A research team led by Jennifer E. Phillips-Cremins, in Penn Engineering’s Department of Bioengineering and in the Perelman School of Medicine’s Department of Genetics, published a study in the journal Cell, finding a correlation between 3D genome misfolding, short tandem repeat instability, and pathologic gene disruption in the class of neurological disorders that includes ALS and Huntington’s disease.

Instabilities inside the DNA that create an unusually long sequence in the gene chain is involved in the diseases’ pathologies. The team of researchers also found another common thread linking this particular class of diseases, called trinucleotide repeat (TNR) expansion disease: the complicated 3D patterns that the DNA is folded into in order to fit in the nucleus of the cell. They found that nearly all of the sequences known to grow unstable in disease are located at the boundaries that separate neighboring folded domains.

At the core of the mystery behind TNR diseases is what causes their repeating sequences to pathologically expand. The same exact repeating patterns appear in hundreds of thousands of other locations along the linear genome, in genes and non-coding regions alike, but are not known to become unstable.

“I wanted to work on this project because I was fascinated by the idea that 3D genome folding — something I had barely even heard of before joining the Cremins lab — could be the missing piece to understanding why certain parts of the genome behave the way they do,” Says researcher Linda Zhou. “In this case, why can repetitive DNA in certain genes become unstable while others do not?”

In trying to determine what makes the unstable repeats associated with TNR diseases different from their stable counterparts, the researchers considered whether their location with respect to genome folding patterns played a role.

“Every human individual has hundreds of thousands of short tandem repeat tracts distributed throughout their genome. The repeats exhibit wide variation in sequence, location in the gene body, normal and mutation length ranges, the cell types they affect and the phenotypes they produce,” Phillips-Cremins says. “But, for the handful of short tandem repeat tracts known to grow unstable in disease, nearly all are localized specifically to genome folding boundaries.”

Read more at the Penn Engineering blog.