Scientists at The Hospital for Sick Children (SickKids) have revealed a previously overlooked layer of genetic variation that could help explain why people experience disease differently, and why some treatments work better for certain populations. 

Tandem repeats are repeated sections of a DNA strand that make up about seven per cent of the human genome. The likelihood of those tandem repeats causing errors in gene function increases each time they repeat, and they are known to cause conditions like Huntington's disease and are implicated in many others, including autism spectrum disorder, schizophrenia and cardiomyopathy. 

Now, a SickKids-led study is the first to show that in addition to the length of the tandem repeat, subtle changes in the composition of short tandem repeats (STRs) can also have a big impact on how genes work. 

Published in Genome Biology, the research team analyzed genomic data from over 3,000 individuals in the general population and found that about seven per cent of STRs in the human genome show variations in the sequence composition. 

"These changes in STR composition aren't rare, they're a normal part of human genetic diversity. This is a new dimension of genetic variation that's been hiding in plain sight," says study-lead Dr. Ryan Yuen, Senior Scientist in the Genetics & Genome Biology program. 

STRs closely linked to brain development and function 

In addition to describing the prevalence of STRs in the general population, the research team made several other findings that may inform future research and precision therapeutic development in support of Precision Child Health, a movement at SickKids to individualize care for every patient. 

First, they discovered that variable STRs are often located close to Alu elements, repetitive DNA sequences whose function is still relatively unknown. These STRs appear more frequently at splice junctions in genes involved in brain development and function. 

"We saw clear patterns, like these diverse repeats appearing in genes related to neurodevelopment and brain function," says Dr. Sasha Mitina, a Research Fellow in the Yuen Lab and the study's first author. "Genes affected by these variations are linked to critical biological processes and may help explain individual differences in health and disease." 

The study also found distinct patterns in STR variability among different ethnic groups, a finding the research team believes may help scientists better predict disease risk and tailor treatments to different populations in the future. 

"A new dimension of genetic variation" 

Most tools and algorithms only look at the length of tandem repeats. Using an algorithm developed by Yuen and through expertise at The Centre for Applied Genomics (TCAG) at SickKids, the team was able to detect both repeat size and composition, even with short-read sequencing data. 

"Our approach lets us see both size and sequence composition," says Yuen. "We're still only scratching the surface, but these regions may hold the answers to some of the unknowns in our genome and contain potential targets for future disease studies." 

As long-read sequencing becomes more common, the researchers expect to uncover even more hidden variation as well as new insights into neurodevelopmental conditions, eventually informing the future of clinical genomics. 

This study was funded by the Canadian Institutes of Health Research (CIHR).