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Genetic and parent-of-origin influences on X chromosome choice in Xce heterozygous mice

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Abstract

X chromosome inactivation is unique among dosage compensation mechanisms in that the two X chromosomes in females are treated differently within the same cell; one X chromosome is stably silenced while the other remains active. It is widely believed that, when X inactivation is initiated, each cell makes a random choice of which X chromosome will be silenced. In mice, only one genetic locus, the X-linked X controlling element (Xce), is known to influence this choice, because animals that are heterozygous at Xce have X-inactivation patterns that differ markedly from a mean of 0.50. To document other genetic and epigenetic influences on choice, we have performed a population-based study of the effect of Xce genotype on X-inactivation patterns. In B6CAST F1 females (Xceb/Xcec), the X-inactivation pattern followed a symmetric distribution with a mean of 0.29 (SD = 0.08). Surprisingly, however, in a population of Xceb/Xcec heterozygous B6CAST F2 females, we observed significant differences in both the mean (p = 0.004) and variance (p = 0.004) of the X-inactivation patterns. This finding is incompatible with a single-locus model and suggests that additional genetic factors also influence X chromosome choice. We show that both parent-of-origin and naturally occurring genetic variation at autosomal loci contribute to these differences. Taken together, these data reveal further genetic complexity in this epigenetic control pathway.

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Acknowledgments

The authors are grateful to Weihong Jiang and Stephanie Merrett for their assistance with animal husbandry. They also thank Dr. Karl Broman for statistical advice and Drs. Ron Conlon and Marisa Bartolomei for helpful discussions. This work was supported in part by research grant GM45441 from the NIH.

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Correspondence to Huntington F. Willard.

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Chadwick, L.H., Willard, H.F. Genetic and parent-of-origin influences on X chromosome choice in Xce heterozygous mice. Mamm Genome 16, 691–699 (2005). https://doi.org/10.1007/s00335-005-0059-2

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  • DOI: https://doi.org/10.1007/s00335-005-0059-2

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