Abstract
In eutherian mammals, one X-chromosome in every XX somatic cell is transcriptionally silenced through the process of X-chromosome inactivation (XCI). Females are thus functional mosaics, where some cells express genes from the paternal X, and the others from the maternal X. The relative abundance of the two cell populations (X-inactivation pattern, XIP) can have significant medical implications for some females. In mice, the ‘choice’ of which X to inactivate, maternal or paternal, in each cell of the early embryo is genetically influenced. In humans, the timing of XCI choice and whether choice occurs completely randomly or under a genetic influence is debated. Here, we explore these questions by analysing the distribution of XIPs in large populations of normal females. Models were generated to predict XIP distributions resulting from completely random or genetically influenced choice. Each model describes the discrete primary distribution at the onset of XCI, and the continuous secondary distribution accounting for changes to the XIP as a result of development and ageing. Statistical methods are used to compare models with empirical data from Danish and Utah populations. A rigorous data treatment strategy maximises information content and allows for unbiased use of unphased XIP data. The Anderson–Darling goodness-of-fit statistics and likelihood ratio tests indicate that a model of genetically influenced XCI choice better fits the empirical data than models of completely random choice.
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References
Lyon MF : Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 1961; 190: 372–373.
Morey C, Avner P : The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever. PLoS Genet 2011; 7: e1002212.
Brown CJ, Lafreniere RG, Powers VE et al: Localization of the X inactivation centre on the human X chromosome in Xq13. Nature 1991; 349: 82–84.
Carrel L, Willard HF : X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434: 400–404.
Heard E, Clerc P, Avner P : X-chromosome inactivation in mammals. Annu Rev Genet 1997; 31: 571–610.
Morleo M, Franco B : Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders. J Med Genet 2008; 45: 401–408.
Migeon BR : The role of X inactivation and cellular mosaicism in women’s health and sex-specific diseases. JAMA 2006; 295: 1428–1433.
Orstavik KH : X chromosome inactivation in clinical practice. Hum Genet 2009; 126: 363–373.
Cattanach BM, Perez JN, Pollard CE : Controlling elements in the mouse X-chromosome. II.Location in the linkage map. Genet Res 1970; 15: 183–195.
Cattanach BM, Isaacson JH : Controlling elements in the mouse X chromosome. Genetics 1967; 57: 331–346.
Cattanach B, Rasberry C : Identification of the mus castaneus Xce allele. Mouse Genome 1994; 92: 114.
Cattanach BM, Williams CE : Evidence of non-random X chromosome activity in the mouse. Genet Res 1972; 19: 229–240.
Kristiansen M, Knudsen GP, Bathum L et al: Twin study of genetic and aging effects on X chromosome inactivation. Eur J Hum Genet 2005; 13: 599–606.
Naumova AK, Olien L, Bird LM et al: Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human. Eur J Hum Genet 1998; 6: 552–562.
Cau M, Addis M, Congiu R et al: A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting LOWE syndrome. J Hum Genet 2006; 51: 1030–1036.
Renault NK, Dyack S, Dobson MJ, Costa T, Lam WL, Greer WL : Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females. Eur J Hum Genet 2007; 15: 628–637.
Renault NK, Renault MP, Copeland E, Howell RE, Greer WL : Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2. J Hum Genet 2011; 56: 390–397.
Abkowitz JL, Taboada M, Shelton GH, Catlin SN, Guttorp P, Kiklevich JV : An X chromosome gene regulates hematopoietic stem cell kinetics. Proc Natl Acad Sci USA 1998; 95: 3862–3866.
Fialkow PJ : Primordial cell pool size and lineage relationships of five human cell types. Ann Hum Genet 1973; 37: 39–48.
Tonon L, Bergamaschi G, Dellavecchia C et al: Unbalanced X-chromosome inactivation in haemopoietic cells from normal women. Br J Haematol 1998; 102: 996–1003.
Amos-Landgraf JM, Cottle A, Plenge RM et al: X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet 2006; 79: 493–499.
Prchal JT, Prchal JF, Belickova M et al: Clonal stability of blood cell lineages indicated by X-chromosomal transcriptional polymorphism. J Exp Med 1996; 183: 561–567.
Wengler G, Gorlin JB, Williamson JM et al: Nonrandom inactivation of the X chromosome in early lineage hematopoietic cells in carriers of Wiskott-Aldrich syndrome. Blood 1995; 85: 2471–2477.
Busque L, Mio R, Mattioli J et al: Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 1996; 88: 59–65.
Sandovici I, Naumova AK, Leppert M et al: A longitudinal study of X-inactivation ratio in human females. Hum Genet 2004; 115: 387–392.
D’Agostino R, Stephens M : Goodness-of-fit Techniques. Marcel Dekker, Inc., 1986.
Fey MF, Peter HJ, Hinds HL et al: Clonal analysis of human tumors with M27 beta, a highly informative polymorphic X chromosomal probe. J Clin Invest 1992; 89: 1438–1444.
Swierczek SI, Agarwal N, Nussenzveig RH et al: Hematopoiesis is not clonal in healthy elderly women. Blood 2008; 112: 3186–3193.
Okamoto I, Patrat C, Thepot D et al: Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development. Nature 2011; 472: 370–374.
Bittel D, Theodoro M, Kibiryeva N, Fischer W, Talebizadeh Z, Butler M : Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet 2008; 5: 309–313.
Bolduc V, Chagnon P, Provost S et al: No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans. J Clin Invest 2008; 118: 333–341.
Starmer J, Magnuson T : A new model of random X chromosome inactivation. Development 2009; 1: 1–10.
Nicodemi M, Prisco A, Self-assembly DNA : binding of the blocking factor in X chromosome inactivation. PLoS Comput Biol 2007; 11: e210.
Jonkers I, Barakat T, Achame E et al: RNF12 is an X-encoded dose-dependent activator of X chromosome inactivation. Cell 2009; 5: 999–1011.
Bacher CP, Guggiari M, Brors B et al: Transient colocalization of X-inactivation centres accompanies the initiation of X-inactivation. Nat Cell Biol 2006; 8: 293–299.
Acknowledgements
Manuscript preparation: Marc Renault. Funding: Canadian Institutes of Health Research (CIHR), the Killam Foundation, the Natural Sciences and Engineering Council (NSERC) of Canada.
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Renault, N., Pritchett, S., Howell, R. et al. Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice. Eur J Hum Genet 21, 1396–1402 (2013). https://doi.org/10.1038/ejhg.2013.84
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DOI: https://doi.org/10.1038/ejhg.2013.84
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