The Origin of MicroRNA Genes: Uncovering the Mechanism of PALREV

Friday - December 22 2023, 21:32 UTC - 11 months ago

Researchers at the University of Helsinki have uncovered a mechanism, PALREV, for the origin of microRNA genes from noncoding DNA sequences. PALREV has an essential role to play for evolutionary processes, such as adaptation, and creates new genes at a surprisingly frequent rate.

Researchers at the University of Helsinki have uncovered a mechanism that instantaneously generates DNA palindromes, potentially leading to the creation of new microRNA genes from noncoding DNA sequences. This discovery, which was made while studying DNA replication errors and their impact on RNA molecule structures, offers new insights into gene origins. The complexity of living organisms is encoded within their genes, but where do these genes come from? Researchers at the University of Helsinki resolved outstanding questions around the origin of small regulatory genes, and described a mechanism that creates their DNA palindromes. Under suitable circumstances, these palindromes evolve into microRNA genes.

The human genome contains ca. 20,000 genes that are used for the construction of proteins. Actions of these classical genes are coordinated by thousands of regulatory genes, the smallest of which encode microRNA molecules that are 22 base pairs in length. While the number of genes remains relatively constant, occasionally new genes emerge during evolution. Similar to the genesis of biological life, the origin of new genes has continued to fascinate scientists.

All RNA molecules require palindromic runs of bases that lock the molecule into its functional conformation. Importantly, the chances of random base mutations gradually forming such palindromic runs are extremely small, even for the simple microRNA genes. Hence, the origin of these palindromic sequences has puzzled researchers. Experts at the Institute of Biotechnology, University of Helsinki, Finland resolved this mystery, describing a mechanism that can instantaneously generate complete DNA palindromes and thus create new microRNA genes from previously noncoding DNA sequences.

In a project funded by the Academy of Finland, researchers studied errors in DNA replication. Ari Löytynoja, the project leader, compares DNA replication to typing of text.“DNA is copied one base at a time, and typically mutations are erroneous single bases, like mis-punches on a laptop keyboard. We studied a mechanism creating larger errors, like copy-pasting text from another context. We were especially interested in cases that copied the text backward so that it creates a palindrome.” .

Researchers recognized that DNA replication errors could sometimes be beneficial. They described these findings to Mikko Frilander, an expert in RNA biology. He immediately saw the connection to the structure of RNA molecules.“In an RNA molecule, the bases of adjacent palindromes can pair and form structures resembling a hairpin. Such structures are crucial for the function of the RNA molecules,” he explains.

Researchers decided to focus on microRNA genes due to their simple structure: the genes are very short – just a few tens of bases – and they have to fold into a hairpin structure to function correctly.

A central insight was to model the gene history using a custom computer algorithm. According to postdoctoral researcher Heli Mönttinen, this enables the closest inspection of the origin of genes thus far.“The whole genome of ten plant species was run through our algorithm in a supercomputer,” she says.

The algorithm helped researchers uncover cases where a gene was instantaneously formed through a single replication error, creating a complete DNA palindrome. This mechanism for the origin of new genes was named Palindrome-mediated Rapid Evolution (PALREV).

PALREV provides an explanation for the emergence of regulatory genes in all organisms, including humans. As Ari Löytynoja points out, the creation of new genes is a surprisingly frequent phenomenon.“New genes are created at a rate that suggests they have an important role to play for evolutionary processes, such as adaptation to new environmental pressures,” he adds.