Putting Singapore on the Global Genetics Map

When perusing the label on a drug packet, you will likely be presented with two dose recommendations: one for adults and one for children. While you may find that you respond perfectly well to the recommended adult option, another person may need a lower dose, or even experience an severe allergic reaction. Decades of accumulating research is revealing that this variability in drug response and much more is linked to differences in our genes.

Identifying and using the genetic variations present across populations to improve diagnosis, treatment, disease prediction and prevention forms the cornerstone of precision medicine. However, this diversion from the traditional one-size-fits-all approach to medicine requisites large catalogues of genetics data. And while numerous genome sequencing projects have been initiated over the past decade, there is a gross underrepresentation of Asian genetics data, which can mean wide discrepancies in the delivery of precision medicine to more than half of the world’s population.

This is why, in 2016, Singapore launched the ambitious SG10K project, which, as its name suggests, aimed to sequence the genomes of 10,000 Singaporeans. Given the country’s unique mix of Chinese, Malay, and Indian ethnic groups—which together represent about 80% of the global Asian population—the SG10K stands as the world’s largest multi-ethnic Asian genetics database. The results of the SG10K pilot study, which analysed the sequences of nearly 5,000 individuals, have been published in the journal Cell.

Truly Unique Yet Deeply Connected

Like the traditional one-size-fits-all approach to medicine, centring the majority of genetics studies in European and Western populations ignores the fact that Caucasians differ from Asians and other racial groups in both genetics and traits. In fact, the SG10K pilot study showcases just how unique Asian genes are.

By studying the genomic sequences of 2,780 Chinese, 903 Malays, and 1,127 Indians, researchers involved in the SG10K pilot study, who hailed from A*STAR, the National University of Singapore (NUS), Duke-NUS Medical School and public hospitals in Singapore, identified 98.3 million genetic variants. Of these, more than half—52 million genetic variants—had never been reported before. The existence of this enormous amount of novel genetic variation in Asians underscores the importance of performing genetics studies in local ethnic and underrepresented groups, especially for the future of precision medicine.

While unique compared to Caucasians, Singapore’s multi-ethnic population is highly representative of the genetic diversity found across South and East Asia. In fact, by tracing their ancestries, the study found that the majority of Singaporean Chinese and Indian populations are closely related to those from south China and the south Indian subcontinents respectively. The migration of these groups from China and India then likely led to a mixing of genes with those of the indigenous people of the Malay Archipelago.

“This study shows that there are a significant proportion of individuals whose genomes are kind of a mosaic: they have ancestry components from other ethnic groups,” said Professor Liu Jianjun, Deputy Executive Director of A*STAR’s Genome Institute of Singapore (GIS) and one of the senior authors on the paper. “So, even though we comprise three different ethnic groups, we are definitely much more closely connected than we think.”

This vast interconnectedness means that findings from SG10K can have transformative effects on genetics research and far-reaching applications for Asian populations around the globe.

Looking Back to the Future

Far from simply satisfying our deep curiosity about where we come from, understanding our ancestry can tell us how we have evolved into the people we are today, and in turn allow us to make predictions for the future, said Liu, who was recently awarded the President’s Science Award for his contributions to genetics research in Asian population.

In Singapore’s three major ethnic groups, the SG10K pilot study identified 20 locations on chromosomes—known as loci—where gene sequences may have been altered due to natural selection. Fourteen of these 20 loci have links to human traits and disease, which may explain why some are more or less common among Asians than other populations.

For example, changes in one locus called ALDH2, which is responsible for alcohol metabolism, may explain the ‘Asian flush’ phenomenon common in its namesake population. Additionally, two other loci, EDAR and PRSS53, are commonly linked to hair morphology in East Asians and may explain the evolution in scalp hair thickness.

A better understanding of exactly what certain genetic variations mean and which are important in terms of health and disease will ultimately enable scientists and clinicians to design more accurate diagnostic screens for diseases and the risk of adverse reactions to treatment.

“Ultimately, the idea behind precision medicine is to give the right dose of the right drug to the right person,” Liu noted. “But we also need to think bigger and look at how we can change the risk profiles of populations, to help prevent or delay disease onset, because this will have a much bigger impact overall.”

Reference:

Wu, D., Dou, J., Chai, X., Bellis, C., Wilm, A., et al. Large-scale whole-genome sequencing of three diverse Asian populations in Singapore. Cell 179, 736–749.e15 (2019).