The Complex Genetics of Mouse Reproduction and Arhritis

Sammanfattning: ABSTRACT Optimal breeding of mice is very important in biomedical science today. The understanding why some strains breed better and some worse enable scientists to create better in vivo models for human diseases. The aim of this thesis was to identify and characterize new genetic regions linked to reproductive performance and autoimmune inflammation in female mice. Collagen-induced arthritis (CIA) is an animal model for autoimmunity and rheumatoid arthritis (RA), and this animal model was used for the study of autoimmune reactivity in the female mice. RA is a very common autoimmune disease, which approximately affects 1-1.5% of the world population, and particularly women are affected. In Paper I the results of a genetic analyse (QTL analyse) of crossings between two inbred mouse strains, one moderate breeder (B10.Q) and one “high breeder” mouse (NFR/N) are summarized. Several new significant loci were identified for reproductive traits, such as litter size (Fecq3-4), pregnancy rate (Pregq1-4) and neonatal growth (Neogq1). In paper II, a congenic B10.Q strain carrying a fecundity locus (Fecq4) of NFR/N origin is characterized. This congenic strain showed a higher breeding performance and larger litter size than the parental B10.Q strain. In addition, the Fecq4 mice did respond stronger to the standard superovulation protocol. The possible role of some candidate genes is discussed. Paper III summarizes the QTL-results of an autoimmunity study (the CIA model) of aged multipareous female mice of the same strains and crossings as those used for reproductive studies. One new significant locus , now denoted Cia40, was identified. Finally, in paper IV, the results of studies of a congenic B10.Q mouse carrying a Cia40 locus of NFR/N origin are summarized. Females, but not males, of the Cia40 congenic strain showed altered response to CIA. The congenic Cia40 fragment also contained a reproductive locus named Pregq2, which negatively interfered with the reproductive performance of the congenic mice. Possible candidate genes have been discussed.