-CoV-2. We used the approach on 752 clinical samples in duplicates, amounting to a total of 1536 samples which could be sequenced on a single S4 sequencing flow cell on NovaSeq 6000. Our analysis suggests a high concordance between technical duplicates and a high concordance of detection of SARS-CoV-2 between the COVIDSeq as well as RT-PCR approaches. An in-depth analysis revealed a total of six samples in which COVIDSeq detected SARS-CoV-2 in high confidence which were negative in RT-PCR. Additionally, the assay could detect SARS-CoV-2 in 21 samples and 16 samples which were classified inconclusive and pan-sarbeco positive respectively suggesting that COVIDSeq could be used as a confirmatory test. The sequencing approach also enabled insights into the evolution and genetic epidemiology of the SARS-CoV-2 samples. The samples were classified into a total of 3 clades. This study reports two lineages B.1.112 and B.1.99 for the first time in India. This study also revealed 1,143 unique single nucleotide variants and added a total of 73 novel variants identified for the first time. To the best of our knowledge, this is the first report of the COVIDSeq approach for detection and genetic epidemiology of SARS-CoV-2. Our analysis suggests that COVIDSeq could be a potential high sensitivity assay for the detection of SARS-CoV-2, with an additional advantage of enabling the genetic epidemiology of SARS-CoV-2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247115PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888613PMC
March 2021

Chronic systemic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 05 12;1866(5):158905. Epub 2021 Feb 12.

CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address:

Inflammation is a constant in Non-Alcoholic Fatty Liver Disease (NAFLD), although their relationship is unclear. In a transgenic zebrafish system with chronic systemic overexpression of human IL6 (IL6-OE) we show that inflammation can cause intra-hepatic accumulation of triglycerides. Transcriptomics and proteomics analysis of the IL6-OE liver revealed a deregulation of glycolysis/gluconeogenesis pathway, especially a striking down regulation of the glycolytic enzyme aldolase b. Metabolomics analysis by mass spectrometry showed accumulation of hexose monophosphates and their derivatives, which can act as precursors for triglyceride synthesis. Our results suggest that IL6-driven repression of glycolysis/gluconeogenesis, specifically aldolase b, may be a novel mechanism for fatty liver. This mechanism may be relevant for NAFLD in lean individuals, an emerging class of NAFLD prevalent more in Asian Indian populations.
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http://dx.doi.org/10.1016/j.bbalip.2021.158905DOI Listing
May 2021

Genomic analysis of patients in a South Indian Community with autosomal dominant cortical tremor, myoclonus and epilepsy suggests a founder repeat expansion mutation in the gene.

Brain Commun 2021 19;3(1):fcaa214. Epub 2020 Dec 19.

Multidisciplinary Research Unit, Tirunelveli Medical College, Tirunelveli 627011, Tamil Nadu, India.

Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy is a non-progressive disorder characterized by distal tremors. Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported globally with different genetic predispositions of autosomal dominant inheritance with a high degree of penetrance. In south India, Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported in a large cohort of 48 families, in which the genetic defect was not identified. This report pertains to the whole-genome analysis of four individuals followed by repeat-primed PCR for 102 patients from a familial cohort of 325 individuals. All the patients underwent extensive clinical evaluation including neuropsychological examinations. The whole-genome sequencing was done for two affected and two unaffected individuals, belonging to two different families. The whole-genome sequencing analysis revealed the repeat expansion of TTTTA and TTTCA in intron 4 of the gene located on chromosome 8 in the patients affected with Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy, whereas the unaffected family members were negative for the similar expansion. Further, the repeat-primed PCR analysis of 102 patients showed the expansion of the TTTCA repeats in the intron 4 of gene. All patients registered for this study belong to a single community called "Nadar" whose nativity is confined to the southern districts of India, with reported unique genetic characteristics. This is the largest and most comprehensive single report on clinically and genetically characterized Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy patients belonging to a unique ethnic group worldwide.
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http://dx.doi.org/10.1093/braincomms/fcaa214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811760PMC
December 2020

DALIA- a comprehensive resource of Disease Alleles in Arab population.

PLoS One 2021 13;16(1):e0244567. Epub 2021 Jan 13.

CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi, India.

The Arab population encompasses over 420 million people characterized by genetic admixture and a consequent rich genetic diversity. A number of genetic diseases have been reported for the first time from the population. Additionally a high prevalence of some genetic diseases including autosomal recessive disorders such as hemoglobinopathies and familial mediterranean fever have been found in the population and across the region. There is a paucity of databases cataloguing genetic variants of clinical relevance from the population. The availability of such a catalog could have implications in precise diagnosis, genetic epidemiology and prevention of disease. To fill in the gap, we have compiled DALIA, a comprehensive compendium of genetic variants reported in literature and implicated in genetic diseases reported from the Arab population. The database aims to act as an effective resource for population-scale and sub-population specific variant analyses, enabling a ready reference aiding clinical interpretation of genetic variants, genetic epidemiology, as well as facilitating rapid screening and a quick reference for evaluating evidence on genetic diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244567PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806169PMC
May 2021

Genome-Wide Computational Analysis and Validation of Potential Long Noncoding RNA-Mediated DNA-DNA-RNA Triplexes in the Human Genome.

Methods Mol Biol 2021 ;2254:61-71

CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi, India.

Long noncoding RNAs are well studied for their regulatory actions through interaction with DNA regulating biological roles of DNA, RNA, or protein. However, direct binding of lncRNA with DNA is rarely demonstrated in experiments. The present protocol explains genome wide computational strategies to choose lncRNAs that can bind directly to the chromatin by forming highly stable DNA-DNA-RNA triplexes. The chapter also focuses on biophysical methods that can be used to validate the computationally derived lncRNA-gene targets in vitro.
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http://dx.doi.org/10.1007/978-1-0716-1158-6_5DOI Listing
March 2021

A Distinct Phylogenetic Cluster of Indian Severe Acute Respiratory Syndrome Coronavirus 2 Isolates.

Open Forum Infect Dis 2020 Nov 18;7(11):ofaa434. Epub 2020 Sep 18.

CSIR Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India.

Background: From an isolated epidemic, coronavirus disease 2019 has now emerged as a global pandemic. The availability of genomes in the public domain after the epidemic provides a unique opportunity to understand the evolution and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus across the globe.

Methods: We performed whole-genome sequencing of 303 Indian isolates, and we analyzed them in the context of publicly available data from India.

Results: We describe a distinct phylogenetic cluster (Clade I/A3i) of SARS-CoV-2 genomes from India, which encompasses 22% of all genomes deposited in the public domain from India. Globally, approximately 2% of genomes, which to date could not be mapped to any distinct known cluster, fall within this clade.

Conclusions: The cluster is characterized by a core set of 4 genetic variants and has a nucleotide substitution rate of 1.1 × 10 variants per site per year, which is lower than the prevalent A2a cluster. Epidemiological assessments suggest that the common ancestor emerged at the end of January 2020 and possibly resulted in an outbreak followed by countrywide spread. To the best of our knowledge, this is the first comprehensive study characterizing this cluster of SARS-CoV-2 in India.
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http://dx.doi.org/10.1093/ofid/ofaa434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543508PMC
November 2020

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

Int J Infect Dis 2021 Jan 9;102:460-462. Epub 2020 Nov 9.

CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), Mathura Road, Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201002, India. Electronic address:

An epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus diseases (C0VID-19) initially reported in Wuhan, China has 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 the disease. Since the virus evolves by accumulating base substitutions, mutations in the viral genome could possibly affect the accuracy of RT-PCR-based detection assays. The recent availability of genomes of SARS-CoV-2 isolates motivated us to assess the presence and potential impact of variations in target sites of the oligonucleotide primers and probes used in molecular diagnosis. We catalogued a total of 132 primer or probe sequences from literature and data available in the public domain. Our analysis revealed that a total of 5862 unique genetic variants mapped to at least one of the 132 primer or probe binding sites in the genome. A total of 29 unique variants were present in ≥ 1% of genomes from at least one of the continents (Asia, Africa, Australia, Europe, North America, and South America) that mapped to 36 unique primers or probes binding sites. Similarly, a total of 27 primer or probe binding sites had cumulative variants frequency of ≥ 1% in the global SARS-CoV-2 genomes. These included primers or probes sites which are used worldwide for molecular diagnosis as well as approved by national and international agencies. We also found 286 SARS-CoV-2 genomic regions with low variability at a continuous stretch of ≥ 20bps that could be potentially used for primer designing. This highlights the need for sequencing genomes of emerging pathogens to enable evidence-based policies for development and approval of diagnostics.
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http://dx.doi.org/10.1016/j.ijid.2020.10.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834429PMC
January 2021

Clericuzio-type poikiloderma with neutropenia in a patient from India.

Am J Med Genet A 2021 01 27;185(1):278-281. Epub 2020 Oct 27.

Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

A 9-year-old boy presented for evaluation of variegated skin pigmentation. Palms and soles revealed honeycombed hyperpigmented hyperkeratosis. Irregular, firm, skin coloured nodules suggestive of cutaneous calcification were present on both elbows. Total leucocyte count and absolute neutrophil count were 3720/mm3 and 420/mm3 respectively. The neutropenia was not cyclical. Systematic analysis of the whole exome data revealed a homozygous mutation in USB1 gene; chr16:g.58043892TA>-[1/1]. A final diagnosis of poikiloderma with neutropenia- Clericuzio type (PNC) was made. Naegeli Franceschetti Jadassohn, dermatopathia pigmentosa reticularis, PNC and dyskeratosis congenita, all can present with overlapping cutaneous manifestations. Subtle clinical details like thickened nails, hyperextensible joints, calcinosis cutis, characteristic facies and a preceding erythematopapular rash strongly favor the diagnosis of PNC. The index case highlights two novel findings: obliterated dermatoglyphics and mucin deposition (features not described hitherto in PNC).
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http://dx.doi.org/10.1002/ajmg.a.61943DOI Listing
January 2021

IndiGenomes: a comprehensive resource of genetic variants from over 1000 Indian genomes.

Nucleic Acids Res 2021 01;49(D1):D1225-D1232

TVMC, Tirunelveli Medical College, Tirunelveli, Tamil Nadu 627011, India.

With the advent of next-generation sequencing, large-scale initiatives for mining whole genomes and exomes have been employed to better understand global or population-level genetic architecture. India encompasses more than 17% of the world population with extensive genetic diversity, but is under-represented in the global sequencing datasets. This gave us the impetus to perform and analyze the whole genome sequencing of 1029 healthy Indian individuals under the pilot phase of the 'IndiGen' program. We generated a compendium of 55,898,122 single allelic genetic variants from geographically distinct Indian genomes and calculated the allele frequency, allele count, allele number, along with the number of heterozygous or homozygous individuals. In the present study, these variants were systematically annotated using publicly available population databases and can be accessed through a browsable online database named as 'IndiGenomes' http://clingen.igib.res.in/indigen/. The IndiGenomes database will help clinicians and researchers in exploring the genetic component underlying medical conditions. Till date, this is the most comprehensive genetic variant resource for the Indian population and is made freely available for academic utility. The resource has also been accessed extensively by the worldwide community since it's launch.
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http://dx.doi.org/10.1093/nar/gkaa923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778947PMC
January 2021

ATP7A Clinical Genetics Resource - A comprehensive clinically annotated database and resource for genetic variants in ATP7A gene.

Comput Struct Biotechnol J 2020 2;18:2347-2356. Epub 2020 Sep 2.

CSIR Institute of Genomics and Integrative Biology, Mathura Road, Delhi 110 025, India.

ATP7A is a critical copper transporter involved in Menkes Disease, Occipital horn Syndrome and X-linked distal spinal muscular atrophy type 3 which are X linked genetic disorders. These are rare diseases and their genetic epidemiology of the diseases is unknown. A number of genetic variants in the genes have been reported in published literature as well as databases, however, understanding the pathogenicity of variants and genetic epidemiology requires the data to be compiled in a unified format. To this end, we systematically compiled genetic variants from published literature and datasets. Each of the variants were systematically evaluated for evidences with respect to their pathogenicity and classified as per the American College of Medical Genetics and the Association of Molecular Pathologists (ACMG-AMP) guidelines into Pathogenic, Likely Pathogenic, Benign, Likely Benign and Variants of Uncertain Significance. Additional integrative analysis of population genomic datasets provides insights into the genetic epidemiology of the disease through estimation of carrier frequencies in global populations. To deliver a mechanistic explanation for the pathogenicity of selected variants, we also performed molecular modeling studies. Our modeling studies concluded that the small structural distortions observed in the local structures of the protein may lead to the destabilization of the global structure. To the best of our knowledge, ATP7A Clinical Genetics Resource is one of the most comprehensive compendium of variants in the gene providing clinically relevant annotations in gene.
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http://dx.doi.org/10.1016/j.csbj.2020.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501406PMC
September 2020
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