Study eyes role of ‘translator’ in disease

While errors in the genetic code dominate disease study, even a properly written code might lead to complications thanks to information getting ‘lost in translation’ as the body constructs its basic building blocks.

A molecule called tRNA – or transfer ribonucleic acid – is an essential component of the human genome that acts as a translator by taking the body’s genetic code and translating it into proteins, one of the key building blocks of the human body.

When researchers investigate the human genome’s relation to disease, they have traditionally focused on mutations in the code for proteins. But now Western researchers have shown that the genes-encoding tRNAs can also have mutations that cause the code to be misread in greater numbers than previously thought.

Think of it like a translator app on your phone – if it has errors in its software, the output is going to be wrong, even if the original text is correct.

“This actually changes the way we think about the genetic code,” said lead author Mathew Berg, a PhD candidate at the Schulich School of Medicine & Dentistry. “We have shown that variation in tRNA has the potential to lead to a protein being made improperly, which can lead to misfolding and malfunction of the protein.”

The research team, led by Schulich professors Christopher Brandl, Robert Hegele and Patrick O’Donoghue, say this is significant because many human diseases like Alzheimer’s disease and diseases of the heart muscle are linked to misfolded proteins.

“Genetic variation is one of the major reasons why some people acquire a disease while others do not. We expect that an individual with 10 abnormal tRNAs might be more likely to acquire a disease than someone with one,” said Brandl. “Another interesting aspect of what we saw is that the profile of tRNAs in even the limited group we looked at was very diverse. No two individuals were the same.”

The researchers point out that all previous evidence suggested there were minimal variations in the tRNA genes, likely attributed to the fact that it hadn’t been looked at this closely before. Based on previous evidence, the team only expected to find one or two mutants in the tRNA.

The group, including PhD candidate Dan Giguere, came up with a new way to sequence and read the tRNA to get a better picture of the variation that exists between individuals. This deep sequencing data gathered at Western showed that human tRNA variation was previously underestimated by more than 30-fold.

In a group of 84 people in London, Ont., they found individuals contain, on average, 66 variants in their tRNA genes.

“Because tRNA variation has been hard to analyze, it has largely been overlooked in genetic association studies. Our work suggests that it is important to look at the tRNA genes and we also provide the tools to do so,” Brandl said.

Next, the group wants to get a better understanding of exactly how these genes are contributing to disease and determine whether it can be reversed. They also expect that they’ll find even greater variation by looking at more diverse populations from other areas around the world.

The study, Targeted sequencing reveals expanded genetic diversity of human transfer RNAs, was published today in journal RNA Biology.