Indian Genome Variation Consortium Project: Genetic Map of India

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Prof. Samir K. Brahmachari, Director General, CSIR & Secretary, Department of Scientific & Industrial Research

Dr Mitali Mukherjee, Scientist, Institute of Genomics and Integrative Biology, Delhi

Dr Samam Habib, Scientist, Central Drug Research Institute, Lucknow

Contemporary India comprising nearly 1/6th of the world population is a huge melting pot of human diversity brought about by wave upon wave of human migrations followed by admixtures with the existing populations. It is organized into various ethnic, religious, caste groups and isolated tribal populations. There are over 4693 communities, 325 functioning languages and 25 scripts.

Indian Genome Variation Project completed recently, was aimed at studying diversity of 1000 biomedically important and pharmaco-genetically relevant genes in populations representing the genetic spectrum of India. A careful effort was first made to select representative populations of diverse linguistic, ethnic origins from all the major geographical zones of the country from Kashmir to Kanyakumari and from Gujarat to Assam. This ambitious project is also unprecedented in terms of the number of participants—over half a dozen Institutes and over 150 CSIR scientists contributed to it.

The Institute of Genomics and Integrative Biology (IGIB), Delhi, Centre for Cellular and Molecular Biology (CCMB), Hyderabad, Indian Institute of Chemical Biology (IICB), Kolkata, Central Drug Research Institute (CDRI), Lucknow, Industrial Toxicological Research Centre (ITRC), Lucknow, Institute of Microbial Technology (IMTECH), Chandigarh, The Indian Statistical Institute (ISI), Kolkata, Anthropological Survey of India and The Centre for Genomic Applications (TCGA), a public-private partnership were closely involved in the study

Increased life-expectancy and life-style changes have ushered in complex diseases like diabetes, asthma, cardiovascular disorders, epilepsy, schizophrenia and bipolar disorder. Nearly 1% of the Indian population suffers from complex diseases that need expensive interventions and prolonged medication, which again, are not free of side–effects. Identifying optimum dosage and a suitable schedule of medication customized for each individual to minimize side effects is a major challenge.

Uses of Gene Mapping
There are over 6 million differences at the basic genetic level between two unrelated individuals. Variations at the level of single nucleotides are commonly referred to as Single Nucleotide Polymorphism (SNP). Most variations arise randomly and do not affect survival. Complex disorders are a consequence of the cumulative effect of a large number of variations that independently have small effects that are, individually neither necessary nor sufficient, to cause the disease. Of course, the interplay of environment, diet and lifestyle are often triggering factors.

IGVCP sought to provide answers to vexing questions such as “which genetic marker(s) predisposes an individual to a certain genetic disease/disorder placing him at greater risk or, how do certain groups of people respond to a given drug. It focused on actions that can be initiated with the current levels of knowledge; with disorders where the number of genes involved is known. For example, as in the case of ocular and muscular problems, diabetes and drug metabolism/response genes. The exciting outcome of the IGVCP is that it has presented scientists with a clear genetic profile of our populations and has shown that there is a strong association between genetic and linguistic profiles in India.

IGVC results have revealed that though India is a conglomerate of diverse ethnic and linguistic lineages nevertheless they cluster into broader groups of genetic homogeneity and there are significant differences in the frequencies of disease-associated genetic markers between the groups. With IGVdb, scientists can scan the national frequencies of the 1000 genes.

A closer scrutiny will no doubt reveal finer nuances of the genetic pre-disposition that the Indian population has to certain diseases and ultimately, facilitate personalized therapies for people by matching drug design to their genetic profile. In the era of predictive medicine, each individual could have a personalized health regime based on his/her genetic make-up.

Clues for Disease Association and Drug Response
The results of this study will help in making predictions of diseases and effectiveness of specific drugs used for various diseases, and in designing future scientific studies to understand genetic underpinnings of major diseases in India. These results have also provided the first set of insights into the processes of human adaptation to different environments in India.

This study has revealed that a known protective genetic marker against HIV-1 is virtually absent in India, implying that we do not have a natural or genetic protection against HIV-AIDS. This validates the HIV epidemiology data and further reiterates for a national policy to combat this dreaded disease.

The IGVdb data has major implications in designing drug-discovery studies and selecting suitable populations for testing drug efficacy. It has suggested that the Indian populations are likely to respond differently to salbutamol (drug for bronchial asthma). This information also provides a framework that will enable identification of specific populations with differential response to different classes of drugs for future studies on epidemiology and drug response determinants.

Incidence of the more severe form of malaria caused by Plasmodium falciparum is high in India (~0.9 million cases reported annually). However, some, but not all, infected individuals develop severe complications. Polymorphisms in more than 30 human genes have been associated with susceptibility/resistance to severe malaria. Data from IGVC revealed significant differences in genotype frequencies of the Single Nucleotide Polymorphisms (SNP) in populations residing in P. falciparum-endemic and non-endemic regions of India.

IGVCP has mapped a SNP (in the gene CYP1B1), which is an allele for Primary Open Angle Glaucoma (POAG) across the different population groups. Over 70 per cent of the POAG cases appear to be inherited although the pattern of inheritance does not seem to clearly follow the classical laws of Mendelian inheritance. Glaucoma is now included in the list of disorders that can be investigated using the IGVdb.

Cardiovascular Diseases
Increased levels of Homocysteine (Hcy) are associated with a range of disorders including pediatric acute lymphoblastic leukemia, ischemic stroke and cardiovascular disease. Normally, Hcy plays an important role in the metabolic cycle of Methionine. Any anomaly in the levels of Hcy impairs the Methionine cycle and interferes with the balance of critical proteins required by the body. Folates and Vitamin B 12 are dietary factors that are instrumental in maintaining the conversion of Hcy to Methionine via an enzyme called MTHFR. Mutations in the MTHFR gene can lead to altered levels of Hcy. The allele MTHFR C677T ( a tiny change where base T replaces base C) is one of the better known polymorphism responsible for raising Hcy levels. The IGVdb provides information that can be used to home in on populations that could benefit from supplementation of folate and Vitamin B 12 in their diets—thus effectively short circuiting their predisposition to cardio vascular diseases because of a genetic condition.

Neurological Disorders
IGVdb is a treasure trove for those studying the genetic pre-disposition of neurological disorders such as Schizophrenia and bipolar disorders. The IGVdb clearly establishes that polymorphisms of certain genes on Chromosome 22 that are known to be associated with these two disorders, vary markedly across ethnic groups in India. Polymorphisms in one gene—MLC1—has been associated with both these neuro –psychiatric disorders/ IGVdb will allow scientists to work out, on large and diverse population sample, how polymorphic alleles interact with other genes.
Gene-disease association studies have been carried out in India earlier too. But these were restricted both geographically as well in sample size. With IGVDb has come a quantum change in the way we look at populations and genetic predispositions. It is the harbinger of a paradigm shift in our way of addressing the healthcare problem on a pan- India basis yet focusing on an individual at a personal level as well.

The critical importance of IGVdb lies in the fact that there now is, for the first time in India, a scientific basis for the identification of appropriate cohort groups for pooling samples to arrive at a gene-disease association applicable across the length and breadth of the country.

After the second phase of IGVdb there will be enough data to fashion tools for population-specific, pro-active medical interventions that can bring affordable healthcare to the doorstep of every Indian citizen. (PIB Features)

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