Genetics, Vol. 164, 1481-1494, August 2003, Copyright © 2003

An N-Ethyl-N-Nitrosourea Mutagenesis Screen for Epigenetic Mutations in the Mouse

Ivona Perceca,b, Joanne L. Thorvaldsena, Robert M. Plengeb, Christopher J. Krappa, Joseph H. Nadeaub, Huntington F. Willardb,c, and Marisa S. Bartolomeia
a Howard Hughes Medical Institute and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,
b Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
c Center for Human Genetics, University Hospitals of Cleveland, Cleveland, Ohio 44106

Corresponding author: Marisa S. Bartolomei, University of Pennsylvania School of Medicine, 360 CRB, 415 Curie Blvd., Philadelphia, PA 19104., bartolom{at}mail.med.upenn.edu (E-mail)

Communicating editor: N. A. JENKINS

The mammalian epigenetic phenomena of X inactivation and genomic imprinting are incompletely understood. X inactivation equalizes X-linked expression between males and females by silencing genes on one X chromosome during female embryogenesis. Genomic imprinting functionally distinguishes the parental genomes, resulting in parent-specific monoallelic expression of particular genes. N-ethyl-N-nitrosourea (ENU) mutagenesis was used in the mouse to screen for mutations in novel factors involved in X inactivation. Previously, we reported mutant pedigrees identified through this screen that segregate aberrant X-inactivation phenotypes and we mapped the mutation in one pedigree to chromosome 15. We now have mapped two additional mutations to the distal chromosome 5 and the proximal chromosome 10 in a second pedigree and show that each of the mutations is sufficient to induce the mutant phenotype. We further show that the roles of these factors are specific to embryonic X inactivation as neither genomic imprinting of multiple genes nor imprinted X inactivation is perturbed. Finally, we used mice bearing selected X-linked alleles that regulate X chromosome choice to demonstrate that the phenotypes of all three mutations are consistent with models in which the mutations have affected molecules involved specifically in the choice or the initiation of X inactivation.




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