In cancer research, one person's junk is increasingly becoming another person's treasure. Scientists have now uncovered new evidence showing how recently evolved "junk DNA" genetic elements can become integrated into ancient cellular pathways that regulate cancer. These findings may provide fresh insights into how evolutionary forces shape disease and reveal potential new targets for cancer research.
In a new study published today in the journal Science Advances ( 10.1126/sciadv.aeb5510 ), researchers from Arizona State University and an international team led by Tianjin Medical University, examined the evolutionary history of "junk DNA" molecules that were first identified a generation ago from the human genome project.
The phrase "junk DNA" often refers to DNA elements that do not produce proteins and possibly do not contribute to organism performance. Numerous classes of such elements make up much of the human genome. Scientists questioned why they were there. But further research proved this was a misnomer when they were found to play an important role in helping regulate how genes function, including emerging insights into how they may be associated with diseases like cancer.
Now referred to as long noncoding RNAs (lncRNAs), many are unique to primates and humans, and so scientists have increasingly recognized them as important players in cancer.
Lurking in the oldest branches of life
By performing a comparative genomic study, the researchers found that many cancer-associated lncRNAs first emerged on the scene as smaller, non-functional RNA fragments, or microRNA elements, through increased transcription. These gradually expanded in length to become lncRNAs by incorporating additional genetic material, and eventually became integrated into deeply conserved, vital cellular pathways that evolved hundreds of millions of years ago.
"Our findings suggest that cancer-associated long noncoding RNAs are not simply recent evolutionary additions," said Michael Lynch, professor in the Biodesign Center for Mechanisms of Evolution at Arizona State University and co-author of the study. "Instead, they can gradually become integrated into regulatory systems that have existed for hundreds of millions of years, illustrating how evolution continually reshapes the architecture of cellular networks in ways that become relevant to diseases like cancer."
Using genomic sequence analyses of 18,000 lncRNAs across 17 animal species, the researchers reconstructed how lncRNAs first emerged and retraced their biological roles over almost 500 million years of evolutionary time. Overall, ~5000 lncRNAs were identified and found to be associated with at least one cancer type. These were retained for further investigation. During the evolutionary trajectory of primates, the studied lncRNAs showed significant expansion of their genomic segments, alongside a notable increase in their overall expression abundance.
The team explored the role of one particular lncRNA, MIR497HG, as a striking example of this process.
The molecule appears to have originated in a common human and primate ancestor as a microRNA some 29 million years ago, before a time when humans and macaques diverged.
Around that time, a single DNA mutation, changing the DNA code from A-to-T, created a new green "go" light to sputter out short bursts of RNA expression, and thus, MIR497HG was born.
After humans and macaques diverged 29 million years ago, a long form of MIR497HG first emerged, entirely unique to humans. As it grew and expanded, the molecule became interconnected to ancient regulatory networks (473 million years ago) ---important pathways necessary for multicellular life, including metabolism, stress responses and programmed cell death. Once expanded, they could repurpose these pathways for a brand-new role, where misexpression could be cancer-causing.
Lab experiments reenforce findings
