A mathematical analysis of HDV genotypes: From molecules to cells

Hepatitis D virus (HDV) is classified according to eight genotypes. The various geno-types 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 ac-cording 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 im-portant 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 responsi-ble 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 repli-cation 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.