The Genome India Project

The Genome India Project, initiated in 2020 by the Department of Biotechnology under the Ministry of Science and Technology, Government of India, is dedicated to sequence the human genome in the country. Under the project; 10,000 human genomes have been sequenced which will further be used to create a genetic map of India. (1) The project is an effort to strengthen India’s reliance on its genetic data echoing the legacy of the Human Genome Project. The project is being led by the Centre for Brain Research, Indian Institute of Science, Bengaluru with 20 collaborating centres across the country. Each genome sequence, amounting to 80 GB, contributes to a total sequencing data of 8 Petabytes. The data will be securely stored at the Indian Biological Data Centre in Faridabad, facilitating further research and analysis. (2)

Decoding the Aims & Objectives

India being a land of diverse cultures with over 4600 population groups, shares a varied genetic makeup. This gave rise to the need to create a ‘human reference genome’ for the Indian population. A human genome reference sequence is an accepted subset of the human genome sequence that is used by researchers as a standard for comparison to DNA sequences generated in their studies. (3) The aim of the scientists involved is to provide the highest-quality, consensus representations of the gene sequences, keeping the structural diversity found in the human genome among populations. The genome reference sequence serves as a basic structural framework but does not constitute an individual’s whole DNA sequence. The data derived from the Genome India Project will play a pivotal role in shaping this standard 'human reference genome', ensuring it accurately reflects the genetic diversity prevalent among India's population.

From obscurity to revolution: The rise of genetics

While the discovery of the DNA double helix by Watson and Crick in 1953 was a landmark moment, genetics had its roots in earlier work by Gregor Mendel and others. However, Watson and Crick's contribution provided a crucial foundation for the field's explosive growth.

Polymerase Chain Reaction was introduced in 1980s which unfolded frontiers of innovation in healthcare diagnostics. This technique allowed for the rapid amplification of minute DNA samples, making genetic analysis accessible and scalable. This paved the way for the development of molecular genetics, a field that explores the role of genes and their products at the molecular level.

The Human Genome Project, completed in 2003 was a landmark moment in the history of genetic testing. By sequencing the entire human genome, it provided a comprehensive blueprint of human genetic makeup. This vast dataset propelled further advancements in genetic testing, personalising medicine, and opening doors for new diagnostic tools and potential gene therapies. However, this dataset not being adequately representative of the Indian population paved the need for Indian subcontinent-specific genetic analysis leading to the structurisation of the Genome India Project.

Fig.1: Roadmap of the genetic advancement

Genomic advancement in healthcare

Genomics has been pivotal in revolutionizing healthcare diagnostics, paving the way for personalised medicine to take center stage. This approach emphasizes tailoring disease diagnosis and treatment plans to each individual, offering a detailed understanding of their specific health challenges. Pharmacogenomics stands out as a recent breakthrough, customizing medications based on an individual's unique response to drugs. For instance, when considering the use of Abacavir, a medication for managing HIV, HLA-B*5701 testing can determine the appropriate treatment plan. Patients testing positive for HLA-B*5701 are advised not to take Abacavir. Similarly, for the use of Trastuzumab, HER2 protein expression must be evaluated. If the expression is (2+ or 3+), Trastuzumab will likely be effective. (4) Moreover, the advent of the CRISPR technique in 2012 has paved a new era of genetic editing, offering unprecedented precision and efficiency in modifying genetic material. This breakthrough holds immense potential for treating genetic disorders and advancing medical research.

In prenatal care, non-invasive prenatal testing (NIPT) represents a significant advancement in genetics applied to healthcare. By analysing the genetic makeup of the fetus from the mother's blood sample, NIPT provides a safer and less invasive alternative to traditional methods such as amniocentesis. This technique holds promise for early detection of fetal disorders while minimizing risks of harm due to invasive procedures in pregnancy.

Polygenic Risk Score

A recent breakthrough in genetics is the advent of Polygenic Risk Scores (PRS), offering a sophisticated method to assess the likelihood of developing certain diseases. PRS integrates multiple genetic variants associated with a particular condition, providing a comprehensive score that reflects an individual's genetic predisposition to that disease. (5) By combining various versions of multiple genes linked to a specific disease, PRS offers an in-depth understanding of genetic risk factors. Each individual possesses a unique PRS for each disease, enabling targeted analysis and risk assessment. To calculate the Polygenic Risk Score, researchers tally the total count of both risk-increasing and risk-decreasing genetic variants. Risk-increasing variants are those that occur more frequently in individuals with the disease, indicating an elevated susceptibility if these variants are present. This meticulous calculation method allows for a precise estimation of disease risk based on an individual's genetic profile. (6)

Techniques of Genetic Testing 

Genetic sequencing is deciphering the complete sequence of DNA base pairs in an individual. Out of all the techniques available including Polymerase Chain Reaction (PCR), Microarray analysis, and Florescent In-Situ Hybridisation (FISH); Next Generation Sequencing (NGS) is the most popular one. It is rapid, accurate and cost-effective to screen large amounts of DNA. DNA NGS involves DNA fragmentation, library preparation, massively parallel sequencing, bioinformatics analysis, and variant/mutation annotation and interpretation. DNA fragmentation is used to snip the targeted DNA into multiple short segments. Library preparation, on the other hand, is the process of modifying DNA segments into sample-specific index, such as sample identification, which aids in identifying the patient for whom the DNA sequencing was conducted. Massive parallel sequencing is performed using an NGS sequencer. The library is uploaded onto a sequencing matrix in a specific sequencer. The sequence information generated from such massive parallel sequencing is analyzed using bioinformatics software which uses base calling, read alignment, variant identification, and variant annotation. During this process, the sequence information is compared to a human genome reference sequence to identify whether there are any variants/mutations in the targeted sequences. (7)

Public Health Implications of Genetic Mapping

The first-ever genome of India was mapped in 2009.(8) Since then, there have been continuous efforts to create a genetic repository of the Indian population. Ind-Gen is one of the initiatives funded by the Council for Scientific and Industrial Research (CSIR) which specifically caters to the role of genetic epidemiology in Public Health. With the recent completion of the Genome India Project, has given a strong hope to aid genetic data in assisting public health priorities. Genetic dataset holds key promises in Public Health through: 

• Genetic mapping has enabled the pinpointing of specific genes implicated in certain diseases within select segments of the Indian population. For instance, through this process, researchers have identified that heart failure among young Indians can be attributed to mutations in the MYBPC3 gene, encoding Cardiac Myosin Binding Protein-C. This genetic variant is prevalent in approximately 4% of the South Asian population, elevating the risk of heart failure by up to sevenfold (9). Similarly, another mutation known as LAMB3 has been linked to Epidermolysis Bullosa, a severe skin condition, with a higher incidence observed in South India. (10)  These findings underscore the importance of conducting region-specific genetic studies, highlighting nuances that may be overlooked in a global genetic repository.

  
  

• Exploring the prevalence of specific disorders within distinct population subsets falls within the domain of population genetics. This field sheds light on the distribution and frequency of genetic traits and diseases among different demographic groups. By conducting genetic assessments, researchers can identify vulnerable populations at heightened risk of certain disorders. This knowledge is invaluable in devising targeted prevention strategies aimed at mitigating the impact of these disorders within susceptible communities.

• One of the most significant roles of genetic assessment is in the prevention and identification of cancer disorders. Genetic testing can be utilized at identifying at-risk family members in certain syndromes such as Multiple Endocrine Neoplasia type 2, Von Hippel-Lindau disease, and familial Adenomatous Polyposis are few such examples in. (11) The advent of genetic screening for cancer detection is well employed in the prevention and management of Breast Cancer. The personalized approach to cancer detection and prevention can be a boon to reduce the Public Health burden of cancer.

  
  

The global genomic market size is expected to reach 94.65 USD by the end of 2028. (12) Pioneer clinical genetic expert and the co-founder of Genomics for Understanding Rare Disease International Alliance Network (GUaRDIAN) project Dr Vinod Scaria states “Precision medicine is a reality. Around 30% of cancer therapeutic approvals in the last decade are targeted therapies. Almost all professional guidelines presently include recommendations for somatic/germline testing for major tumours. Pre-emptive Pharmacogenomics testing is a reality.”

Way Ahead

The entire dataset will be stored at the Indian Biological Data Centre (IBDC), Faridabad, Haryana and will be made available as a digital public repository. The wealth of genetic data generated presents an opportunity for researchers to uncover insights that can significantly enhance public healthcare in the country. The Genome India Project has laid the foundation for further exploration of the nation's genetic landscape and has established a benchmark for future studies. However, the government must prioritize the expansion of genetic testing efforts, making it more accessible and affordable to all segments of the population. By leveraging genetic data, we can address the unique healthcare needs of vulnerable population subsets and work towards a healthier future for all.

References

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10. Buchroithner B, Klausegger A, Ebschner U, Anton-Lamprecht I, Pohla-Gubo G, Lanschuetzer CM, et al. Analysis of the LAMB3 gene in a junctional epidermolysis bullosa patient reveals exonic splicing and allele-specific nonsense-mediated mRNA decay. Lab Invest [Internet]. 2004 [cited 2024 Mar 4];84(10):1279–88. Available from: https://www.nature.com/articles/3700164

11. Rasmussen A, Alonso E, Ochoa A, De Biase I, Familiar I, Yescas P, et al. Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease. BMC Med Genet [Internet]. 2010 [cited 2024 Mar 4];11(1):4. Available from: http://dx.doi.org/10.1186/1471-2350-11-4

12. HealthWorld ET. The future of genomics in India [Internet]. ETHealthWorld. 2023 [cited 2024 Apr 8]. Available from: https://health.economictimes.indiatimes.com/news/industry/the-future-of-genomics-in-india/100060290