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

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.

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 SAMD12 gene.

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 SAMD12 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 SAMD12 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.

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

Aim: 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. Materials & methods: 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. Results: 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. CYP3A4, ABCB1 and ALB are the most shared pharmacogenes. Fifteen COVID-19 therapeutics were predicted as likely drug-drug interaction candidates when used with four CYP inhibitor drugs. Conclusion: Our findings provide actionable insights for future validation studies and improved clinical decisions for COVID-19 therapy in Indians.

Genetic epidemiology of autoinflammatory disease variants in Indian population from 1029 whole genomes.

BACKGROUND: Autoinflammatory disorders are the group of inherited inflammatory disorders caused due to the genetic defect in the genes that regulates innate immune systems. These have been clinically characterized based on the duration and occurrence of unprovoked fever, skin rash, and patient's ancestry. There are several autoinflammatory disorders that are found to be prevalent in a specific population and whose disease genetic epidemiology within the population has been well understood. However, India has a limited number of genetic studies reported for autoinflammatory disorders till date. The whole genome sequencing and analysis of 1029 Indian individuals performed under the IndiGen project persuaded us to perform the genetic epidemiology of the autoinflammatory disorders in India. RESULTS: We have systematically annotated the genetic variants of 56 genes implicated in autoinflammatory disorder. These genetic variants were reclassified into five categories (i.e., pathogenic, likely pathogenic, benign, likely benign, and variant of uncertain significance (VUS)) according to the American College of Medical Genetics and Association of Molecular pathology (ACMG-AMP) guidelines. Our analysis revealed 20 pathogenic and likely pathogenic variants with significant differences in the allele frequency compared with the global population. We also found six causal founder variants in the IndiGen dataset belonging to different ancestry. We have performed haplotype prediction analysis for founder mutations haplotype that reveals the admixture of the South Asian population with other populations. The cumulative carrier frequency of the autoinflammatory disorder in India was found to be 3.5% which is much higher than reported. CONCLUSION: With such frequency in the Indian population, there is a great need for awareness among clinicians as well as the general public regarding the autoinflammatory disorder. To the best of our knowledge, this is the first and most comprehensive population scale genetic epidemiological study being reported from India.

Phenylhydrazine hydrochloride induced dosedependent embryo cytotoxicity in zebrafish.

Phenylhydrazine hydrochloride (PHZ) is a chemical compound. PHZ and its derivatives were used firstly as antipyretics, treatment of blood disorders such as polycythaemia Vera. For many years phenyl hydrazine was used for experimental induction of anaemia in animal models. However, this compound is reported to cause damage to red blood cells, potentially resulting in anaemia and consequential secondary involvement of other tissues, such as the spleen and liver. Recent studies suggest that PHZ cause genotoxicity in mice models. The aim of our study is to study the effect of PHZ in embryonic and larval stage of zebra fish model. Zebra fish embryos and larvae were used in this study. Working concentration prepared from 0.05 gm of PHZ stock solution. The embryos and larvae were exposed to different concentrations of PHZ (0.1, 0.3, 0.5, 0.7 0.9, 1.0, 3.0, 5.0, 7.0 9.0 and 10.0 µg/mL) and (0.1, 0.3, 0.5, 0.7, 0.9 and 1.0 µg/mL) respectively. Survival rate, mortality rate, hatching rate and phenotypic anomalies were studied in developing embryos. Heart rate and apoptosis were evaluated to assess the PHZ toxicity in larval stage of Zebra fish. Statistical analysis was performed by Pearson correlation and P values < 0.05 were considered statistically significant. The LC50of PHZ in embryo and larvae was found to be 0.7µg/mL. PHZ treated embryos showed that survival rate was decreased during 72hpf. In the case of mortality, 0.7 µg/mL and above concentration mortality rate was significantly increased between 48 and 72 hpf and the none embryos survived after 72 hpf. We observed delayed hatching rate in treated embryos when compared to control embryos. 0.5 µg/mL treated larvae showed significantly (p<0.05) decreased heart rate 20% at 96 hrs. Phenotype anomalies such as enlarged yolk sac, yolk sac split, pericardial edema, notochord anomaly appeared at higher concentration of PHZ treated embryos. Acridine orange fluorescence staining revealed that high apoptotic cells were detected at caudal fin region of larvae on day 3 at a concentration of 0.7µg/mL treated group. Our study suggests that PHZ causes multiple phenotypic abnormalities and toxicity on zebrafish embryos and larvae with respect of dose and time dependent manner.