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Functional and Evolutionary Analysis of Host Synaptogyrin-2 in Porcine Circovirus Type 2 Susceptibility
The evolution of mammalian species has been influenced by viruses for millions of years, leaving signatures of adaptive evolution within genes encoding for viral interacting proteins. Synaptogyrin-2 (SYNGR2) is a transmembrane protein implicated in promoting bacterial and viral infections. A genome-wide association study of pigs experimentally infected with porcine circovirus type 2b (PCV2b) uncovered a missense mutation within SYNGR2 (p.Arg63Cys) associated with viral load. In this study, CRISPRCas9 mediated gene editing of the porcine kidney 15 (PK15, wtSYNGR2+p.63Arg) cell line generated a SYNGR2 knock-out clone (emSYNGR2-del) and a clone homozygous for the alternate SYNGR2 p.63Cys allele (emSYNGR2+p.63Cys). Infection of both edited PK15 clones resulted in decreased PCV2b replication compared to wildtype PK15 (P<0.05). This effect was consistent across other genetically distinct PCV2a and PCV2d isolates. A reduction in total viral genome copies within edited clones at 24 hours compared to wildtype PK15, indicates a potential function of SYNGR2 in the early stages of PCV2 infection. Evaluation of 751 wild and domestic pig sequences revealed the SYNGR2 p.63Cys allele is unique to domestic pigs and more predominant in European than Asian breeds, with the highest frequency in Duroc (0.683). A single SYNGR2 haplotype contained the SYNGR2 p.63Cys allele and was otherwise identical to another haplotype nearly fixed within European wild boar (0.977) and completely absent from Asian wild boar. Therefore, we hypothesize that the SYNGR2 p.63Cys allele arose post-domestication in ancestral European swine. Decreased genetic diversity amongst domestic swine homozygous for the SYNGR2 p.63Cys allele compared to SYNGR2 p.63Arg, corroborates a rapid increase in frequency of the SYGNR2 p.63Cys allele due to positive selection. Signatures of adaptive evolution across mammalian species were also identified within the intraluminal loop domains of SYNGR2, coinciding with the location of the SYNGR2 p.Arg63Cys variant. Therefore, SYNGR2 may reflect a novel component of the host-virus evolutionary arms race across mammals with SYNGR2 p.Arg63Cys representing a species-specific example of putative adaptive evolution.
Walker, Lianna Rayne, "Functional and Evolutionary Analysis of Host Synaptogyrin-2 in Porcine Circovirus Type 2 Susceptibility" (2022). ETD collection for University of Nebraska - Lincoln. AAI29166949.