Moumita Chaki

The Indian Genome Variation database (IGVdb): A project overview

Indian population, comprising of more than a billion people, consists of 4693 communities with several thousands of endogamous groups, 325 functioning languages and 25 scripts. To address the questions related to ethnic diversity, migrations, founder populations, predisposition to complex disorders or pharmacogenomics, one needs to understand the diversity and relatedness at the genetic level in such a diverse population. In this backdrop, six constituent laboratories of the Council of Scientific and Industrial Research (CSIR), with funding from the Government of India, initiated a network program on predictive medicine using repeats and single nucleotide polymorphisms. The Indian Genome Variation (IGV) consortium aims to provide data on validated SNPs and repeats, both novel and reported, along with gene duplications, in over a thousand genes, in 15,000 individuals drawn from Indian subpopulations. These genes have been selected on the basis of their relevance as functional and positional candidates in many common diseases including genes relevant to pharmacogenomics. This is the first large-scale comprehensive study of the structure of the Indian population with wide-reaching implications. A comprehensive platform for Indian Genome Variation (IGV) data management, analysis and creation of IGVdb portal has also been developed. The samples are being collected following ethical guidelines of Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT), India. This paper reveals the structure of the IGV project highlighting its various aspects like genesis, objectives, strategies for selection of genes, identification of the Indian subpopulations, collection of samples and discovery and validation of genetic markers, data analysis and monitoring as well as the project’s data release policy.Indian population, comprising of more than a billion people, consists of 4693 communities with several thousands of endogamous groups, 325 functioning languages and 25 scripts. To address the questions related to ethnic diversity, migrations, founder populations, predisposition to complex disorders or pharmacogenomics, one needs to understand the diversity and relatedness at the genetic level in such a diverse population. In this backdrop, six constituent laboratories of the Council of Scientific and Industrial Research (CSIR), with funding from the Government of India, initiated a network program on predictive medicine using repeats and single nucleotide polymorphisms. The Indian Genome Variation (IGV) consortium aims to provide data on validated SNPs and repeats, both novel and reported, along with gene duplications, in over a thousand genes, in 15,000 individuals drawn from Indian subpopulations. These genes have been selected on the basis of their relevance as functional and positional candidates in many common diseases including genes relevant to pharmacogenomics. This is the first large-scale comprehensive study of the structure of the Indian population with wide-reaching implications. A comprehensive platform for Indian Genome Variation (IGV) data management, analysis and creation of IGVdb portal has also been developed. The samples are being collected following ethical guidelines of Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT), India. This paper reveals the structure of the IGV project highlighting its various aspects like genesis, objectives, strategies for selection of genes, identification of the Indian subpopulations, collection of samples and discovery and validation of genetic markers, data analysis and monitoring as well as the project’s data release policy.

OCA1 in Different Ethnic Groups of India is Primarily Due to Founder Mutations in the Tyrosinase Gene

Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders characterized by an abnormally low amount of melanin in the eyes, skin and hair, and associated with common developmental abnormalities of the eye. Defects in the tyrosinase gene (TYR) cause a common type of OCA, known as oculocutaneous albinism type 1 (OCA1). The molecular basis of OCA has been studied extensively in different population groups, but very little information is available on Indian patients. Our investigation covering thirteen ethnic groups of India, some representing >20 million people, revealed that among 25 OCA families 12 were affected with OCA1, and that these cases were primarily due to founder mutations in TYR. We detected nine mutations and eight SNPs in TYR, of which six mutations (five point mutations & one gross deletion) were novel. In contrast to most reports describing compound heterozygotes, the presence of homozygotes in 10 out of the 12 pedigrees underscores the lack of intermixing between these ethnic groups in India. Haplotype analysis suggested a few founder chromosomes causing the disease in the majority of the patients. Direct detection of the mutations prevalent in specific ethnic groups could be used for carrier detection and genetic counselling.

Comprehensive analysis of the molecular basis of oculocutaneous albinism in Indian patients lacking a mutation in the tyrosinase gene

Background  Oculocutaneous albinism (OCA) refers to a group of inherited disorders where the patients have little or no pigment in the eyes, skin and hair. Mutations in genes regulating multi‐step melanin biosynthesis are the basis of four ‘classical’ OCA types with overlapping clinical features. There are a few reports on defects in TYR and a single report on SLC45A2 in Indians affected with OCA but no report on OCA2 (a major locus related to the disease) and TYRP1.

SNPs in genes with copy number variation: A question of specificity

The specificity of single nucleotide polymorphisms (SNPs) is likely to be compromised with most of the current PCRbased methods used to genotype a target locus in the presence of a highly homologous duplicated region. Such a lack of locus specificity could inflate the heterozygosity of the SNPs. We reasoned that public database for SNPs might be influenced by false allele calls, specifically in genes with copy number variation (CNV). Therefore, we compared the fraction of SNPs with high heterozygosity values (≥ 0.4) in NCBI dbSNP for genes with and without CNVs. Our observation highlights the challenges of selecting SNPs in genes with CNV for usage in complex biological studies.

Comprehensive analysis of the molecular bases of OCA in Indians

Background OCA is a group of autosomal recessive disorders characterized by hypopigmentation and abnormalities related to ocular development. Mutations in genes regulating melanin-biosynthesis cause four classical types of OCA (OCA 1-4). The clinical spectrum of OCA often depends on the pigmentation threshold of a patient, highlighting the importance of ethnicspecific SNPs. We aimed to understand the molecular bases of OCA in India, where it is one of the four major causes of childhood blindness.