Computational methods for inferring location and genealogy of overlapping genes in virus genomes: approaches and applications

Viruses may evolve to increase the amount of encoded genetic information by means of overlapping genes, which utilize several reading frames. Such overlapping genes may be especially impactful for genomes of small size, often serving a source of novel accessory proteins, some of which play a crucial role in viral pathogenicity or in promoting the systemic spread of virus. Diverse genome-based metrics were proposed to facilitate recognition of overlapping genes that otherwise may be overlooked during genome annotation. They can detect the atypical codon bias associated with the overlap (e.g. a statistically significant reduction in variability at synonymous sites) or other sequence-composition features peculiar to overlapping genes. In this review, I compare nine computational methods, discuss their strengths and limitations, and survey how they were applied to detect candidate overlapping genes in the genome of SARS-CoV-2, the etiological agent of COVID-19 pandemic.