More Powerful DNA Mapping Could Help Scientists Better Understand Friedreich’s Ataxia

Researchers at Tufts University have developed a new, more powerful method of analyzing DNA sequencing to better identify and understand complex genomic rearrangements (CGRs), which are involved in many genetic disorders and cancers.

CGRs can occur in diseases where expansion of repetitive DNA sequences is a core feature, such as Friedreich’s ataxia, Huntington’s disease, and fragile X syndrome. They are created by DNA breaks that are not repaired properly. This can lead to abnormal DNA structures that impair an accurate readout of messages encoded in DNA.

Friedreich’s ataxia, a genetic condition that affects the nervous system and muscles, is caused by the insertion of a small DNA sequence in the FXN gene. This sequence has three nucleotides, GAA, that can be abnormally repeated up to 1,000 times in the FXN gene. This creates genetic instability and can lead to the formation of CGRs.

Identifying and understanding CGR formation is important because it not only affects what happens to DNA, but also how a cell behaves.

In the past, visualizing and identifying CGRs was time-consuming and required complex high-resolution bio-imaging.

But in the study, “Nanopore sequencing of complex genomic rearrangements in yeast reveals mechanisms of repeat-mediated double-strand break repair,” published in the journal Genome Research, researchers describe a more powerful and efficient approach to analyzing CGRs.

This new approach uses a DNA-sequencing device developed by Oxford Nanopore Technologies that allows researchers to analyze longer DNA sequences with greater accuracy. For example, previous technology allowed scientists to read DNA in segments of only a few hundred nucleotides. With this new hand-held DNA sequencing device, they can analyze DNA fragments that are tens of thousands of nucleotides in length. This provides a fuller picture of the CGRs, according to a Tufts University news release.

Researchers tested the new device on a yeast model with GAA repetitions similar to those found in patients with Friedrich’s ataxia. The analysis showed that DNA sequences with GAA repetitions are more susceptible to breaking and forming CGRs involving different chromosomes.

This new method could provide scientists with a comprehensive landscape of abnormal CGRs and additional information about possible outcomes.

“This is a groundbreaking approach to analyzing CGRs and determining their origins and outcomes,” said Sergei Mirkin, PhD, professor and chair of the Department of Biology at Tufts University and senior author of the study. “This research could significantly advance the way the scientific community deciphers, diagnoses and treats certain genetic disorders and other diseases caused by disruptions of the genome.”