Originally published as Genetics Published Articles Ahead of Print on April 2, 2006.

Genetics, Vol. 173, 2103-2110, August 2006, Copyright © 2006
doi:10.1534/genetics.105.054882

Genetic Control of X Chromosome Inactivation in Mice: Definition of the Xce Candidate Interval

Lisa Helbling Chadwick*,{dagger}, Lisa M. Pertz*, Karl W. Broman{ddagger}, Marisa S. Bartolomei§ and Huntington F. Willard*,1

* Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27708, {dagger} Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, {ddagger} Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland 21205 and § Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

1 Corresponding author: Institute for Genome Sciences and Policy, Duke University, Box 3382, 101 Science Dr., Durham, NC 27708.
E-mail: hunt.willard{at}duke.edu

In early mammalian development, one of the two X chromosomes is silenced in each female cell as a result of X chromosome inactivation, the mammalian dosage compensation mechanism. In the mouse epiblast, the choice of which chromosome is inactivated is essentially random, but can be biased by alleles at the X-linked X controlling element (Xce). Although this locus was first described nearly four decades ago, the identity and precise genomic localization of Xce remains elusive. Within the X inactivation center region of the X chromosome, previous linkage disequilibrium studies comparing strains of known Xce genotypes have suggested that Xce is physically distinct from Xist, although this has not yet been established by genetic mapping or progeny testing. In this report, we used quantitative trait locus (QTL) mapping strategies to define the minimal Xce candidate interval. Subsequent analysis of recombinant chromosomes allowed for the establishment of a maximum 1.85-Mb candidate region for the Xce locus. Finally, we use QTL approaches in an effort to identify additional modifiers of the X chromosome choice, as we have previously demonstrated that choice in Xce heterozygous females is significantly influenced by genetic variation present on autosomes (CHADWICK and WILLARD 2005). We did not identify any autosomal loci with significant associations and thus show conclusively that Xce is the only major locus to influence X inactivation patterns in the crosses analyzed. This study provides a foundation for future analyses into the genetic control of X chromosome inactivation and defines a 1.85-Mb interval encompassing all the major elements of the Xce locus.