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.

X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability

“…The absence of a consistent pattern of X inactivation between mothers and daughters supports a generational resetting of X inactivation. 21 In previous studies of X-linked diseases, large deletions were more likely to cause skewing than point mutations. 22 Although this might be true in CGD carriers as well, we analyzed only granulocytes, and therefore differences in other tissues might show different patterns.…”

Sex disparities in melanoma outcomes: The role of biology

“…X chromosome inactivation likely has profound but somewhat unpredictable effects on tumorigenesis in women compared with in men. The inactivation process is not entirely understood and until recently was thought to be a random process; however, recent studies suggest otherwise [109,110]. Approximately 15% of X chromosomes escape inactivation and another 10% show variable patterns of inactivation [111].…”

“…Decreased B cell activation, differentiation and survival [64] Low CD 3 + T lymphocytes [53] Increased T cell apoptosis [151] Low IL2 and TH1 responses and thus suppression of T and B-lymphocytes development [53] Oxidative processes -Decreased oxidative damage to mitochondrial DNA [82] -Estrogen protects cells against oxidative stress and acts as a direct antioxidant [82] -High level of anti-oxidant enzymes [86] -High oxidative damage to mitochondrial DNA (4-fold higher compared with women) [82] -Androgens diminish protection against oxidative stress [85] -Decreased number of anti-oxidants and anti-oxidant enzymes [86] -Elevated ROS cellular environment promote tumor metastasis [75,86,87] Sex chromosomes -X chromosome inactivation process: [55,108,109] Decreased tissue X chromosome oncogenes expression [mi-RNAs, cancer/testis antigens (CT-X)] [117][118][119][120][121] Tissue mosaicism in X chromosome associated oncogenes -Lack of Y chromosome associated oncogenes -No X chromosome inactivation process: [55,108,109] Monosomic expression of X chromosome specific oncogenes Increased tissue expression of X chromosome oncogenes -Y chromosome associated oncogene expression [TSPY] [133][134][135][136]139] DNA binding sites to elicit transcriptional regulation of target genes. Studies from androgen receptor knockout mouse models demonstrate that androgens influence the promotion of tumorigenesis in liver and prostate cancer and promote both tumorigenesis and metastasis in bladder, lung, kidney cancers [43], which have sex disparities in outcome favoring women (Table 1, Supplemental Fig.…”

X-Chromosome Genetic Association Test Accounting for X-Inactivation, Skewed X-Inactivation, and Escape from X-Inactivation

“…In this study, we denote this phenomenon of skewed XCI as XCI-S. The skewness of XCI has been defined using an arbitrary threshold as inactivation of one of the alleles in more than 75% of cells [Abkowitz et al, 1998;Chabchoub et al, 2009;Minks et al, 2008;Naumova et al, 1998;Renault et al, 2013;Sharp et al, 2000;Wong et al, 2011]. Extreme or severe skewness, which is defined as inactivation of one of the alleles in more than 90% of cells, has also been observed [Amos-Landgraf et al, 2006;Busque et al, 1996;Champion et al, 1997;Gale et al, 1997;Hatakeyama et al, 2004;Minks et al, 2008;Sharp et al, 2000;Tonon et al, 1998;Willard, 2000;Wong et al, 2011].…”