Every person carries several genetic mutations and if they occur in two copies these will lead to serious recessive diseases. The 1.5 billion people of South Asia are more vulnerable to rare genetic population-specific diseases than elsewhere in the world because of the endogamous marriages or marrying within the same ethnicity, community, caste, etc.
A study led by co-senior authors Dr. Kumarasamy Thangaraj of CSIR-Centre for Cellular and Molecular Biology (CCMB) and Dr. David Reich of Broad Institute MIT & Harvard, Cambridge, U.S., in collaboration with other institutes, has identified that about a third of population here have had such strong defective genes passed on through generations.
“We have analysed samples from more than 2,800 individuals from over 275 distinct SA populations belonging to various social and linguistic groups from India, Pakistan, Nepal, Sri Lanka, and Bangladesh, using about 6,00,000 genome-wide markers,” said Dr. Thangaraj in the presence of CCMB Director R.K. Mishra at a press conference on Tuesday.
“We found that 81 out of 263 unique South Asian groups, including 14 groups with estimated census sizes of over a million, have a genetic mutation base with recessive diseases much more than the one that occurred in both Finns and Ashkenazi Jews in the West,” he said,” he said.
This source of risk for genetic recessive diseases was quite different from that due to marriages among close relatives (consanguineous marriages), which was also a major cause of recessive disease in South Asia, said the study published in the online edition of ‘Nature Genetics,’ on July 17.
Giving an example of the founder event disease gene mapping, the authors highlighted the case of the Vysya community, with a census size of more than three million and endogamous for centuries where the occurrence of a defective gene causing ailments was about 1.2-fold stronger than that in the Finnish population.
The Vysya community have an approximately 100-fold higher rate of ‘butyrylcholinesterase’ deficiency than other groups, and Vysya ancestry is a known counter-indication for the use of muscle relaxants such as ‘succinylcholine’ or ‘mivacurium’ given prior to surgery. So, this disease was likely to occur at a higher rate due to the defective gene in the community.
The authors had analysed six patients from Hyderabad and Bengaluru with a progressive ‘Pseudorheumatoid Dysplasia’ (PPD), a disease known to be caused by mutations in the WISP3 gene. Of the six with a mutation, five were from non-consanguineous marriages, and they passed on the genetic mutation to their offspring. The children, however, died within 10 years as “none could identify the genetic reasons or diagnose the ailments which led to their deaths”.
“Our study provides opportunity for discovering population-specific disease causing genes in communities known to pass on such recessive diseases. Mapping mutations responsible for population-specific disease would help in developing strategies for diagnosis, counselling, management and modifying the clinical course of these disorders and reduce the disease burden,” explained Dr. Thangaraj.
The CCMB scientist hoped that the study would motivate researchers, health officials and policy makers in South Asia to study the genetic features specific to each of these groups and translate it to an actionable medical research.
Giving an example, he said ‘Dor Yeshorim’, a community genetic testing programme among Orthodox Ashkenazi Jews, screens students for common recessive disease causing mutations and results are put into a confidential database.
Matchmakers check the database whether the potential couple was “incompatible” in the sense of both being carriers for a recessive mutation at the same gene. The strategy has helped reduce the rate of many recessive diseases to near-zero among Orthodox Ashkenazi Jews so a similar strategy could be effective here too.
CCMB Director Dr. Mishra pointed out that the current effort led by CSIR-CCMB would enable a paradigm shift in facilitating and accelerating predictive and personalised medicine.