Since the completion of the Human Genome Project in 2003, a new technology of massively parallel sequencing of short DNA fragments referred to as the Next Generation Sequencing (NGS) has emerged. Unlike Sanger sequencing that sequences one DNA fragment at a time, NGS method sequences millions of short DNA fragments in parallel at the same time. The short­ read sequencing market is dominated by lllumina sequencing machines. Over the years these machines have become more and more powerful generating huge amount of data, as a result of which the cost of sequencing has dramatically declined.

Third generation single molecule sequencing enables sequencing of long DNA fragments Short-read sequencing technology can generate sequence data from fragments up to a length of 250 – 300 bp. To cover 3 billion bases of a human genome, the machine has to sequence a minimum of 10 million unique fragments. In reality the machine sequences~ l billion fragments. These fragments are assembled into a full human genome by mapping them to a human reference sequence. The short-read sequencing technology falls short in its accuracy while covering highly repetitive regions of the genome, or regions that does not map well with the reference genome due to large-scale genetic alterations, often seen in cancer genomes.

Third generation sequencing technology by Pacific Biosciences (PacBio) and Oxford Nanopore Technology (ONT) have overcome this limitation by enabling sequencing of long DNA fragments 30 kb to over 500 kb in length). PacBio technology passes the long DNA strand through the enzyme DNA polymerase tethered into a nanometer size space and captures a fiuorescent signal released during incorporation of a base during strand synthesis.In PacBio technology, each well sequences one DNA molecule and there are 4 million wells on a single chip.

ONT technology detects a change in the current when a DNA strand passes through a nanopore embedded in a synthetic membrane separating two chambers with a potential difference between them. The impedance differs for each nucleotide creating a unique signature that is recorded and interpreted by the machine as A, T G or C. The smallest ONT machine Minion is slightly larger than a fiash drive and operates on a bench top producing sequence data in real time. The technology has brought sequencing to remote areas where lllumina and PacBio platforms don’t operate and was instrumental in detecting pathogenic outbreaks in remote areas of Africa and Asia.

The role of genomics in personalized medicine, agriculture, and environmental science.

Impact of genomics has been felt most profoundly in cancer
Cancer being a genetic disease experienced profound knowledge growth by new genomics technologies. The following areas in cancer were significantly impacted. Discovery of cancer driver genes in most human cancers:

• Personalization of therapy
• Discovery of drug resistance mechanisms
• Non-invasive Technologies for early cancer diagnosis and disease progression

Targeting monogenic diseases with a goal to cure using genome editing technologies.

Clustered regularly interspaced short palindromic repeat (CRISPR) and Base Editing technologies are used to reverse genetic alterations associated with hereditary diseases. There are over 2000 rare genetic diseases (Mendelian diseases) resulting from the loss of function of a gene.These technologies have the potential to reverse the function and cure the disease.

Development of Genomic Medicine
The range of therapeutic drugs has broadened, encompassing small molecules, biologics, and nucleic acid-based therapies, exemplified by the mRNA vaccine’s success in providing protection against COVID-19.

Microbiome and Metagenomics
The close interactions between humans and microbes living within and around us have been revealed by sequencing. Therapeutic strategies to restore and re-establish positive interactions and remediate disease-causing interactions are gaining momentum in the fight against cancer and many chronic and acute diseases.

Impact on agriculture, animal husbandry and aquaculture
Using genomics knowledge, varieties with higher productivity, improved nutritional content and resistance to diseases are being created to support the growing global population.

Pharmacogenomic applications
Improving the efficacy and reducing the toxicity of drugs has been achieved by the identification of genes that modulate drug metabolism. A personalized approach of matching drugs with patients is now considered before making treatment decisions.

Diagnostic applications
Genomics has significantly improved our understanding of diseases at a genetic and molecular level enabling development of a large array of DNA-based diagnostic tests. In many instances these diagnostic tests have led to development of drugs to treat the disease.For example, drugs to treat breast and ovarian cancer patients carrying BRCAl/2 mutations have extended the life patients significantly.

Population Genomic Applications

• Sequencing of ancient DNA have revealed different stages of origin of present-day humans from the protohuman species that lived over 700,000 years ago. The presence of segments of ancient human DNA in our present-day genome suggests close interactions between modern day humans and their protohuman ancestors. Genes that endowed us to communicate and build abstract concepts are being discovered using comparative genomics of ancient populations.
• Sequencing populations from different regions of the world has established that the modern humans originated in Africa and migrated out of Africa in two waves to colonize the world. These findings have profound implications in understanding the evolution of different cultural practices, food habits and predisposition to diseases in different regions of the world.
• Discovery of genes associated with diseases is made possible by population genomic studies. GenomeAsia lO0K study sequenced healthy population from India and other South East Asian countries to reveal a large number of population groups and prevalence of certain diseases within them, paving a way to identify targetable genes and pathways for therapeutic intervention.

Pandemic Preparedness and Bioterrorism

Genomic technologies play a vital role in detecting and managing emerging infectious diseases and potential bioterrorism threats. By closely monitoring active bioagents in the environment, these technologies offer the ability to identify and control calamitous pathogens.The exceptional sensitivity of sequencing technology allows for the detection of even minute levels of pathogenic agents, enabling prompt remediation measures to be taken before they escalate into serious public hazards.

Recreational Genomics
Genomics is pioneering an emerging consumer market, exploring ancestry,familial connections, and food and beverage preferences. This rapidly growing field is still advancing as science strives to substantiate these claims.

The decrease in cost of sequencing will enable KGDC to capture the immense diversity of form and function in each of the four different domains by sequencing more samples and enable comparative genomics to be performed at scale. Subtle features in the genome shaped by the environment or by interspecies interactions will be revealed to foster a deeper understanding of the interconnectedness between different groups of organisms.

The challenges and opportunities presented by vast amounts of genomic data

• Data science and artificial intelligence: Analyzing and interpreting genomic data for new discoveries and insights

In the digital era, the Kerala Genome Data Centre (KGDC) will play a pivotal role in transforming Kerala’s bio-economy and revolutionizing our approach to understanding and utilizing genomic information. It goes much beyond being a simple data repository; it generates large amount of valuable data and acts as a crucial conduit that bridges the gap between raw data generation and actionable insights, driving breakthroughs in medicine, biology, agriculture, animal health, bio-manufacturing and other sectors.

Just as oil was a valuable resource in the industrial age, genomic data is now being recognized as the “new oil” of the 21st century due to its immense potential. Just like the investment needed for drilling an oil well, considerable investment to generate the genomic data Similarly like crude oil, raw genomic data has limited utility. It needs to be refined, structured, and processed to unlock its true value. The KGDC serves as the “refinery” forthis new oil, transforming the vast amounts of raw genomic sequences into structured, searchable, and valuable information. One of the remarkable aspects of the KGDC is its local approach to data collection but making it valuable globally. Not only by generating the unique genomic data that Kerala possess, it casts a wide net, collating data from various sources such as different, public databases, proprietary databases of research institutions (through licensing), and healthcare providers worldwide. This inclusiveness ensures that the KGDC manages a diverse and complex landscape of genomic information, making it an invaluable resource for research and healthcare endeavours across the globe.
Moreover, the impact of the KGDC extends beyond human health. Genomics has proven to be essential in understanding the genetic makeup of various organisms, including agricultural crops and livestock. By incorporating genomic data from agriculture and animals, the KGDC can facilitate advancements in these sectors. This, in turn, can lead to improved crop yields, disease resistance, and better breeding practices for animals, benefiting food security and the general economy.

Additionally, the concept of “One Health” is closely related to genomics.It emphasizes the interconnectedness of human health, animal health, and the environment.The KGDC’s approach to collecting and managing genomic data from diverse sources aligns with the One Health perspective. By having a comprehensive understanding of genomic information across different species, Government officials, researchers and healthcare professionals can address zoonotic diseases, study genetic factors influencing human-animal interactions, and develop innovative solutions for a healthier planet.

KGDC serves as a critical infrastructure in the digital era, refining raw genomic data into actionable insights.Its global approach to data collection and management ensures that it remains an invaluable resource for research, healthcare, agriculture, animal health, and the overarching goal of promoting One Health. As genomics continues to unleash the potential of the “new oil,” the KGDC plays a central role in driving progress and innovation in a world increasingly driven by information.
Genomics data holds significant potential for transforming Kerala into a knowledge-based economy, per the vision outlined in the KKEM. This potential is rooted in three key areas:

• Education and Training: The integration of genomics data into educational curricula across various levels, as well as its use for training in healthcare and research institutions, will help develop a workforce skilled in genomics, propelling advances in this field. 

• Policy-Making: By offering insights into population health trends, genomics data can guide informed policy-making, fostering public health initiatives, personalized medicine, and healthcare infrastructure development, and promoting R&D in genomics.

• Enhancing Infrastructure Performance: The incorporation of genomics data into healthcare infrastructure can improve service provision, from personalized treatments to disease control, boosting the healthcare system’s efficiency and effectiveness. Moreover, the digitization of genomics data will contribute to Kerala’s broader digital transformation, promoting data-driven decision-making-a cornerstone of a knowledge­ based economy. However, robust data governance measures are crucial for ensuring data privacy and security. Genomics data would become both a crucial asset and part of infrastructure itself, necessitating its effective management for enhanced learning, policy-making, and infrastructure performance can help Kerala transform into a Knowledge economy

• Genomic Data as a Public Good: The KGDC firmly establishes genomic data as a public good. By turning raw genomic data into structured, actionable information, it fuels numerous fields, from clinical diagnostics to research and drug discovery. This data doesn’t adhere to geographical or sectoral boundaries; it’s global, diverse, and multidisciplinary. The KGDC handles this multifaceted landscape, transforming raw sequences into a comprehensive genomic database that serves a multitude of purposes in healthcare, research, and beyond.

• Technological Drivers: The KGDC leverages state-of-the-art ‘Big Data’ technologies like cloud computing, machine learning, and the Internet of Things. These technologies enable the KGDC to handle the collection, integration, validation, and real-time analysis of vast amounts of data. Such a feat is only possible because of the KGDC’s commitment to staying on the cutting edge of technology, ensuring it can meet the evolving needs of a rapidly advancing field.