Genetic dissection reveals multiple autosomal elements involved in the X chromosome inactivation pathway in the mouse

X chromosome inactivation is the chromosome-based epigenetic silencing mechanism employed by eutherian mammals to equalize the expression of X-linked genes between males and females. It results in the silencing of most genes on one X chromosome during early female embryogenesis. While the basic features of this complex process are well established, the genetic and molecular mechanisms remain incompletely understood. In the mouse, genetic control of inactivation requires genetic elements within the X inactivation center (Xic) on the X chromosome including, Xist, Tsix and Xce . While all factors known to be necessary for silencing map to the Xic, it has long been posited that unidentified autosomal factors are essential to the process. Chemical mutagenesis was used in the mouse to screen for mutations in novel factors involved in X inactivation. Three genetically distinct autosomal mutations were identified with the screen that induce dominant effects on X chromosome inactivation early in embryogenesis. Genetic mapping analysis demonstrated that regions of mouse chromosomes 15, 10 and 5 harbor loci involved in the mutant X inactivation phenotypes. Significantly, these results represent the first direct genetic evidence for multiple autosomal loci affecting events in the pathway and thus demonstrate that both X-linked and autosomal loci are involved in the genetic control of X inactivation.