Exome_Sequencing_of_the_lupus__suppressor__locus_Sle18

Proposal: Exome Sequencing of the lupus “suppressor” locus Sle18. Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease with complex genetic inheritance. Mouse models have confirmed the polygenic nature of SLE. Previous linkage studies in (C57BL/6x129)F2 mice have mapped a 129-derived lupus susceptibility locus (Sle16) on chromosome 1 (spanning from 170 to 185.7 Mbp) [1]. A C57BL/6 congenic line (named B6.129-Sle16) carrying the Sle16 locus has been shown to develop lupus-associated autoantibodies and immune complex mediated glomerulonephritis [2]. Subsequent analyses have also demonstrated the presence of a locus on chromosome 3 capable of suppressing the autoimmune features driven by Sle16. This locus has been named Sle18. The phenotypic analysis of B6.129-Sle16Sle18 double congenic strain, carrying both Sle16 and the Sle18 loci, confirmed that these mice were protected from the development of autoimmunity [3]. The key goal of our research proposal is to identify the critical “suppressor” gene(s) in the Sle18 locus and assess the relevance of the orthologous genes in humans. Exome sequencing of Sle18 locus would be pivotal for generating a list of candidate genes that could explain our phenotypic and functional data. The identification and characterisation of “suppressor” pathways will pave the way to the design of new therapeutic targets. References 1. Bygrave, A.E., et al., Spontaneous autoimmunity in 129 and C57BL/6 mice-implications for autoimmunity described in gene-targeted mice. PLoS Biol, 2004. 2(8): p. E243. 2. Carlucci, F., et al., Genetic dissection of spontaneous autoimmunity driven by 129-derived chromosome 1 Loci when expressed on C57BL/6 mice. J Immunol, 2007. 178(4): p. 2352-60. 3. Carlucci, F., et al., Identification and characterization of a lupus suppressor 129 locus on chromosome 3. Journal of immunology, 2010. 184(11): p. 6256-65.