Health Science Reviews

By Mené Muller

In 1961, Francis Crick and Sydney Brenner deciphered our genetic code. By reading and decoding our chromosomes as linear strings of letters, like sentences in a novel, our genes seemed like an open book. But what if the letters started jumping off the page?

A new study by researchers at Columbia University shows that bacteria is challenging the boundaries of chromosomes by creating free-floating genes, raising the possibility that similar genes exist outside of our own genome.

The relentless arms-race between bacteria and viruses has led to bewildering discoveries of bacteria’s ability to fend for themselves. Most known bacterial immune systems attempt to identify and destroy any foreign viral nucleic acids. This study discovered a new bacterial defence mechanism in which bacteria can leverage DNA synthesis to create genetic weapons. Through a unique process of rolling-circle reverse transcription of non-coding RNA (ncRNA), these Defence-associated Reverse Transcriptase (DRT2) systems synthesise de novo genes when a virus attacks. This discovery not only adds to our knowledge on bacterial immune systems, but also challenges the conventional understanding of how genetic information is encoded and expressed.

The Columbia University researchers created a new technique called cDNA immunoprecipitation and sequencing (cDIP-seq) which was used alongside traditional RNA immunoprecipitation (RIP-seq) to identify the DNA produced by the reverse transcriptase. This profiling revealed long but repetitive cDNA products within the defence system’s RNA molecule. This portion of the RNA molecule folds into a loop, and the reverse transcriptase travels around the loop to create the repetitive DNA. It’s like you were trying to photocopy a book, but the copier just started churning out the same page over and over again. Secondstrand cDNA synthesis is then triggered by the presence of phage in the DRT2-expressing cells, resulting in long double-stranded DNA molecules (Figure 1).

Figure 1: Model for the antiphage defence mechanism of DRT2 systems (adapted from Tang et al. 2024).

To the surprise of the investigating researchers, this DNA molecule is transcribed to produce messenger RNA (mRNA) with a never-ending open reading frame called neo. Neo translation exploits a ribosome rescue pathway to produce Neo proteins that arrest cell growth, protecting the larger bacterial population from the spread of phage by preventing the virus from replicating and infecting neighbouring cells.

This groundbreaking work expands the potential of genome coding through RNA template de novo gene creation, challenging the traditional belief that genetic information is confined to the linear sequence of DNA within our 23 chromosomes. These findings are particularly significant given the large proportion (98.5%) of non coding DNA in higher organisms, much of which produces RNA with known regulatory functions. The researchers propose that additional examples of Neo-like protein-coding genes may still be hidden within our own genomes, waiting to be discovered. Furthermore, the unique properties of the reverse transcriptase responsible for creating Neo could offer promising new avenues for genome editing in gene therapies.

Reference:

Stephen Tang, Valentin Conte, Dennis J. Zhang, Rimantė Žedaveinytė, George D. Lampe, Tanner Wiegand, Lauren C. Tang, Megan Wang, Matt W. G. Walker, Jerrin Thomas George, Luke E. Berchowitz, Marko Jovanovic, Samuel H. Sternberg. De novo gene synthesis by an antiviral reverse transcriptase. Science, 2024; DOI: 10.1126/science.adq0876