Searching for Missing Genomes

Enormous strides have been made to unravel the secrets of the human genome, so why are we missing the genetic information of most of the planet?

In the summer of 2020, a 63-year-old African American woman with colon cancer was treated with a common chemotherapy known as fluoropyrimidines at the National Institutes of Health (NIH) Clinical Centre in Bethesda, Maryland. But over the coming weeks, she began to develop a severe side-effect known as pancytopenia – a rapid and sudden decrease of red and white blood cells and platelets – causing her to be rushed into intensive care.

This kind of reaction is surprisingly common. Around 38,000 cancer patients in England and approximately 154,000 patients in the US are initiated on fluoropyrimidine-based treatments every year. While fluoropyrimidines help save lives, between 20% and 30% of the people who receive these drugs require lower doses, because their bodies struggle to process them. If given the standard dose, they experience reactions which can vary from severe to fatal.

Like many adverse drug reactions, this is thought to be at least in part due to variations in the human genome, the strings of billions of letters or chemical bases which comprise our DNA. But while all humans share 99.9% of our genome, the remaining 0.1% varies markedly from one individual to another, or between ethnic groups. Differences in the underlying sequence behind a particular gene – which can be anything from a few hundred to several million bases – can have profound and far-reaching consequences for our health.

In recent years, genetic-sequencing studies have started to get to the bottom of why some people react so badly to fluoropyrimidines, pinpointing four different variations of a gene called DPYD which is involved in metabolism, as the likely cause. Healthcare systems around the world have now begun sequencing the DNA of certain cancer patients and screening for each of these four variants before determining their chemotherapy dose.

The only problem is that these studies were done entirely on white people, or as geneticists say, "individuals of European ancestry". While different variants of DPYD may serve as warning signs for people of other ethnicities, we do not have enough data to be sure of which variants are most applicable to different ethnic groups. "Ethnic minority patients will usually be given conventional doses of the drugs," says Munir Pirmohamed, a pharmacologist at the University of Liverpool in the UK. "Some of these patients will carry other ethnic-specific variants which also affect their ability to metabolise these drugs, but we do not currently genotype for those, largely because we do not know."  READ MORE...