In a pair of findings with major historical and medical significance, an international research team has found strong evidence for two distinct ancestral populations in the genes of modern people of India.
Following this ancient mixture, the researchers report, many groups in India have been genetically isolated from one another, growing from a small number of “founder” individuals.
The two ancestral patterns predict disease risk factors unique in India, said co–first author David Reich, an HMS associate professor of genetics and an associate member of the Broad Institute of Harvard and MIT. And, like European groups who share a genetic heritage, such as Finns and Ashkenazi Jews, many of the Indian groups are at increased risk for recessive-gene disorders, which require inheritance of disease genes from both mother and father.
The study, in the Sept. 24 Nature, was led by scientists at the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad, India, the Broad Institute, HMS and HSPH.
The great majority of the genome is identical across any two humans. However, the approximately 0.1 percent of the genome that varies can be studied to reconstruct the historical origins of modern populations and to learn why some individuals and groups have different rates of disease than others. These studies have been very successful in the last few years, but have left out people of Indian descent.
To remedy that, Reich and his colleagues analyzed DNA from 25 diverse groups across India. The study included groups from 13 states, six language families and traditionally “upper” and “lower” castes. The scientists surveyed more than 500,000 genetic markers throughout the human genome (known as single nucleotide polymorphisms, or SNPs) in 132 samples. In the process, they uncovered new details about the history and medical genetics of the world’s second most populous nation.
“Indians seem to have a unique set of ancestries,” wrote Aravinda Chakravarti, director of the Center for Complex Disease Genomics at Johns Hopkins University School of Medicine, in an accompanying commentary. “Each population is the same with respect to common descent from two major peoples, but different by virtue of its ancestry proportions and specific genomic content inherited—much like the many hands that can be dealt from a deck of cards.”
The finding that nearly all Indian groups descend from mixtures of two ancestral populations applies to traditional “tribes” as well as “castes.” “It is impossible to distinguish castes from tribes using the data,” said co–first author Kumarasamy Thangaraj, a senior research scientist at CCMB. “The genetics proves they are not systematically different. This supports the view that castes grew directly out of tribal-like organizations during the formation of Indian society.”
The study suggests that nearly all Indians alive today carry various mixtures of genomic contribution from the two ancient populations. One group the authors call “Ancestral North Indians” is genetically most similar to western Eurasians (including Europeans) and accounts for 40 to 80 percent of the ancestry found in the Indian genomes. The rest comes from the “Ancestral South Indians,” a distinct population not closely related to populations anywhere else in the world.
In one example of the medical significance of the shared Ancestral South Indian legacy, four percent of people in India carry a genetic variation inherited from these distant relatives that puts them at a whopping sevenfold higher risk of heart failure. Learning more about such gene-based disease risk could help improve detection, prevention and treatment of diseases common to South Asians.
The only exception to the mixed ancestries of all Indians came from the Andaman Islanders, who have exclusive descent from the Ancestral South Indian lineage. “The Andamanese are unique,” said coauthor Nick Patterson, a mathematician and researcher at the Broad Institute.
Understanding their origins provides a window onto the history of the Ancestral South Indians, and the period tens of thousands of years ago when they diverged from other Eurasians.”
After the general mixing of ancestry, many distinct Indian groups arose from a small number of founder individuals and then remained isolated with almost no gene flow even with their neighbors.
“India is genetically not a single large population, but instead is best described as many smaller isolated populations,” said Lalji Singh, senior author of the Nature paper and the former director of CCMB.
“The most important medical implication of this work is that hundreds of millions of people in India today may be susceptible to a high rate of recessive diseases,” Reich said. “It is important to carry out studies to identify what those diseases are and to follow this up by finding the mutations that cause the diseases.”
The international team wants to extend its initial findings by generating more detailed genomic maps for specific Indian populations, identifying which are most at risk for the recessive diseases. This should better inform care of individuals and families at high risk.
Chakravarti also lauded the new statistical methods to probe population relationships and ancestry.
“In studying Indian genetic variation we also developed a novel toolkit for understanding the relationships among groups and the history of mixture,” said co–first author Alkes Price, an HSPH assistant professor of epidemiology. “We believe that these tools can drive future studies not only of Indian history but of groups worldwide.”
Students may contact David Reich at reich@genetics.med.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflict of interest.
Funding Sources: The National Institutes of Health, a Burroughs Wellcome Career Development Award in the Biomedical Sciences, the Council of Scientific and Industrial Research of the Government of India, and a UKIERI Major Award; the authors are solely responsible for the content of this work.
