Large-scale genomic analysis reveals recurrent patterns of intertypic recombination in human Enteroviruses



Recombination is a driving force for the emergence, evolution and virulence/epidemics of Enteroviruses, a major genus of Picornaviridae important for human and animal health. By analyzing 2949 complete genomes/coding sequences, we provide for the first time a thorough and global overview of the patterns of intertypic recombination and hotspots between the genogroups of this genus. Two prominent recombination hotspots are identified, at the 5UTR-capsid region junction, and at the beginning of the P2 region. In general, P2 was enriched in recombination events. Key phylogenetic groups implicated in recombination events are E71 and CVA6 in Enterovirus A species, E30 and E6 in Enterovirus B species, Poliovirus 1 and 2 in Enterovirus C species. In addition, many recombination events involve donors that have not been sequenced yet, thus strongly suggesting an enormous environmental reservoir of genetic variation with a high potential for the emergence of new modified pathogens by recombination.

Major findings:

  • The capsid region is a recombination coldspot in EVs.
  • The 5UTR-VP4 junction is a recombination hotspot.
  • P2 is a recombination hotspot, especially in EV-B & EV-C.

figure1
Figure 1. Recombination events in Enterovirus A, B and C. Triangles depict recombination events.


figure2
Figure 2. Phylogenetic tree of the 5’UTR of human Enteroviruses A-D and human Rhinoviruses A-C.


Key players in recombination events:



figure3
Figure 3. Recombination donors. Our analyses highlight Enterovirus A-71 as the most frequently detected donor of genetic material in the Enterovirus A species. CVB4, E-30 and CVB3 are the most frequently detected donors in the Enterovirus B Species. Poliovirus 2 is the most frequently detected donor in the Enterovirus C species. However, in many cases the donor was not known, based on our stringent criteria of more than 90% sequence identity.


figure4
Figure 4. Recombination Acceptors. Our analyses highlight Enterovirus A-71 and CV-A6 as the most frequently detected acceptors of genetic material in the Enterovirus A species. E-30 and E-6 are the most frequently detected acceptors in the Enterovirus B Species. Lastly, Poliovirus 2 is the most frequently detected acceptor in the Enterovirus C species.


figure5
Figure 5. Donor/acceptor recombination Network for EV-A. Grey arrows depict recombination events where the donor organism had ≥90% identity with the corresponding serotype in NCBI BLAST. Enterovirus A-71 plays a critical role as both donor and acceptor.


figure6
Figure 6. Donor/acceptor recombination network for EV-B. Grey arrows depict recombination events where the donor organism had ≥90% identity with the corresponding serotype in NCBI BLAST. CV-B3 is the major donor, along with E30 and CV-B4 whereas E-30 is the major acceptor, along with E6 and CV-B5.


figure7
Figure 7. Donor/acceptor recombination Network for EV-C. Grey arrows depict recombination events where the donor organism had ≥90% identity with the corresponding serotype in NCBI BLAST. Poliovirus 2 plays a central role in the exchange of genetic material within the Enterovirus C species.


Download supplementary material here:

Supp. Files 1-18
S19_Simplots.zip
S20_Recombinations