|Abstract:||Viral infection during pregnancy in humans is associated with increased risk for congenital abnormalities. In pigs, maternal infection with porcine reproductive and respiratory syndrome virus (PRRSV) increases inflammatory cytokines in the offspring, influences myogenic gene expression, and decreases total muscle fiber number. Disease and inflammation during gestation influences DNA methylation. Methylation, consisting of a methyl group attached to a cytosine followed by a guanine, is associated with gene silencing. The methylome is established throughout gestation and may be influenced by maternal disease. Therefore, the influence of virus induced maternal inflammation on the methylome in developing muscles was investigated. The hypothesis was that the genome would be hypermethylated in the offspring of infected pigs (Sus scrofa). Pregnant pigs were inoculated with either PRRSV or sterile culture medium (CON) and longissimus dorsi muscle samples were collected from offspring at birth. Reduced representation bisulfite sequencing was used to determine methylation status of individual CpG sites throughout the genome. Differentially methylated CpG sites were used in pathway and gene ontology analysis. Overall frequency of methylated CpG sites was virtually unchanged between PRRSV (46.36% of CpG sites methylated) and CON offspring (46.30%). Despite this, methylation patterns differed between treatments with 5593 cytosines from 717 genes hypermethylated and 566 cytosines from 262 gene hypomethylated in PRRSV piglets as compared to CON piglets. Several genes were extremely hypermethylated in PRRSV piglets, including FcγRII, MEF2C, citrate synthase, and PRKAB2. Additionally, genes from several disease response pathways were hypermethylated, along with genes from the thyroid hormone signaling pathway and oxidative phosphorylation pathway, possibly affecting myosin heavy chain expression in PRRSV piglets and suggesting that immune responses may be down regulated in PRRSV piglets. Differential methylation, mostly hypermethylation, was also present in the fast twitch muscle fibers, IGF1R, and several IGF binding proteins. Overall, there is evidence that maternal inflammation leads to hypermethylaiton of genes and decreased muscle growth during development.