Characterization of X chromosome inactivation using integrated analysis of whole-exome and mRNA sequencing.
Characterization of X chromosome inactivation using integrated analysis of whole-exome and mRNA sequencing.
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DOI：
10.1371/journal.pone.0113036
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Craig DW
中科院分区：
文献类型：
--
作者：
Szelinger S;Malenica I;Corneveaux JJ;Siniard AL;Kurdoglu AA;Ramsey KM;Schrauwen I;Trent JM;Narayanan V;Huentelman MJ;Craig DW
在女性中，X染色体失活（XCI）是一种表观遗传的基因剂量补偿机制，通过细胞中一个X拷贝的失活。亲本染色体之一的随机XCI导致表达来自母本或父本遗传的活性X的等位基因的细胞的比例大致相等，并且由XCI比率定义。偏XCI比率提示非随机失活，其在X连锁遗传条件下可发挥重要作用。目前的方法依赖于间接的、半定量的基于DNA甲基化的测定来估计XCI比率。在这里，我们报告了一种直接的方法来估计XCI比率的集成，家庭三人组为基础的全外显子组和mRNA测序使用相位传输的等位基因加上等位基因特异性表达分析。我们将这种方法应用于计算机数据和轻度认知障碍的临床患者，但没有明确的诊断或理解表型的分子机制。模拟结果表明，定相和非定相杂合等位基因表达可用于估计XCI比率。对患者外显子组的分离分析揭示了Xp22.31上的从头、间质性、1.7 Mb缺失，该缺失起源于父系遗传的X，并且先前与异质性、神经学表型相关。分阶段的等位基因表达数据表明，83∶20的中度偏态XCI有利于母系遗传的细胞遗传学正常X的表达，并表明新生事件对父系拷贝的有害影响可能被偏态XCI所抵消，偏态XCI有利于野生型X的表达。本研究显示了综合测序方法在XCI比率估计中的实用性。
In females, X chromosome inactivation (XCI) is an epigenetic, gene dosage compensatory mechanism by inactivation of one copy of X in cells. Random XCI of one of the parental chromosomes results in an approximately equal proportion of cells expressing alleles from either the maternally or paternally inherited active X, and is defined by the XCI ratio. Skewed XCI ratio is suggestive of non-random inactivation, which can play an important role in X-linked genetic conditions. Current methods rely on indirect, semi-quantitative DNA methylation-based assay to estimate XCI ratio. Here we report a direct approach to estimate XCI ratio by integrated, family-trio based whole-exome and mRNA sequencing using phase-by-transmission of alleles coupled with allele-specific expression analysis. We applied this method to in silico data and to a clinical patient with mild cognitive impairment but no clear diagnosis or understanding molecular mechanism underlying the phenotype. Simulation showed that phased and unphased heterozygous allele expression can be used to estimate XCI ratio. Segregation analysis of the patient's exome uncovered a de novo, interstitial, 1.7 Mb deletion on Xp22.31 that originated on the paternally inherited X and previously been associated with heterogeneous, neurological phenotype. Phased, allelic expression data suggested an 83∶20 moderately skewed XCI that favored the expression of the maternally inherited, cytogenetically normal X and suggested that the deleterious affect of the de novo event on the paternal copy may be offset by skewed XCI that favors expression of the wild-type X. This study shows the utility of integrated sequencing approach in XCI ratio estimation.
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