title: Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice.
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.
authors: Department of Pathology, Dalhousie University, Halifax, NS, Canada.
authors: Nisa K E
authors: NK
authors: Renault
authors: Sonja M
authors: SM
authors: Pritchett
authors: Robin E
authors: RE
authors: Howell
authors: Wenda L
authors: WL
authors: Greer
authors: Carmen
authors: C
authors: Sapienza
authors: Karen Helene
authors: KH
authors: Ørstavik
authors: David C
authors: DC
authors: Hamilton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000378:metabolism*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008875:Middle Aged; D049951:X Chromosome Inactivation / Q000235:genetics*; D055815:Young Adult
references: Blood. 1995 May 1;85(9):2471-7
references: 7537115
references: Br J Haematol. 1998 Sep;102(4):996-1003
references: 9734650
references: Nature. 2011 Apr 21;472(7343):370-4
references: 21471966
references: Blood. 1996 Jul 1;88(1):59-65
references: 8704202
references: Nature. 1961 Apr 22;190:372-3
references: 13764598
references: Nature. 1991 Jan 3;349(6304):82-4
references: 1985270
references: Genet Res. 1970 Apr;15(2):183-95
references: 5480753
references: Ann Hum Genet. 1973 Jul;37(1):39-48
references: 4759903
references: Hum Genet. 2009 Sep;126(3):363-73
references: 19396465
references: Eur J Hum Genet. 1998 Nov-Dec;6(6):552-62
references: 9887372
references: Nature. 2005 Mar 17;434(7031):400-4
references: 15772666
references: J Hum Genet. 2006;51(11):1030-1036
references: 16955230
references: J Hum Genet. 2011 May;56(5):390-7
references: 21412246
references: Genetics. 1967 Oct;57(2):331-46
references: 5584570
references: J Med Genet. 2008 May;45(5):309-13
references: 18156436
references: Eur J Hum Genet. 2007 Jun;15(6):628-37
references: 17342157
references: Nat Cell Biol. 2006 Mar;8(3):293-9
references: 16434960
references: Development. 2009 Jan;136(1):1-10
references: 19036804
references: PLoS Genet. 2011 Jul;7(7):e1002212
references: 21811421
references: J Clin Invest. 2008 Jan;118(1):333-41
references: 18097474
references: J Med Genet. 2008 Jul;45(7):401-8
references: 18463129
references: J Exp Med. 1996 Feb 1;183(2):561-7
references: 8627167
references: Genet Res. 1972 Jun;19(3):229-40
references: 5075805
references: Cell. 2009 Nov 25;139(5):999-1011
references: 19945382
references: JAMA. 2006 Mar 22;295(12):1428-33
references: 16551715
references: Hum Genet. 2004 Oct;115(5):387-92
references: 15338278
references: J Clin Invest. 1992 May;89(5):1438-44
references: 1349026
references: Blood. 2008 Oct 15;112(8):3186-93
references: 18641369
references: Annu Rev Genet. 1997;31:571-610
references: 9442908
references: PLoS Comput Biol. 2007 Nov;3(11):e210
references: 17997592
references: Am J Hum Genet. 2006 Sep;79(3):493-9
references: 16909387
references: Eur J Hum Genet. 2005 May;13(5):599-606
references: 15756296
references: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3862-6
references: 9520458