Characterization of the chicken SAA.R90S mutation

Amyloid arthropathy in chickens is a debilitating disease triggered by bacterial infection. The disease leads to substantial economic loss and is a major animal welfare concern, contributing to the widespread overuse of antibiotics. A hallmark of amyloid arthropathy is the deposition of serum amyloid A (SAA) in the large joints of affected birds. Bacterial infection initiates an acute phase response increasing SAA production in the liver, which accumulates at sites of infection. Interestingly, brown layers are most affected by amyloid arthropathy, whilst white layers are resistant to the disease. Differential disease susceptibility has an immunological basis but underlying genetic risk factors are not understood. Using a whole genome sequencing approach, we discovered a variant in the SAA gene in white layers predicted to cause an arginine to serine substitution at position 90 (SAA.R90S). When overexpressed in chicken hepatocellular carcinoma cells, SAA.R90S was found to be expressed at a higher rate, more prone to aggregation and secreted to a greater degree than the wild-type SAA protein. RNASeq analysis showed that the R90S mutant exerted a differential effect on the expression of core transcription factors linked to cell fate determination and cell differentiation. A comparative analysis to murine IL-6/SAA stimulated CD4 T-cells suggests that SAA.R90S might block an induced cell fate change towards pro-inflammatory T-helper-17-cells, which are required for immunological protection against pathogenic bacteria during an acute phase response. Our results provide first mechanistic insights into the genetic resistance of white layers to amyloid arthropathy and could be applied to commercial layer breeding programs.