The findings, published in the journal Science Advances, highlight the importance of microRNA genes, which are located in the non-coding portion of the human genome and regulate the activity of protein-producing genes.

Human DNA contains genes encoding about 2,000 different microRNA molecules, which help control the levels of proteins involved in nearly all biological processes. While the genome contains instructions for building roughly 20,000 proteins, those protein-coding genes make up just over 1 percent of the genome. Much of the remaining DNA contains regulatory elements that control how and when proteins are produced.

Among these regulatory elements are microRNAs — short molecules about 20 nucleotides long that influence gene expression.

“MicroRNAs are the cooks who decide how much of a recipe's ingredients to use: how much salt to add to a soup, how much crumble topping to add to a cake. If, for some reason, a cook adds ten times more salt or three times less flour than the recipe calls for, the dish will turn out bad. MicroRNA mutations cause certain detriments in the work of these cooks: one's hands shake, another loses track of proportions. As a result, the entire physiological process of adding individual ingredients is disrupted,” Professor Piotr Kozłowski from the Institute of Bioorganic Chemistry of the Polish Academy of Sciences said.

The new study shows that mutations in microRNA genes often damage these regulatory molecules and interfere with the processes they control.

“Most mutations in microRNA genes lead to damage to these genes and can therefore disrupt the processes they control, among them diseases, including cancer. This demonstrates that mutations in microRNA genes, until recently almost completely ignored in genetic research, must be seriously considered,” Kozłowski said.

Because microRNAs are extremely short molecules, even small changes in their genetic sequence can have major effects on their function.

“Mutations either lead to a significant reduction in microRNA levels in the cell or to a change in the precision of their excision from the so-called +precursors+, leading to changes in their function,” Kozłowski added.

The research is part of a broader programme funded by a MAESTRO grant from the Polish National Science Centre. In earlier work under the same project, Kozłowski’s team detected and characterised thousands of mutations in microRNA genes and identified those that appear particularly frequently in cancer.

The researchers also developed experimental, computational and statistical tools to analyse mutations in microRNA genes and other non-coding regions of the genome.

They additionally created a database of human microRNAs associated with cancer.

“We have already detected several very promising genes, such as microRNA-142, which is the most frequently mutated microRNA gene in all cancers, particularly in blood cancers (lymphomas and leukaemias). Others, like microRNA-205, are frequently altered in melanoma. At this stage, we do not yet have diagnostic tools in the strict sense, but these studies provide a solid foundation for developing them,” Kozłowski said.

He added that the findings could eventually support the development of new treatments aimed at restoring the normal function of damaged microRNAs.

“Genetic research has not ended with the genome sequence. What we have discovered so far is just the tip of the iceberg. The vast majority of the human genome is still an unexplored +desert+, with countless breakthroughs still waiting ahead. Evolution is not cavalier – it is not that this 99 percent of +non-coding+ DNA serves no purpose. We simply need to learn to read it,” Kozłowski said.

PAP - Science in Poland, Ludwika Tomala (PAP)

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