Interregional Coevolution Analysis Revealing Functional and Structural Interrelatedness between Different Genomic Regions in Human Mastadenovirus D

Abstract

Human mastadenovirus D (HAdV-D) is exceptionally rich in type among the seven human adenovirus species. This feature is attributed to frequent intertypic recombination events that have reshuffled orthologous genomic regions between different HAdV-D types. However, this trend appears to be paradoxical, as it has been demonstrated that the replacement of some of the interacting proteins for a specific function with other orthologues causes malfunction, indicating that intertypic recombination events may be deleterious. In order to understand why the paradoxical trend has been possible in HAdV-D evolution, we conducted an interregional coevolution analysis between different genomic regions of 45 different HAdV-D types and found that ca. 70% of the genome has coevolved, even though these are fragmented into several pieces via short intertypic recombination hot spot regions. Since it is statistically and biologically unlikely that all of the coevolving fragments have synchronously recombined between different genomes, it is probable that these regions have stayed in their original genomes during evolution as a platform for frequent intertypic recombination events in limited regions. It is also unlikely that the same genomic regions have remained almost untouched during frequent recombination events, independently, in all different types, by chance. In addition, the coevolving regions contain the coding regions of physically interacting proteins for important functions. Therefore, the coevolution of these regions should be attributed at least in part to natural selection due to common biological constraints operating on all types, including protein-protein interactions for essential functions. Our results predict additional unknown protein interactions. IMPORTANCEHuman mastadenovirus D, an exceptionally type-rich human adenovirus species and causative agent of different diseases in a wide variety of tissues, including that of ocular region and digestive tract, as well as an opportunistic infection in immunocompromised patients, is known to have highly diverged through frequent intertypic recombination events; however, it has also been demonstrated that the replacement of a component protein of a multiprotein system with a homologous protein causes malfunction. The present study solved this apparent paradox by looking at which genomic parts have coevolved using a newly developed method. The results revealed that intertypic recombination events have occurred in limited genomic regions and been avoided in the genomic regions encoding proteins that physically interact for a given function. This approach detects purifying selection against recombination events causing the replacement of partial components of multiprotein systems and therefore predicts physical and functional interactions between different proteins and/or genomic elements.

Recombinant type Human mastadenovirus D85 associated with epidemic keratoconjunctivitis since 2015 in Japan

“…The detected recombined region of the first event was from position 15 983‐16 983 bp in the strain sequence, affecting the coding region of the L3 :pV and identified by six of seven recombination detection algorithms with significant support ( P < 0.05). In contrast, the recombined region of the second event covered the position from between 17 854 and 19 750 bp in the strain sequence, affecting the loops of the hexon, L1 and L2 (Figure B), which have been demonstrated to be frequently recombined in this species . The second event was detected independently by the seven algorithms in RDP with strong support ( P < 10 −14 ) (Figure C).…”

Virus–Host Coevolution with a Focus on Animal and Human DNA Viruses

“…Exactly in HAdV-D strains it is often observed that homologous recombination has a driving force in adenovirus evolution (Crawford-Miksza and Schnurr 1996;Gonzalez et al 2015;Ismail et al 2018a;Kaján et al 2017;Robinson et al 2013;Walsh et al 2009). Predominantly, intraspecies recombination events are common, but intergenus recombinants have also been reported already: the head domain of the porcine adenovirus 5 (genus Mastadenovirus) fibre seems to be of atadenoviral origin (Nagy et al 2002), though a porcine atadenovirus has not been discovered yet.…”

The complete genome sequence of human adenovirus 84, a highly recombinant new Human mastadenovirus D type with a unique fiber gene

“…Further evaluation of our phylogenetic and recombination analysis data (Table 1 and Figure 1) revealed that in addition to the already mentioned types, several additional types appear to have contributed to the final composition of the HAdV-84 genome, through multiple recombination events. Recombination is one of the major driving forces in HAdV evolution (Gonzalez et al, 2015;Robinson et al, 2013). The penton base's variable loop is most similar to that of HAdV-8, while the remaining penton base backbone is more similar to HAdV-43.…”