Robustness, Efficiency, Inflammation and Diseases under the control of SOCS-2 – REIDSOCS

Mastitis is a serious burden for the milk industry due to the altered quality of milk and increased cost for production. Beside hygienic measures, genetic selection for improved immunity against mammary infections and resistance to mastitis is considered, and implemented in breeding programs of several dairy breeds worldwide. However, resistance to mastitis is a highly complex trait which genetically-determined biological basis is mostly unknown. Based on a genome-wide association study for a mastitis trait, the milk somatic cell count (SCC) in dairy sheep, we identified a point mutation in the SH2 binding domain of SOCS-2, leading to the loss of ligand recognition. The frequency of this mutation was surprisingly high (22%) in the studied population. Additionally, size, weight and milk production were significantly increased in ewes carrying the mutated socs2 allele when compared to wild type sheep. Altogether these results gave strong evidence for a causal mutation controlling mastitis in sheep and highlighted the major role of SOCS-2 as a potential tradeoff factor between host’s inflammatory response to mammary infections, and milk production.
The purpose of the REIDSOCS project is to study the role of SOCS-2 in the predisposition to bacterial infections, and explore its pleiotropic effect on both health and production traits. Indeed, SOCS-2 belongs to a protein family that regulates the JAK/STAT signaling pathways originating from several cytokine and hormone receptors. Regulatory mechanisms of inflammatory responses and their impact on the issue of infectious diseases are still not completely resolved. Investigations will be performed at the levels of the sheep population, animal and cells.
- At the population levels, a precise description of the allele frequencies and their evolution will be conducted. The genetic association of the Socs2 genotype with various production traits will be investigated in order to hypothesize on the history of the mutation. An insightful strategy for the management of the mutation in the sheep breeding scheme is proposed as a deliverable. More generally, the project will provide means on how to manage known causal mutations with pleiotropic effects on production versus functional traits in bred livestock.
- At the animal and systems levels, the role of the point mutation, independently of the genetic background, will be investigated in sheep after genome edition. The objective is to introduce the SOCS-2 mutation in a mastitis-resistant genetic background and to definitively prove the predisposition to bacterial infections.
- Furthermore, after non-meiotic introgression of the mutation into the murine genome, the mechanisms associated with impaired SOCS-2 functions will be determined using in vitro and in vivo experiments. These studies also aim at determining the repertoire of genes and pathways leading to abnormal cell functions in various cell types and consequently, to an increased predisposition to bacterial infections. By this way, we will define the SOCS-2-related interactome by identifying the proteins and associated signaling pathways leading to milk production and altered immunity to bacterial infections. This information will be used in return to look for other altered expression or mutations in the repertoire of factors that are protective against mammary infections.
Altogether, the project will open up new avenues for the genetic improvement of animal health, but also provide new knowledge on the mechanisms of immune and inflammatory regulation.