A longitudinal twin study of skewed X chromosome-inactivation.
A longitudinal twin study of skewed X chromosome-inactivation.
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DOI：
10.1371/journal.pone.0017873
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发表时间：
2011-03-22
期刊：
影响因子：
3.7
通讯作者：
Mill J
中科院分区：
文献类型：
--
作者：
Wong CC;Caspi A;Williams B;Houts R;Craig IW;Mill J
X染色体失活（XCI）是一种关键的表观遗传机制，涉及男性和女性之间X连锁基因的剂量补偿。在任何给定的细胞中，早期雌性发育中的 XCI 过程被认为在等位基因之间是随机的，并且一旦建立就以克隆方式维持。然而，最近的研究表明，XCI 可能并不总是随机的，并且随着年龄的增长，偏向失活可能会变得更加普遍。影响此类 XCI 偏差及其随时间变化的因素在很大程度上尚不清楚。为了阐明随机、遗传和环境因素对 XCI 纵向变化的影响，我们检查了 5 岁和 10 岁同卵双胞胎 (MZ) (n = 23) 和双卵双胞胎 (DZ) (n = 22) 女性双胞胎样本中的 X 失活谱。与等位基因 XCI 比率高度一致的同卵双胞胎相比，异卵双胞胎的一致性水平要低得多。虽然 XCI 模式在 5 岁至 10 岁之间较为稳定，但随着时间的推移，存在一些漂移，10 岁时更极端的 XCI 偏差的患病率增加。据我们所知，这项研究代表了对偏差 XCI 模式的最早纵向评估，并表明偏差 XCI 可能在儿童早期就已经建立。我们的数据还表明 MZ 孪生与等位基因 XCI 比率的建立之间存在联系，并证明建立后 XCI 的获得性倾斜主要由随机机制介导。这些数据对于我们理解复杂疾病中的性别差异以及同卵双胞胎之间表型不一致的潜在原因具有重要意义。
X-chromosome inactivation (XCI) is a pivotal epigenetic mechanism involved in the dosage compensation of X-linked genes between males and females. In any given cell, the process of XCI in early female development is thought to be random across alleles and clonally maintained once established. Recent studies, however, suggest that XCI might not always be random and that skewed inactivation may become more prevalent with age. The factors influencing such XCI skewing and its changes over time are largely unknown. To elucidate the influence of stochastic, heritable and environmental factors in longitudinal changes in XCI, we examined X inactivation profiles in a sample of monozygotic (MZ) (n = 23) and dizygotic (DZ) (n = 22) female twin-pairs at ages 5 and 10 years. Compared to MZ twins who were highly concordant for allelic XCI ratios, DZ twins showed much lower levels of concordance. Whilst XCI patterns were moderately stable between ages 5 and 10 years, there was some drift over time with an increased prevalence of more extreme XCI skewing at age 10. To our knowledge, this study represents the earliest longitudinal assessment of skewed XCI patterns, and suggests that skewed XCI may already be established in early childhood. Our data also suggest a link between MZ twinning and the establishment of allelic XCI ratios, and demonstrate that acquired skewing in XCI after establishment is primarily mediated by stochastic mechanisms. These data have implications for our understanding about sex differences in complex disease, and the potential causes of phenotypic discordance between MZ female twins.
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