The Genomic Route To Targeted Cures

What The Study Found

The largest genomic study of population groups in Asia, generating and analysing whole-genome sequences of 1,739 ­individuals from 219 groups.

• Tribal populations had more Denisovan admixture than non-tribals.

• Non-Indo-European speakers had more Denisovan admixture than Indo-European speakers.

• Upper caste groups had lesser Denisovan admixture than ­non-upper caste groups.

• Indo-European speaking populations of Pakistan had the lowest level of Denisovan admixture.

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On December 5, 2019, scientists from the GenomeAsia 100K project published an article (‘The GenomeAsia 100K Project enables genetic discoveries across Asia’) in the prestigious science journal Nature. It is the largest genomic study of Asian populations, covering 1,739 individuals from 219 different population groups and 64 countries. India has the maximum number of whole-genome sequences at 598. Besides enabling a better understanding of how Asian populations were formed, the resulting work will also make it possible to find out which medicines suit them better, based on genetic data.

The need for a more varied genetic database from populations across the world was highlighted in 2009, when analysis revealed that 96 per cent of participants in genome-wide association studies (GWAS) were of European descent. GWAS studies associate certain diseases with specific variations and the lack of data from different parts of the world meant medicines eit­her couldn’t be catered to suit them or were entirely unsuitable to them.

“We show that the variant data produced by this project improve variant filtering for the discovery of dise­ase-associated genes of rare diseases. We show that Asia has sizable founder populations and that further studies in these populations may be useful for the discovery of rare-disease-associated genes,” the paper says. For ­example, the researchers found that carbamezepine, an anti-convulsant, may have adverse effects on about 400 million South-East Asians who form part of the Austronesian language group. The paper also mentions that drugs like clopidogrel, peginterferon and warfarin “showed the largest variation between populations in predicted adverse drug responses”.

Dr Partha P. Majumder, founder of National Institute of Biomedical Genomics, Kalyani, and one of the co-authors, tells Outlook that the “differential carbamezepine effect among Austronesians was so striking that we decided to report this quickly. We also report about warfarin, a commonly used blood-thinning drug, used for prevention of blood clots, especially for ind­ividuals at high risk for heart attacks.”

Using the data, the scientists were able to reveal a DNA variant in a gene (NEUROD1), which is probably res­ponsible for a particular kind of diabetes. Another DNA variant in the haemoglobin gene has been linked to beta-thalassemia found only in South Indians, says Majumder.

The scientists discovered close to 200,000 DNA markers in Asians, which had been previously unreported in existing genetic databases. Majumder explains their significance, saying that “the catalogues that are now used for disease-association studies in Asia, including India, are those that have primarily been generated in western populations, hence of limited use in Asia.” The scientists also found 23 per cent of previously unreported protein variants. “Since alterations of proteins are usually associated with disease, we specifically investigated those DNA variants that alter proteins,” says Majumder.

“Medicines will become more specific and more useful to us. More imp­ortantly, we will not use the medicines that do not work for us,” Dr Ch Mohan Rao, distinguished scientist at the Council of Scientific and Industrial Research and former director at the Centre for Cellular & Molecular Biology, tells Outlook. Rao says that the same medicines used in the West are “being used without context in Asia, but now studies show that certain mutations (in DNA) are probably benign.”

“While the fundamental biology discovered by genetic studies at individual sites in the genome are mostly shared across humanity, studies carried out primarily in a single population means we miss low-hanging fruit in other populations, and limit the utility of genomic prediction across other populations,” says Vagheesh Narasimhan, fellow at the Reich lab, department of genetics, Harvard Medical School. He adds that scientists are currently able to predict “heritable risk of complex diseases several-fold more accurately in European populations than in non-Europeans,” putting it down to a lack of similar databases in other countries. “Studies such as this one will help close that gap,” he adds.

The study also paints a finer picture of how the South Asian populations were formed, while throwing up interesting facets. Close to 4 million years ago, two precursors to modern-day ­humans—the Neanderthal and the Denisovan—evolved. While it was earlier thought that the homo sapien (modern human) wiped out both, our DNA contains a large admixture with them, the degree of mixing varying across Asia. In India, the researchers found that tribal and non-Indo European speakers had more Denisovan DNA than the non-tribals and Indo-European speakers. Elite-caste groups have lesser Denisovan DNA, with Indo-European speakers of Pakistan having the least, he adds.

Majumder says the simplest explanation is that Indo-European-speaking migrants, who came to the subcontinent from the north-west, mixed with “an indigenous group ancestral to present-day south Indians; the ancestral group had a high level of Denisovan admixture.”

Using an approach from a previous study, the researchers also tried to identify the degree to which populations are “inherited as identical by ­descent (IBD).” The researchers found multiple Asian urban populations with IBD scores close to or above the Fin­nish population. “For example, samp­les from an outpatient hospital in Chennai, a city with a census size of 9 million, had an IBD score that was ­approximately 1.3 times greater than the score for the Finnish group,” the paper says. Majumder explains: “It is, therefore, possible that some urban populations may have arisen from a small number of founders and then numerically expanded quickly.”

“With such large numbers of samples being sequenced, we now have the ­potential to study population movements and mixtures in much finer ­detail. Databases like this will also enable better estimates of ancestry and genealogy,” says Narasimhan.

When the Human Genome Project began in 1990, India was not part of it. “Fortunately, we did not miss out beca­use the whole database was in public. But we did not develop the technology as fast as other countries,” says Dr Rao, adding that now things have changed with Indian scientists doing a large part of the work. “With India participating in the research our technology and capacity building has increased dramatically. Now we are not second to anyone.”