The answers to medical mysteries at times come from people who have little to do with medicine.
For long, medical researchers were baffled at why young healthy men in India, with no history of smoking or high blood pressure, were falling prey to sudden cardiac events. The cause, it turned out, was a specific mutation—a 25-base-pair deletion—in a gene called MYBPC3.
This discovery came from population geneticists studying Indian ancestry. K. Thangaraj and his colleagues at the Centre for Cellular and Molecular Biology screened thousands of individuals across caste groups, tribes and regions and found that nearly 4 per cent of south Asians carry the mutation. The mutation raises the risk of cardiomyopathy (thickening of the heart muscles that can lead to heart failure) several fold and is found almost exclusively in the Indian subcontinent.
“The mutation is largely absent outside south Asia,” says Thangaraj. “That means it emerged in an ancestral population here and spread through generations.”
The mutation’s geography tells a story of ancient migration. Himalayan populations in Ladakh and other high-altitude regions show an almost complete absence of the MYBPC3 deletion. “Their ancestry and migration history are different,” explains Thangaraj. “The mutation never entered those lineages.”
It is here that ancient DNA and medicine intersect most sharply. India is unusually important for such research because of its genetic complexity. Over tens of thousands of years, waves of migration brought hunter-gatherers in contact with incoming agriculturalists and pastoralists, and communities grew increasingly endogamous, marrying within caste, clan or tribe for generations. India today has more than 4,600 such groups.
“When populations remain isolated for long periods, recessive mutations accumulate,” says geneticist Gyaneshwer Chaubey of Banaras Hindu University (BHU). “You begin seeing community-specific genetic diseases.”
A recessive disorder appears only when a child inherits the same harmful mutation from both parents—rare in large mixed populations, but common in endogamous populations, where many people share distant common ancestors.
“Our studies suggest many Indian populations carry their own recessive disease burdens,” says Thangaraj. “Some of these conditions are very rare globally but relatively common within particular communities.” This is accentuated by marriages within the same caste. Traits such as low lean muscle mass, high carbohydrate accumulation, baldness, poor eyesight, heart disease and even certain cholesterol patterns may have some recessive genetic contribution.
Niraj Rai, who heads Ancient DNA Laboratory at the Birbal Sahni Institute of Palaeosciences in Lucknow, raises a concern about how medicine is practised in India. “The problem is that the textbooks medical students study are largely written using European genetic datasets,” he says. “We still do not have enough large-scale Indian genetic data or a complete framework for understanding diseases in Indian populations. For example, vitamin D3 deficiency may sometimes have a genetic component linked to recessive genes. Similarly, vitamin B12 deficiency may also involve genetic factors. Sometimes people take B12 supplements and still do not respond effectively.”
This is where genomics begins moving from academic research into public health policy. “What we are learning can help in genetic counselling and early screening,” says Chaubey. “If you know which mutations are common in which populations, you can identify diseases much earlier.”
The implications stretch far beyond rare disorders. Ancient DNA research is also changing how scientists think about Indian diets, specifically what ancient Indians actually ate. Stable isotope analysis of ancient skeletons from the Indus Valley and later sites shows that many early Indians consumed substantial animal protein. Chemical analysis of bones and dental calculus, says Rai, can reveal not just whether ancient people ate meat, but the kind of fats and proteins in their diets. “Human biology evolved on protein-rich diets,” he says. “About 60 to 70 per cent protein should ideally be there. We changed it.” He is sharply critical of the transition to heavily carbohydrate-based agricultural diets after the Neolithic revolution.
Modern dietary science remains contested and is far more complex than a simple meat-versus-agriculture debate. But ancient DNA and isotope studies are unquestionably forcing historians to rethink assumptions about Indian food history, especially the idea that vegetarianism was always dominant.
Rai is equally blunt about milk. “In India, 70 to 80 per cent of people do not have the lactose digestion gene, but they consume milk,” he says. “Most tribes do not have this mutation, but now their children consume milk. Milk is second-grade protein compared to meat.”
India is the world’s largest milk producer. Genetically, most Indians are lactose intolerant: the enzyme lactase, which breaks down milk sugar, is naturally produced by infants but falls off sharply after childhood. Certain populations developed mutations allowing lactase production to continue into adulthood, which is known as lactase persistence. It is common in northern Europe but unevenly distributed in India.
Chaubey’s research team, which included Chandana Basu of the BHU, found high lactase persistence among communities such as the Rors of Haryana, the Jats and the Toda tribe of the Nilgiris, all historically associated with pastoralism. But it is far less common elsewhere in India.
While working in Cambridge, Chaubey met Anurag Kadian, an IITian and a researcher from the Ror community who invited him to Haryana to study the population. “People insisted we drink milk before giving samples,” he recalls. “I drank three large glasses and became ill. They could drink litres without any problem.” More than 85 per cent of the Ror population, it turned out, carried lactase persistence mutations, far above the Indian average. “Most Indians do not carry strong lactase persistence mutations,” says Chaubey.
The relationship between genetics, diet and modern disease is becoming increasingly important as India faces an epidemic of diabetes and cardiovascular illnesses. Ancient DNA may also help explain why certain populations respond differently to medicines. Genetic variants affecting drug metabolism vary significantly across Indian communities. A drug dosage calibrated for European populations may not behave the same way in Indian patients. That gap is what the Genome India Project hopes to address. India is home to one in six people on earth and holds more genetic diversity than most continents combined. Yet, until recently, it remained largely absent from global genomics databases, which were dominated by European populations. So risk models for diabetes, heart disease and cancer were calibrated on European genomes, and Indian variants were often misclassified for lack of a reference database.
“If an Indian patient undergoes genomic testing, many normal Indian variants appear suspicious simply because they are absent from western databases,” says Thangaraj.
Launched in 2020, the project has sequenced nearly 10,000 whole genomes from 83 Indian populations—the largest genomic mapping effort in the country. Samples were collected from tribal groups, castes, linguistic communities and isolated regions to generate millions of previously undocumented variants. “This data will help in diagnostics, drug development, rare disease screening and population-specific medicine,” says Thangaraj.
The project may eventually help doctors build India-specific risk scores for diabetes and cardiovascular illnesses, since European-derived scores often perform poorly in South Asians. It could also reveal which populations are vulnerable to specific disorders and which medicines work best across genetic backgrounds, helping clinicians tell harmless variants apart from disease-causing ones.
Ancient DNA and health
Impact of endogamy
* Long-term endogamy increased some rare genetic disorders in isolated communities
* Certain inherited diseases became more common within specific populations
* Recessive mutations accumulate within isolated, endogamous populations
* Endogamy effectively froze genetic diversity in place roughly 1,900-2,000 years ago
* This also created unique genetic profile for multiple ethnicities
Health patterns
* Higher incidence of type 2 diabetes and cardiovascular disease in some south Asian populations Example: MYBPC3 mutation
* Linked to cardiomyopathy (heart muscle disease); found in around 4% Indians
* Largely absent outside south Asia
Underlying factors
* Population history and genetic structure (including effects from endogamy)
* Modern high-calorie diets and metabolic overload from drop in physical activity
