Synaptogyrin-2 influences replication of Porcine circovirus 2

Autor: Lianna R. Walker, Graham Plastow, Timothy P. L. Smith, Hiep L.X. Vu, Stephen D. Kachman, Daniel C. Ciobanu, Taylor B. Engle, Dan J. Nonneman, Emily R. Tosky, Thomas E. Burkey, Tudor Borza
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Heredity
Swine
Genome-wide association study
Virus Replication
Biochemistry
Small interfering RNAs
Genetics (clinical)
Genetics
Mammals
Synaptogyrins
biology
Eukaryota
Genomics
Viral Load
Nucleic acids
Porcine circovirus
Genetic Mapping
Vertebrates
Viral load
Research Article
Circovirus
DNA Replication
lcsh:QH426-470
Quantitative Trait Loci
Single-nucleotide polymorphism
Locus (genetics)
Quantitative trait locus
Microbiology
Molecular Genetics
03 medical and health sciences
Virology
Genome-Wide Association Studies
Animals
Viremia
Non-coding RNA
Gene
Molecular Biology
Ecology
Evolution
Behavior and Systematics
030102 biochemistry & molecular biology
Organisms
Biology and Life Sciences
Computational Biology
Human Genetics
biology.organism_classification
Genome Analysis
Viral Replication
Gene regulation
lcsh:Genetics
030104 developmental biology
Viral replication
Haplotypes
Genetic Loci
Amniotes
RNA
Gene expression
Viral Transmission and Infection
Genome-Wide Association Study
Zdroj: PLoS Genetics
PLoS Genetics, Vol 14, Iss 10, p e1007750 (2018)
ISSN: 1553-7404
1553-7390
Popis: Porcine circovirus 2 (PCV2) is a circular single-stranded DNA virus responsible for a group of diseases collectively known as PCV2 Associated Diseases (PCVAD). Variation in the incidence and severity of PCVAD exists between pigs suggesting a host genetic component involved in pathogenesis. A large-scale genome-wide association study of experimentally infected pigs (n = 974), provided evidence of a host genetic role in PCV2 viremia, immune response and growth during challenge. Host genotype explained 64% of the phenotypic variation for overall viral load, with two major Quantitative Trait Loci (QTL) identified on chromosome 7 (SSC7) near the swine leukocyte antigen complex class II locus and on the proximal end of chromosome 12 (SSC12). The SNP having the strongest association, ALGA0110477 (SSC12), explained 9.3% of the genetic and 6.2% of the phenotypic variance for viral load. Dissection of the SSC12 QTL based on gene annotation, genomic and RNA-sequencing, suggested that a missense mutation in the SYNGR2 (SYNGR2 p.Arg63Cys) gene is potentially responsible for the variation in viremia. This polymorphism, located within a protein domain conserved across mammals, results in an amino acid variant SYNGR2 p.63Cys only observed in swine. PCV2 titer in PK15 cells decreased when the expression of SYNGR2 was silenced by specific-siRNA, indicating a role of SYNGR2 in viral replication. Additionally, a PK15 edited clone generated by CRISPR-Cas9, carrying a partial deletion of the second exon that harbors a key domain and the SYNGR2 p.Arg63Cys, was associated with a lower viral titer compared to wildtype PK15 cells (>24 hpi) and supernatant (>48hpi)(P < 0.05). Identification of a non-conservative substitution in this key domain of SYNGR2 suggests that the SYNGR2 p.Arg63Cys variant may underlie the observed genetic effect on viral load.
Author summary The cost of managing Porcine Circovirus 2 (PCV2) associated diseases in the US alone costs the swine industry more than $250 million a year. This virus is found in all swine populations in the US, but only a few pigs get sick and show signs of disease. Previous anecdotal field data showed differences between pig breeds in both incidence and severity of PCV2-associated diseases, supporting the role of host genetics in disease susceptibility. This research, including over 1,000 experimentally infected pigs with PCV2, is the largest study ever conducted to understand the role of host genetics in PCV2 related illnesses. We found that a pig’s own genetics can impact the ability of PCV2 to multiply and cause disease. Specifically, we found a mutation in the SYNGR2 gene that influences the ability of the PCV2 virus to replicate, which can affect pig growth and immune system following infection. This research will aid in the development of genetic tests with the ability to predict PCV2 susceptibility. Early identification of pigs that are susceptible to PCV2 infection will result in an improvement in the general health and welfare of pigs.
Databáze: OpenAIRE
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