International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 28 - AUTOSOMAL DOMINANT MUTATIONS DISTORT X CHROMOSOME INACTIVATION CHOICE

J Thorvaldsen
University of Pennsylvania School of Medicine

1) Percec I, 1 Krapp C, 2 Nadeau J, 3 Willard H, 4 Bartolomei M
1) University of Pennsylvania School of Medicine, 2) Case Western Reserve University School of Medicine, 3) Case Western Reserve University School of Medicine and University Hospitals of Cleveland, 4) HHMI and University of Pennsylvania School of Medicine

X inactivation in mice requires elements within the X inactivation center (Xic) on the X chromosome, including the X controlling element, Xce.  Xce is believed to affect choice of which X chromosome is inactivated in the mouse. While all factors necessary for X inactivation map within the Xic, it is posited that unidentified autosomal factors are essential to the process. To identify such novel factors, we have developed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen for dominant mutations that disrupt X inactivation patterns in female mice. A total of 346 G1 females were assayed and dominant mutations that perturb X inactivation patterns were identified in two independent pedigrees (Science 296:1136). Carrier Xce heterozygous females exhibit a shift of their X inactivation pattern from ~30:70 to ~50:50, suggesting an interaction between these mutations and the Xce locus. We have demonstrated the dominant transmission of the mutant phenotypes for at least six generations in both pedigrees. Furthermore, the mutant phenotypes are present in all tissues examined suggesting the mutations act early in the pathway. Importantly, both pedigrees display autosomal modes of inheritance. The genome scan of the first pedigree demonstrates linkage of the mutant phenotype to chromosome 15 while the mutant phenotype is  linked to both chromosomes 5 and 10 in the second pedigree. Our results are consistent with other ENU mutagenesis studies that also have found multiple mutations within individual mouse lines. Significantly, these results represent the first evidence of an autosomal mutation affecting any component of the X inactivation pathway.


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