Unusual DNA structures shed light on the evolution of the hepatitis B virus
The hepatitis B virus (HBV) has a long history with humanity, which can now be reconstructed thanks to recent advances in palaeogenomics, the study of ancient DNA. In 2019, an article published in Science studied the genomes of several ancient strains of HBV found on human bones, the oldest of which date back 10,000 years. By analysing these same sequences in search of unusual DNA structures, a team of French and Czech researchers, including Jean-Louis Mergny, Inserm research director at the Laboratory of Optics and Biosciences (LOB*), has shed new light on this co-evolution in the journal Nucleic Acids Research.
Like the human genome, the HBV genome is made up of a two-stranded DNA structure. This DNA generally takes the form of a double helix. But sometimes other configurations can appear, such as G-quadruplexes. "These structures form a kind of knot in the genome, and can play both a positive role as a regulator and a negative role as an obstacle to DNA replication", explains Jean-Louis Mergny. We still have a lot to understand about these motifs, which are found in the genome of almost all organisms, from human beings to the AIDS virus, as well as helminth parasites. HBV is no exception.
The new study - carried out using a bioinformatics algorithm developed by the team - reveals that the frequency of these motifs in the HBV genome has changed over the last 10,000 years. It has risen from an average of 1.5 G-quadruplexes per 1000 DNA bases in ancient strains to an average of 1.9 per 1000 bases in recent strains. This is the first palaeogenomic study of these unusual DNA structures. Moreover, this frequency in modern strains is very close to that of G-quadruplexes in the current human genome (1.93 per 1000 bases). The researchers hypothesise that there may have been an evolutionary convergence: strains of HBV with a higher number of G-quadruplexes may have been selected by evolution to confer a genetic 'camouflage' enabling the virus to remain undetected in the body while benefiting from the cellular machinery to replicate.
"This observation is in line with the fact that hepatitis B causes a chronic infection, spread over many years, where the virus genome has to co-habit with that of the host in the nucleus of the cell," adds Jean-Louis Mergny. The opposite trend can be seen in other viruses that cause acute infection, such as SARS-CoV-2, whose strains have fewer G-quadruplexes than other viruses in the same family. For these viruses, whose success depends on a very rapid rate of replication, G-quadruplexes are thought to be limiting, and selection pressure is thought to be decreasing. This article paves the way for similar 'archaeovirology' studies on the genomes of other pathogens.