A Point Mutation in Suppressor of Cytokine Signalling 2 (Socs2) Increases the Susceptibility to Inflammation of the Mammary Gland while Associated with Higher Body Weight and Size and Higher Milk Production in a Sheep Model

Abstract

Mastitis is an infectious disease mainly caused by bacteria invading the mammary gland. Genetic control of susceptibility to mastitis has been widely evidenced in dairy ruminants, but the genetic basis and underlying mechanisms are still largely unknown. We describe the discovery, fine mapping and functional characterization of a genetic variant associated with elevated milk leukocytes count, or SCC, as a proxy for mastitis. After implementing genome-wide association studies, we identified a major QTL associated with SCC on ovine chromosome 3. Fine mapping of the region, using full sequencing with 12X coverage in three animals, provided one strong candidate SNP that mapped to the coding sequence of a highly conserved gene, suppressor of cytokine signalling 2 (Socs2). The frequency of the SNP associated with increased SCC was 21.7% and the Socs2 genotype explained 12% of the variance of the trait. The point mutation induces the p.R96C substitution in the SH2 functional domain of SOCS2 i.e. the binding site of the protein to various ligands, as well-established for the growth hormone receptor GHR. Using surface plasmon resonance we showed that the p.R96C point mutation completely abrogates SOCS2 binding affinity for the phosphopeptide of GHR. Additionally, the size, weight and milk production in p.R96C homozygote sheep, were significantly increased by 24%, 18%, and 4.4%, respectively, when compared to wild type sheep, supporting the view that the point mutation causes a loss of SOCS2 functional activity. Altogether these results provide strong evidence for a causal mutation controlling SCC in sheep and highlight the major role of SOCS2 as a tradeoff between the host’s inflammatory response to mammary infections, and body growth and milk production, which are all mediated by the JAK/STAT signaling pathway.

Recent advances in understanding genetic variants associated with economically important traits in sheep (Ovis aries) revealed by high-throughput screening technologies

“…Moioli et al presented the first genome-wide characterization of selective sweeps in dairy sheep and detected nine candidate regions harboring a couple of genes (e.g., PALMD and RFP145) related to the milk production performance [42] . Moreover, other strong candidate genes (e.g., ABCG2, SPP1, SCD, SOCS2, PKD2, MEPE and IBSP) associated with milk production traits have been proposed using selective sweep and GWAS [34,43,44] .…”

Evaluating Sequence-Based Genomic Prediction with an Efficient New Simulator

“…Furthermore, selection is expected to induce a negative correlation between effect and frequency, simply because large-effect QTNs at intermediate frequencies reach fixation or near fixation quickly, e.g., IGF2 in pigs (Ojeda et al 2008), and they would contribute very little to total variance. However, sometimes alleles of large effect can have both positive and detrimental effects and they keep segregating by balancing selection, such as DGAT1 in cattle (Grisart et al 2002) or Socs2 in sheep (Rupp et al 2015). To our knowledge, no GS simulation study has included all these "subtleties" when modeling the quantitative trait.…”

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

“…Furthermore, the effects of inflammatory cytokines on SOCS2 have been poorly investigated, with evidence that some interleukins induce SOCS2 gene expression only in specific cell types [89]. Thus, it has recently reported that in a sheep model, a point mutation in the SOCS2 gene not only resulted in higher body weight and size but also elevated leukocytes count in the milk as a sign of enhanced inflammatory response [90]. In addition, altered SOCS2 expression has also been associated with malignancies [84,[91][92][93].…”