Elements in ‘Dark Genome’ Tied to Disease Progression Differences

Many genetic sequences called transposable elements showed associations with UPDRS scores

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Transposable elements, a common feature in the so-called “dark genome,” are associated with clinical differences in how Parkinson’s disease progresses among different people, a new study indicates.

“Our main finding is that the presence or absence of [transposable elements] changes progression trajectory of [Parkinson’s], and we provided clinical, imaging, and biochemical evidence to support this,” researchers wrote.

Non-reference genome transposable elements (TEs) have a significant impact on the progression of the Parkinson’s disease,” was published in Experimental Biology and Medicine.

It’s long been understood that the genetic code stored in DNA provides instructions for making proteins. But, the parts of DNA that code for proteins account for less than 2% of the total human genome — the rest are non-coding elements whose function has only recently begun to be explored in detail.

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Sulev Koks, MD, PhD, a professor at Murdoch University in Australia and first author of the study, calls these non-coding elements the “dark genome.”

“This fascinating study by Koks and his colleagues demonstrates that the presence or absence of transposable elements controls the progressions trajectory of Parkinson’s Disease. It further underscores the importance of rigorous analysis of these genomic elements is essential for considering therapeutic opportunities,” Steven Goodman, the journal’s editor-in-chief, said in a press release.

One of the most abundant types of non-coding genetic sequences are transposable elements, or TEs. These are repetitive pieces of DNA that can “jump around,” moving between different places in the overall genetic code.

“Transposable elements are part of the genome which is known as the ‘dark genome.’ … The elements inside the dark genome could enhance or slow the progression of Parkinson’s disease and therefore open up new opportunities for precision medicine,” Koks said.

Our study showed that the dark genome may have a much more significant impact on the pathophysiology of complex disease than previously estimated.

Koks and colleagues analyzed genetic data from 1,336 people with Parkinson’s, collected via the Parkinson’s progression markers initiative (PPMI) — a longitudinal, observational study of people with and without Parkinson’s.

The researchers identified 16,438 TEs in these data. None showed a significant association with risk of developing Parkinson’s in statistical models.

The team then looked for associations between TEs and the change in Parkinson’s severity over time in 423 patients followed for four years. This analysis included 3,374 TEs and more than 100 Parkinson’s-related measures.

Results showed many statistically significant associations. For example, more than 200 TEs showed significant associations with scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), a common tool that measures the severity of Parkinson’s. There were about 150 TEs associated with degeneration in the putamen, a brain region that’s heavily impacted in the disease.

“We identified many non-reference TEs to have an impact on the progression of [Parkinson’s], most remarkably on the progression of the UPDRS subscores and degeneration of the putamen,” the researchers wrote.

The team also identified many TEs associated with a primary diagnosis, the first condition patients were diagnosed with when they began experiencing symptoms.

“Patients with certain TEs were more likely to receive incorrect diagnosis at the early visits that was corrected later. The change of diagnosis could indicate the difference in the [disease manifestations] of the subjects with different TE genotypes,” the researchers wrote, noting this finding “could suggest even a separate subtype of the disease.”

“Our study showed that the dark genome may have a much more significant impact on the pathophysiology of complex disease than previously estimated,” Koks said.

The study was designed only to detect associations, not cause-and-effect relationships. The researchers called for more research into how TEs affect Parkinson’s in laboratory models.