The study of human genomics is an evolving revolution

Twenty years ago this month, the human genome was fully sequenced. For as long as we have been human, we have been fascinated by our genetics and its role in making us who we are. Human beings have always been interested in how hereditary factors influence our physical features, traits and skills, and how these in turn interact with the environment. The sequencing of the full human genome unlocked the promise of a greater understanding of some fundamental questions about human biology.

First, here’s some background. Our genetic material is stored inside our cells as chromosomes. Humans have 23 pairs of chromosomes, inheriting one copy from each parent. These chromosomes are made of packed bundles of de-oxyribonucleic acid (DNA). There are four types of nucleotides, defined by their difference in base molecule: adenine (A), thymine (T), cytosine (C) and guanine (G). These bases combine only as A-T and C-G. The main function of DNA is to provide a code to make a product, usually a protein. This is called coding DNA, and sections of protein-coding DNA are individually known as genes. Now DNA can also regulate coding DNA, where it is known as non-coding DNA. Together, coding and non-coding DNA combine to make a whole human genome, which is made up of 3.2 billion base pairs, of which there are only 20,000 or so protein coding genes. Currently, scientific knowledge has progressed more on these 20,000 protein-coding genes than on the remaining 98.5% of the human genome.

A mutation describes a process where the normal nucleotide sequence in a gene is incorrectly added, copied or swapped with other nucleotides. Contrary to popular wisdom, there is nothing inherent in the word ‘mutation’ that suggests that the outcome is undesirable. It simply means a variation that was not intended. A common ‘negative mutation’ is abnormal cell growth that results in cancer, which explains the leading role of genomics in cancer research. An ‘ABO’ blood type variation is a mutation that is non-negative.

Genetic traits can be caused by single genes (monogenic) or by the combined effects of multiple genes (polygenic). Some diseases like Huntington’s disease and cystic fibrosis are monogenic, while height and skin pigmentation are polygenic. A lot of research today is focused on identifying monogenic and polygenic causes of diseases and traits. Another layer of gene regulation is epigenetic. Epigenetics is the study of how heritable changes in a person’s observable traits (phenotype) can occur without any change in their genetic sequence (genotype). In common parlance, this addresses the ‘nature versus nurture’ issue.

The role of non-coding genes, implications of polygenic variations and influence of epigenetics make the study of genomics and its impact on disease and variability very complicated. Recent technologies and reduction in cost have dramatically increased the scale and speed of genomic sequencing. It seems imminently probable that a human genome can be sequenced for as little as $100. A sequenced human genome can then be compared to the reference (first published 20 years ago, and then improved over time) to spot variations. This will mean that researchers can comprehensively study which genes work together to influence a trait. It is then possible to calculate a predictive value, called polygenic scoring, for developing that trait. Continuous improvement in polygenic scoring is one area of innovation in future genomic research. Another field of likely innovation is big-data science related to genomics (bioinformatics) and the technology of gene sequencing itself.

The study of genomics has already delivered some and promises to deliver even more solutions in both precision and personalized medicine, particularly to treat rare diseases. For instance, a technique which involves injecting a virus into the eye to deliver billions of healthy genes to replace a key missing gene for choroideremia patients has provided sustained improvement in vision. While the direct application of genomics has not advanced greatly for chronic diseases like diabetes or on risk factors for cardiovascular disease, the research promises to deliver useful inputs for early diagnosis and conventional treatments. Beyond medicine, genomic sequencing may offer new insights in forensic science, synthetic biology, agriculture and ecology.

In India, the private sector has moved ahead to set up gene-based diagnostic testing and some quaternary medical facilities are now able to offer related medical solutions. The benefits of this currently flow mostly to those with a treatable monogenic disease and patients of some cancers. This is meaningful because India is home to one-third of all rare diseases with an estimated 1 in 20 affected by a rare disorder. Despite this, the real breakthrough for India will come when genomics is integrated with regular medical care and bioinformatics is able to capture a wide spectrum of Indians as its reference database, thus allowing early diagnostics of and intervention in risk factors. This will lower costs and improve treatment efficacy at population scale.

P.S: “Three profoundly destabilizing scientific ideas ricochet through the twentieth century, trisecting it into three unequal parts: the atom, the byte, the gene,” wrote Siddharth Mukherjee, author of ‘The Gene: An Intimate History’.

Narayan Ramachandran is chairman, InKlude Labs. Read Narayan’s Mint columns at www.livemint.com/avisiblehand