The team had been studying three related genes encoded by the INK4/ARF (or CDKN2a/b) locus which is closely associated with human aging. Previous genome-wide association studies (GWAS) from several large consortia have shown that common genetic variants located very near, but not actually in, these genes are associated with diseases of aging such as cancer, heart attack, stroke, type 2 diabetes and frailty. Yet how these variants contribute to the risk of these common human ailments was not known.

The UNC team, led by post-doctoral fellow Christin Burd, PhD, and supervised by UNC Lineberger associate director Ned Sharpless, MD, thought a piece of cellular machinery called a long non-coding RNA might be involved. Long non-coding RNAs are RNA molecules that are not translated into proteins, but which appear to regulate the expression of nearby genes. The number of these molecules encoded in the human genome is unknown, but thought to be in the thousands. However, since the study of these molecules is a new field, the vast majority of these RNAs are of unknown function.

In the course of investigating the link between the aging-related INK4/ARF variants and an associated long non-coding RNA, the team came across a finding so unexpected that, according to Sharpless, they thought it was a simple laboratory mistake for several months, despite multiple repetitions. The group kept observing that expressed non-coding RNA sequences linked to the INK4/ARF locus occurred in what appeared to be the "wrong order." They showed that these mis-ordered RNAs were not a mistake or byproduct of the experimental methodology, demonstrating that blood samples from more than 100 different individuals all contained these unexpected RNA forms. They considered several explanations for the seemingly incorrect sequence of these RNAs, but eventually proved these data represented the unexpected production of circular RNAs. Circular RNAs are very rare in humans, having been viewed as a biological curiosity without known function.

(Science Daily)

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