In 2009, a study in Nature Genetics by the group of Kumarasamy Thangaraj, at the Centre for Cellular and Molecular Biology, Hyderabad, reported a fascinating finding on why a small group of Indians were prone to cardiac failure at relatively young ages. They found that the DNA of such individuals lacked 25 base-pairs in a gene crucial for the rhythmic beating of the heart (scientists call it a 25-base-pair deletion).
Intriguingly, this deletion was unique to the Indian population and, barring a few groups in Southeast Asia, was not found elsewhere. They estimated that this deletion arose around 30,000 years ago, shortly after people began settling in the subcontinent, and affects roughly 4% of the Indian population today.
There must be many other genetic novelties that are linked to the health of the subcontinent’s populace. How do we find such needles in the vast genetic haystack of this region?
Stark genetic differences
A recent study by Jeffrey Wall and his colleagues, at the Institute for Human Genetics, University of California, took a big stride in this direction. The researchers collected DNA from around 5,000 individuals, mainly people from across India, Pakistan, and Bangladesh. This cohort also contained DNA from some Malay, Tibetan, and other South-Asian communities.
Next, they performed whole-genome sequencing to identify all the instances where the DNA either showed a change, was missing, or had additional base-pairs, or ‘letters’.
Their study found stark genetic differences between people from different regions of the subcontinent. While this is to be expected between different countries in the region, it was actually evident even at the level of smaller geographies within India.
Unbiased computational approaches showed little mixing between individuals from different communities. It is a no-brainer that endogamous practices (including caste-based, region-based, and consanguineous marriages) in the subcontinent are responsible for such conserved genetic patterns at the community level. In an ideal scenario, there would have been random mating in a population, leading to greater genetic diversity and lower frequency of variants, which are linked to disorders.
A worrying trend
The study also highlighted a worrying trend in the Indian population. Compared to a relatively outbred population, like that of Taiwan, the South Asian cohort – and within it, the South-Indian and Pakistani subgroups – showed a higher frequency of homozygous genotypes.
Humans typically have two copies of each gene. When an individual has two copies of the same variant, it is called a homozygous genotype. Most genetic variants linked to major disorders are recessive in nature and exert their effect only when present in two copies. (Having different variants – i.e. being heterozygous – is usually protective.)
The researchers also found this using an alternate measure of relatedness within subgroups. The South-Indian and Pakistani subgroups were estimated to have a high degree of inbreeding while the Bengali subgroup showed significantly lower inbreeding. The reasons for this are unclear but could be cultural in nature. At the same time, the three subgroups had 300-600-times higher levels of rare homozygous variants than what would have been predicted if the matings had been random.
As expected, not only did the South Asian cohort have a higher number of variants that could disrupt the functioning of genes, there were also unique variants that were not found in European individuals. These variants can have a major effect on important physiological parameters, leading to higher risk of cardiovascular disorders, diabetes, cancers, and mental disorders.
Map of the Indian genome
It has been some 20 years since scientists published the human genome sequence. In this time, several studies have shown important ethnic differences in the genome. Thanks to this, scientists have sequenced populations from Africa and China – but a detailed map of the Indian genome has been missing.
This is important because of India’s incredible diversity as well as for economic, matrimonial, and geographical reasons. The study hasn’t just highlighted this but also indicated how our cultural aspects might need mending for the sake of population health. This is obviously fraught with sensitivities owing to deep-rooted customs and biases, but we must move away from the idea of genetic puritanism because it will be the simplest way to prevent major hereditary disorders.
An important caveat of this study is that the researchers recruited the cohort from hospitals and other healthcare providers (with the exception of the Bengali subgroup). So the genomes they studied don’t entirely represent the subcontinent’s diversity but could instead be biased towards individuals seeking medical intervention in the first place.
A study that controls for such factors would be a huge task, but shouldn’t be something that we should shy away from. Instead, we need to develop the competence and infrastructure to undertake a study of this magnitude within the country and as a multi-centre collaboration.
Unique genetic variants
Conducting such studies within the country would also help safeguard the many vulnerable communities within the country who might be exploited. Eminent Indian scientists have already voiced apprehensions about sharing sensitive genetic data with multinational companies and foreign research organisations.
Genetics was once practised with the sole aim of ensuring the lineage of European royal families. Since then, we have come a long way, to mapping the human genome and identifying genes linked to haemophilia, skin colour, and cardiac failure. But a number of medical disorders are genetically complex and occur when multiple genes are simultaneously disrupted.
While a detailed genetic association study of major traits in the Indian population would take greater time and effort, data from the new study has shown the prospects of identifying unique genetic variants that could help us develop interventions for major health concerns. As an ambitious nation, we should devote efforts to harness the power of such studies for our well-being.
Navneet A. Vasistha is an assistant professor at the Biotech Research and Innovation Center, University of Copenhagen, where he studies the neurobiological basis of psychiatric disorders.
