The Indian subcontinent is extremely genetically diverse, with about 1.5 billion people forming around 5000 well-defined subgroups. The practice of marrying within the same community or caste means these populations remain relatively separate, and may be vulnerable to specific rare genetic diseases.
Nearly one-third of these subgroups experienced a 'founder event' – where a large population is descended from a small number of ancestors, found the study. And this leads to a high rate of recessive diseases, according to the paper in Nature Genetics.
'Everybody carries a small number of mutations that could cause severe disease, but each person usually only has one copy – and two copies are needed to get sick,' said study co-author Nathan Nakatsuka, at Harvard Medical School (HMS) in Boston, Massachusetts. 'If parents have the same common ancestry, there is a greater risk that they will both carry the same, recessive mutation, so their offspring are at much greater risk of inheriting the two copies needed to manifest disease.'
The scientists analysed data over a 15-year period, from more than 2800 individuals from over 260 distinct populations, organised by factors including caste, geography and religion. They measured the strength of different founder events, by examining stretches of DNA shared between individuals from the same subgroups. More shared DNA sequences indicated a stronger founder event.
They found that 81 subgroups had stronger founder events and therefore greater losses of genetic variation than both Finns and Ashkenazi Jews – historically known to have strong founder events and high rates of recessive disease. Of these South Asian subgroups, 14 had estimated census sizes of more than one million.
'Much of the focus of genetic research in India has been on diseases such as diabetes, thalassemia, or sickle cell anaemia that are prevalent across populations, but that misses the huge burden of disease caused by rare conditions,' said co-senior author Dr Kumarasamy Thangaraj, at the CSIR-Centre for Cellular and Molecular Biology in Hyderabad, India.
The next step will be to map out the genetic origins of disease-inducing variants within the subpopulations. The scientists hope that this will impact rare disease research, prevention, and treatment. It could allow for premarital and prenatal screenings that could reduce disease incidence, and could increase understanding of disease-causing mechanisms, aiding the development of predictive and personalised treatments.
'Our work highlights an opportunity to identify mutations that are responsible for population-specific disease and to test for and decrease the burden of recessive genetic diseases in South Asia,' said co-senior author Professor David Reich at HMS.