Scientists discover tiny parts of DNA that explain why diseases hit people differently

Tiny repeated stretches of DNA in your genome may quietly shape how your body works, how your brain develops and how you respond to disease. A new study from scientists at The Hospital for Sick Children in Toronto reveals that these repeats are more diverse than anyone realized, opening a hidden layer of genetic variation that standard tests usually miss.

About seven per cent of your DNA consists of tandem repeats, short sequences that appear again and again in a row. When those repeats get too long, they can disrupt gene function. That is already known for conditions such as Huntington’s disease, and they have been linked to autism spectrum disorder, schizophrenia and cardiomyopathy.

Until now, most tools treated these repeats like tick marks on a ruler. They counted how many times a small unit repeated and compared that length across people. The new work, published in Genome Biology, shows that length is only part of the story. The exact makeup of those repeating units, called short tandem repeats or STRs, also changes, and those subtle shifts can alter how genes behave.

“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, a Senior Scientist in the Genetics & Genome Biology program.

The team analyzed genome data from more than 3,000 people in the general population. Instead of only counting repeat length, they used a custom algorithm developed at SickKids to read both the size and sequence of STRs, even from standard short read sequencing.

What they found surprised them. Around seven per cent of STRs across the human genome showed variation in their internal sequence, not just their length. In other words, people can share an STR in the same location, yet the repeating pattern itself can differ.

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

These variable STRs were not scattered at random. They often sat next to Alu elements, another form of repetitive DNA whose precise role is still being studied. Many of the STRs with composition changes clustered at splice junctions, the places where gene segments are cut and stitched together when cells build proteins. Those splice sites often belonged to genes involved in brain development and neural activity.

Because STRs can shape how genes are read, changes in their sequence can ripple through important biological pathways. The team saw that STRs with different compositions were linked to genes central to brain formation, neuron growth and communication between nerve cells. That connection may help explain why two people can carry similar overall genetic risk yet develop very different symptoms.

The patterns also differed across populations. The researchers saw distinct STR composition profiles in different ancestral groups. That suggests this new form of variation contributes to population level differences in disease risk and treatment response.

For you, that matters because it pushes genetic research a step closer to truly personalized medicine. It hints that part of what makes one community more vulnerable to a given condition, or more likely to benefit from a specific therapy, may sit inside these tiny repeated stretches that routine tests often ignore.

Most existing software looks at STR length alone. That made sense when scientists had limited computing power and lower resolution data. With their new algorithm and support from The Centre for Applied Genomics at SickKids, Yuen’s group could pull out both length and composition from the same short read data that many clinics already generate.

“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.”

Long read sequencing, which is slowly becoming more accessible, will likely reveal even more fine grained variation in these regions. That will matter for conditions such as autism and other neurodevelopmental disorders, where many families still never receive a clear genetic answer.

The project, funded by the Canadian Institutes of Health Research, fits into the hospital’s broader Precision Child Health vision, which aims to tailor care to each child’s unique biology.

The study suggests that STR composition adds a fresh dimension to the usual picture of genetic difference. Instead of only single letter changes and large structural variants, your genome also carries diversity in the pattern of its repeats.

For a child with a rare condition, that might mean a disease linked not only to a repeat that grows too long, but also to one whose pattern quietly shifted. For a patient starting a new medication, it may help explain why a drug works well in one person yet fails in another, even when their basic genetic test looks similar.

By showing that these repeat patterns are common and functionally important, the work challenges the field to broaden what it considers meaningful variation. It also points to new targets for future studies of brain disorders, heart disease and other complex conditions that have long resisted simple genetic explanations.

Looking ahead, this research could reshape how doctors and scientists interpret genetic tests. If clinical labs begin to track STR composition as well as length, more families may finally receive answers about unexplained conditions, especially in the area of child neurology and mental health.

For precision medicine, understanding STR patterns across populations could improve risk prediction models and help match treatments to the patients most likely to benefit, rather than relying only on broad ethnic labels or single DNA changes.

In research, these findings open a new path for studying complex diseases that involve many genes and subtle regulatory shifts. Scientists can now look more closely at STR rich regions near brain related genes, search for links to conditions such as autism spectrum disorder or schizophrenia and design therapies that target the right pathways.

As long read sequencing becomes routine, even more hidden variation in these repeats will come into focus. That may lead to new biomarkers for early diagnosis, better tools to monitor disease progression and, in the long run, more precise ways to prevent or soften the impact of genetic disorders.

Research findings are available online in the journal Genome Biology.

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