A Mathematical Analysis of HDV Genotypes: From Molecules to Cells

Abstract

Hepatitis D virus (HDV) is classified according to eight genotypes. The various genotypes are included in the HDVdb database, where each HDV sequence is specified by its genotype. In this contribution, a mathematical analysis is performed on RNA sequences in HDVdb. The RNA folding predicted structures of the Genbank HDV genome sequences in HDVdb are classified according to their coarse-grain tree-graph representation. The analysis allows discarding in a simple and efficient way the vast majority of the sequences that exhibit a rod-like structure, which is important for the virus replication, to attempt to discover other biological functions by structure consideration. After the filtering, there remain only a small number of sequences that can be checked for their additional stem-loops besides the main one that is known to be responsible for virus replication. It is found that a few sequences contain an additional stem-loop that is responsible for RNA editing or other possible functions. These few sequences are grouped into two main classes, one that is well-known experimentally belonging to genotype 3 for patients from South America associated with RNA editing, and the other that is not known at present belonging to genotype 7 for patients from Cameroon. The possibility that another function besides virus replication reminiscent of the editing mechanism in HDV genotype 3 exists in HDV genotype 7 has not been explored before and is predicted by eigenvalue analysis. Finally, when comparing native and shuffled sequences, it is shown that HDV sequences belonging to all genotypes are accentuated in their mutational robustness and thermodynamic stability as compared to other viruses that were subjected to such an analysis.

Mathematical and Computational Biology of Viruses at the Molecular or Cellular Levels

“…A zoom-in of Figure 3(A) in [4], where the folding prediction by energy minimization using either mfold/UNAFold [8] or Vienna's RNAfold [9] of MG711735 from genotype 7 [5] is performed, with an SL1-like hairpin that contains the sub-sequence "GAAC" as in SL1 from genotype 3. The secondary structure is drawn using VARNA [10].…”

“…It starts with a mathematical analysis of the RNA motifs in viruses, analyzing data from the web resource RNASIV (RNA structure in viruses) [2] in order to categorize the various RNA structures based on their tree-graph properties via an eigenvalue analysis [3], with the second eigenvalue of the Laplacian matrix belonging to the coarse-grained tree-graph of the RNA secondary structure being examined. The same concept is carried out in [4] for an eigenvalue analysis of HDVdb [5], a database of HDV sequences that is divided into various HDV genotypes, in order to predict whether the peculiar RNA-editing mechanism achieved by a conformational switch in RNA that is known to occur in HDV genotype 3 [6] can occur in other genotypes as well. Two publications that appeared independently at around the same time [4,7] addressed this problem.…”

“…The same concept is carried out in [4] for an eigenvalue analysis of HDVdb [5], a database of HDV sequences that is divided into various HDV genotypes, in order to predict whether the peculiar RNA-editing mechanism achieved by a conformational switch in RNA that is known to occur in HDV genotype 3 [6] can occur in other genotypes as well. Two publications that appeared independently at around the same time [4,7] addressed this problem. A mathematical analysis by computations performed in [4] succeeded to predict that the RNA editing mechanism by a conformational switch in HDV genotype 3 occurs in HDV genotype 7 as well.…”

“…A mathematical analysis by computations performed in [4] succeeded to predict that the RNA editing mechanism by a conformational switch in HDV genotype 3 occurs in HDV genotype 7 as well. Here it is shown more clearly in Figure 1 (a zoom-in of Figure 3(A) in [4]) that the familiar SL1 hairpin from genotype 3 with the GAAC tetraloop is present also in genotype 7, while no systematic way from the computational standpoint was presented in [7] to show the presence of the SL1 hairpin particularly in genotype 7 and not in other genotypes, although the experiment performed in [7] with the added RNA motifs surrounding SL1 in strain dFr7024 (as depicted in Figure 4(D) of [7]) was beneficial. The impact of this finding would be revealed in the future as more data is gathered, but it exemplifies the power of mathematics and computations to predict new findings at the molecular or cellular levels.…”

Improved hepatitis delta virus genome characterization by single molecule full‐length genome sequencing combined with VIRiONT pipeline

“…Pearson's correlation test has been performed, p = 0.37, r = 0.17. fully characterizing quasispecies involving congruent mutations, for example, linked to secondary structure on a unique variant molecule would be of interest. Indeed, as highlighted by Zack et al, the availability of full-length sequences is mandatory for RNA structural analyses and structure/function studies 50. Additionally, knowledge of the evolution of circulating complete genomes during the natural history of HDV infection and under treatment are currently missing.…”