STR Sequence Variability Reveals New Insights into Human Genetic Diversity

Scientists at The Hospital for Sick Children (SickKids) have identified a previously underappreciated form of genetic variation that may help explain why diseases manifest differently among individuals and why some treatments are more effective in specific populations. The study centers on short tandem repeats (STRs), repeated DNA sequences that comprise about seven per cent of the human genome. As these repeats multiply, they can interfere with gene activity and contribute to disorders such as Huntington’s disease, autism spectrum disorder, schizophrenia, and cardiomyopathy.

Published in Genome Biology, the study examined genomic data from more than 3,000 people and found that nearly seven per cent of STRs show differences not only in length but also in internal DNA 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,” said study leader Ryan Yuen.

The researchers discovered that variable STRs are often positioned near Alu elements, repetitive DNA regions whose biological functions remain poorly understood. These STRs frequently appear near splice junctions in genes involved in brain development and neural processes. “We saw clear patterns, like these diverse repeats appearing in genes related to neurodevelopment and brain function,” said Sasha Mitina, first author of the study. “Genes affected by these variations are linked to critical biological processes and may help explain individual differences in health and disease.”

Distinct patterns of STR variability also emerged among different ethnic groups, which may guide future efforts to predict disease susceptibility and optimize treatments for diverse populations. 

While most analytical tools assess only the length of tandem repeats, Yuen’s team used a new algorithm—developed in collaboration with The Centre for Applied Genomics—to detect both the size and sequence composition of STRs using short-read sequencing data. “Our approach lets us see both size and sequence composition,” said 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 sequencing technologies become more advanced, the researchers expect deeper insights into neurodevelopmental and other complex genetic disorders.