A Simple Method to Detect Candidate Overlapping Genes in Viruses Using Single Genome Sequences

Schlub, Timothy E; Buchmann, Jan P; Holmes, Edward C

Gene overlap occurs when two or more genes share the same region of a nucleotide sequence in a genome. This occurs frequently in viruses, especially those with RNA genomes, but has also been observed in bacteria and in eukaryotes including humans (Smith et al. 1977; Keese and Gibbs 1992; Veeramachaneni et al. 2004; Nakayama et al. 2007 ). The high prevalence of gene overlap in viruses has been attributed to two complementary theories: gene "compression" and gene "novelty." Compression theory argues that the size of viral genomes is constrained by factors such as high mutation rates and the small capsid structure housing the genetic material. This constrained genome size subsequently exerts selection pressure on genes to overlap to maximize genetic potential (Belshaw et al. 2007; Chirico et al. 2010) . Gene novelty theory asserts that the constrained nature of viral genomes, combined with their limited noncoding regions, makes the generation of new genes difficult without major changes in genomic structure or input from the host genome. Mutations in current genes that generate a new open reading frame (ORF) then allow the generation of new genes within an established older gene in a process called "overprinting" (Keese and Gibbs 1992; Sabath et al. 2012; Brandes and Linial 2016) . These theories are not mutually exclusive and both processes may be operating in virus genomes. Overlapping genes may also function as a mechanism for regulating gene expression and reduce the probability of mutation fixation in overlapping areas as the resident genes may have competing selection pressures (Krakauer 2000; Dreher and Miller 2006) . Due to these evolutionary constraints, overlapping genes frequently encode proteins with accessory functions that play important roles in pathogenicity or spread (Rancurel et al. 2009 ).