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.
Similar content being viewed by others
References
Adler DA, West JD, Chapman VM (1977) Expression of alpha-galactosidase in preimplantation mouse embryos. Nature 267:838–839
Baader SL, Schilling ML, Rosengarten B, Pretsch W, Teutsch HF, et al. (1996) Purkinje cell lineage and the topographic organization of the cerebellar cortex: a view from X inactivation mosaics. Dev Biol 174:393–406
Bittner RE, Popoff I, Shorny S, Hoger H, Wachtler F (1997) Dystrophin expression in heterozygous mdx/+ mice indicates imprinting of X chromosome inactivation by parent-of-origin-, tissue-, strain- and position-dependent factors. Anat Embryol (Berl) 195:175–182
Blake JA, Richardson JE, Bult CJ, Kadin JA, Eppig JT (2003) MGD: the Mouse Genome Database. Nucleic Acids Res 31:193–195
Borsani G, Tonlorenzi R, Simmler MC, Dandolo L, Arnaud D et al. (1991) Characterization of a murine gene expressed from the inactive X chromosome. Nature 351:325–329
Brockdorff N, Ashworth A, Kay GF, Cooper P, Smith S, et al. (1991) Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351:329–331
Cattanach BM, Isaacson JH (1967) Controlling elements in the mouse X chromosome. Genetics 57:331–346
Cattanach BM, Pollard CE, Perez JN (1969) Controlling elements in the mouse X-chromosome. I. Interaction with the X-linked genes. Genet Res 14:223–235
Clerc P, Avner P (2003) Multiple elements within the Xic regulate random X inactivation in mice. Semin Cell Dev Biol 14:85–92
de La Casa-Esperon E, Loredo-Osti JC, Pardo-Manuel de Villena F, Briscoe TL, Malette JM, et al. (2002) X chromosome effect on maternal recombination and meiotic drive in the mouse. Genetics 161:1651–1659
Disteche CM, Eicher EM, Latt SA (1979) Late replication in an X-autosome translocation in the mouse: correlation with genetic inactivation and evidence for selective effects during embryogenesis. Proc Natl Acad Sci U S A 76:5234–5238
Epstein CJ, Smith S, Travis B, Tucker G (1978) Both X chromosomes function before visible X-chromosome inactivation in female mouse embryos. Nature 274:500–503
Forrester LM, Ansell JD (1985) Parental influences on X chromosome expression. Genet Res 45:95–100
Fowlis DJ, Ansell JD, Micklem HS (1991) Further evidence for the importance of parental source of the Xce allele in X chromosome inactivation. Genet Res 58:63–65
Hogan B, Beddington R, Costantini F, Lacey E (1994) Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press)
Huynh KD, Lee JT (2001) Imprinted X inactivation in eutherians: a model of gametic execution and zygotic relaxation. Curr Opin Cell Biol 13:690–697
Huynh KD, Lee JT (2003) Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature 426:857–862
Ideraabdullah FY, de la Casa-Esperon E, Bell TA, Detwiler DA, Magnuson T, et al. (2004) Genetic and haplotype diversity among wild-derived mouse inbred strains. Genome Res 14:1880–1887
Ihaka R, Gentleman R (1996) R: A language for data analysis and graphics. J Comp Graph Stat 5:299–314
Johnston PG, Cattanach BM (1981) Controlling elements in the mouse. IV. Evidence of non-random X- inactivation. Genet Res 37:151–160
Kratzer PG, Gartler SM (1978) HGPRT activity changes in preimplantation mouse embryos. Nature 274:503–504
Krietsch WK, Fundele R, Kuntz GW, Fehlau M, Burki K, et al. (1982) The expression of X-linked phosphoglycerate kinase in the early mouse embryo. Differentiation 23:141–144
Krietsch WK, Fehlau M, Renner P, Bucher T, Fundele R (1986) Expression of X-linked phosphoglycerate kinase in early mouse embryos homozygous at the Xce locus. Differentiation 31:50–54
Lee JT, Lu N (1999) Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99:47–57
Lee JT, Davidow LS, Warshawsky D (1999) Tsix, a gene antisense to Xist at the X-inactivation centre. Nat Genet 21:400–404
Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373
Mak W, Nesterova TB, de Napoles M, Appanah R, Yamanaka S, et al. (2004) Reactivation of the paternal X chromosome in early mouse embryos. Science 303:666–669
McMahon A, Monk M (1983) X-chromosome activity in female mouse embryos heterozygous for Pgk-1 and Searle’s translocation, T(X; 16)16H. Genet Res 41:69–83
McMahon A, Fosten M, Monk M (1983) X-chromosome inactivation mosaicism in the three germ layers and the germ line of the mouse embryo. J Embryol Exp Morphol 74:207–220
Meller VH (2000) Dosage compensation: making 1X equal 2X. Trends Cell Biol 10:54–59
Monk M, Harper MI (1979) Sequential X chromosome inactivation coupled with cellular differentiation in early mouse embryos. Nature 281:311–313
Mroz K, Carrel L, Hunt PA (1999) Germ cell development in the XXY mouse: evidence that X chromosome reactivation is independent of sexual differentiation. Dev Biol 207:229–238
Nesbitt MN (1971) X chromosome inactivation mosaicism in the mouse. Dev Biol pp 252–263
Ogawa Y, Lee JT (2003) Xite, X-inactivation intergenic transcription elements that regulate the probability of choice. Mol Cell 11:731–743
Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E (2004) Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303:644–649
Papaioannou VE, West JD (1981) Relationship between the parental origin of the X chromosomes, embryonic cell lineage and X chromosome expression in mice. Genet Res 37:183–197
Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379:131–137
Percec I, Plenge RM, Nadeau JH, Bartolomei MS, Willard HF (2002) Autosomal dominant mutations affecting X inactivation choice in the mouse. Science 296:1136–1139
Percec I, Thorvaldsen JL, Plenge RM, Krapp CJ, Nadeau JH, et al. (2003) An N-ethyl-N-nitrosourea mutagenesis screen for epigenetic mutations in the mouse. Genetics 164:1481–1494
Plenge RM, Percec I, Nadeau JH, Willard HF (2000) Expression-based assay of an X-linked gene to examine effects of the X- controlling element (Xce) locus. Mamm Genome 11:405-408
Rastan S, Kaufman MH, Handyside AH, Lyon MF (1980) X-chromosome inactivation in extra-embryonic membranes of diploid parthenogenetic mouse embryos demonstrated by differential staining. Nature 288:172–173
Sado T, Ferguson-Smith AC (2005) Imprinted X inactivation and reprogramming in the preimplantation mouse embryo. Hum Mol Genet 14 Suppl 1:R59–64
Takagi N (2003) Imprinted X-chromosome inactivation: enlightenment from embryos in vivo. Semin Cell Dev Biol 14:319–329
Takagi N, Sasaki M (1975) Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse. Nature 256:640–642
Takagi N, Sugimoto M, Yamaguchi S, Ito M, Tan SS, et al. (2002) Nonrandom X chromosome inactivation in mouse embryos carrying Searle’s T(X;16)16H translocation visualized using X-linked LACZ and GFP transgenes. Cytogenet Genome Res 99:52–58
West JD, Chapman VM (1978) Variation for X chromosome expression in mice detected by electrophoresis of phosphoglycerate kinase. Genet Res 32:91–102
Williams BR, Wu CT (2004) Does random X-inactivation in mammals reflect a random choice between two X chromosomes? Genetics 167:1525–1528
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-005-0059-2