Identification of a putative quantitative trait nucleotide in guanylate binding protein 5 for host response to PRRS virus infection

Abstract

BackgroundPreviously, we identified a major quantitative trait locus (QTL) for host response to Porcine Respiratory and Reproductive Syndrome virus (PRRSV) infection in high linkage disequilibrium (LD) with SNP rs80800372 on Sus scrofa chromosome 4 (SSC4).ResultsWithin this QTL, guanylate binding protein 5 (GBP5) was differentially expressed (DE) (p < 0.05) in blood from AA versus AB rs80800372 genotyped pigs at 7,11, and 14 days post PRRSV infection. All variants within the GBP5 transcript in LD with rs80800372 exhibited allele specific expression (ASE) in AB individuals (p < 0.0001). A transcript re-assembly revealed three alternatively spliced transcripts for GBP5. An intronic SNP in GBP5, rs340943904, introduces a splice acceptor site that inserts five nucleotides into the transcript. Individuals homozygous for the unfavorable AA genotype predominantly produced this transcript, with a shifted reading frame and early stop codon that truncates the 88 C-terminal amino acids of the protein. RNA-seq analysis confirmed this SNP was associated with differential splicing by QTL genotype (p < 0.0001) and this was validated by quantitative capillary electrophoresis (p < 0.0001). The wild-type transcript was expressed at a higher level in AB versus AA individuals, whereas the five-nucleotide insertion transcript was the dominant form in AA individuals. Splicing and ASE results are consistent with the observed dominant nature of the favorable QTL allele. The rs340943904 SNP was also 100 % concordant with rs80800372 in a validation population that possessed an alternate form of the favorable B QTL haplotype.ConclusionsGBP5 is known to play a role in inflammasome assembly during immune response. However, the role of GBP5 host genetic variation in viral immunity is novel. These findings demonstrate that rs340943904 is a strong candidate causal mutation for the SSC4 QTL that controls variation in host response to PRRSV.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1635-9) contains supplementary material, which is available to authorized users.

Genetic architecture of gene expression underlying variation in host response to porcine reproductive and respiratory syndrome virus infection

“…In this study, we aimed to identify genes and mechanisms that affect the susceptibility to PRRSV infection through the integration of eQTL and GWAS analyses. Our results lend further support to the important role of GBP5 in host response to PRRSV infection and also identified additional candidate genes within the top GWAS regions associated with VL and WG reported in earlier studies456.…”

“…A recent study6 showed that pigs with the susceptible genotype (Allele A of WUR10000125, associated with increased VL) expressed GBP5 at a lower level than the resistant genotype and primarily produced an alternate splice form that was predicted to produce a truncated protein. That study focused on the WUR region and tested differential expression and splicing using the 16 animals from trial PHGC3 and validated the results using the 28 animals from trial PHGC5.…”

“…Further, we hypothesize that the eQTL for GBP5 provides control at the post-transcriptional level. Allele A at SNP WUR10000125 is in extremely high LD with a premature stop codon (111 bp upstream of the last exon-exon junction) in the coding region of GBP5 6. If a transcript harbors a premature termination codon whose location is > 50 bp upstream of the final exon-exon junction, it is highly likely to be degraded by the nonsense-mediated decay (NMD) pathway19.…”

“…Nine additional regions were reported to explain a further 5.2% and 8.5% of the genetic variance for VL and WG, respectively4. A recent study of gene expression in this QTL region identified a putative quantitative trait nucleotide in the guanylate binding protein 5 ( GBP5 ) gene, that creates alternative splicing of GBP5 RNA, which decreased wild type RNA levels expressed from the unfavorable allele6. Studies of GBP5 knockout mice indicated that GBP5 functions in host defense, inflammasome assembly, and inflammatory responses to pathogenic bacteria7 and recently another study reported that GBP5 potently restricts HIV-1 and other retroviruses8.…”

Genomics to benefit livestock production: improving animal health

“…Excitingly, this effect was confirmed for a second strain of the virus (Hess et al, 2014), suggesting that it could be possible to select for pigs that are less impacted by PRRSV when it is present. Sequencing of blood samples from pigs showing different viremia and growth responses appears to have identified the causative mutation responsible for reduced susceptibility (Koltes et al, 2015). Other regions of the genome that were identified to influence susceptibility had relatively small effects (less than 2.6% of genetic variance for weight gain and less than 1.2% for virus load) .…”