Rats are an important experimental model for many human diseases, many of which have a genetic component. We are interested in mapping the genomic locations of genes that regulate the development of experimental autoimmune arthritis and related diseases in rats because we strongly suspect that this information will facilitate the identification of similar genes or related biochemical pathways in humans. This project has several components: 1) development of dense genetic, physical and transcription maps of the rat applicable to autoimmune disease-prone and -resistant inbred rat strains; 2) generation and phenotypic characterization of experimental crosses of autoimmune disease-prone and -resistant inbred strains; 3) linkage analysis to identify genomic regions containing disease regulatory genes; 4) development and analysis of congenic inbred rat strains carrying disease resistance genes on a susceptible background or vice versa to facilitate fine mapping and analysis of functional effects. We continue to work on the development of a dense genetic map applicable to the rat strains in which we are interested (DA, LEW, F344, BN, ACI). We have made a major effort to develop an integrated map. Over 1000 markers have been mapped in 1 or more crosses (Ding Y-P et al. Genomics 36:320-327, 1996; Ge L et al. Mammalian Genome 7:856-857, 1996; Zha H-B et al. Genomics 37:386-389, 1996). We have also begun making information derived from our genetic mapping database available on the World Wide Web (www.nih.gov/niams/scientific/ratgbase/). We are fine mapping several autosomal recessive traits including osteopetrosis (op) (Remmers E et al. J. Bone Mineral Res. 11:1856-1861, 1996), agouti, coat color and hood. The op mutation has now been localized to an interval of less than 2.5 cM at end of chromosome 10. Identification of the op gene is important because it appears to represent a defect in an osteoclast differentiation pathway that has not been previously characterized. We also continue to identify and refine the chromosomal locations of Quantitative Trait Loci (QTLs) regulating phenotypes related to collagen arthritis, adjuvant arthritis (in collaboration with M. Griffiths and G. Cannon) and streptococcal cell wall arthritis. For collagen arthritis, we have identified 7 QTLs (Cia1-7) regulating severity (Remmers E et al. Nature Genetics 14:82-85, 1996) and 2 QTLs regulating antibody levels (Ciaa1-2). For adjuvant arthritis, we have identified 3 QTLs (Aia1-3). For streptococcal cell wall arthritis, we have identified 4 putative QTLs. In collaboration with Rachel Caspi (NEI), we have also begun an analysis of experimental autoimmune uveitis and have identified several putative QTLs. The mapping data support our view that some QTLs harbor genes common to multiple autoimmune diseases. Analysis of QTL-congenic rat strains, which we are developing, should allow us to address the """"""""autoimmunity gene"""""""" hypothesis directly.
