The gene content of the X and Y chromosomes has dramatically diverged during evolution. The ensuing dosage imbalance within the genome of males and females has led to unique chromosome-wide regulatory mechanisms with significant and sex-specific impacts on X-linked gene expression. X inactivation or silencing of most genes on one X chromosome chosen at random in females profoundly affects the manifestation of X-linked diseases, as males inherit a single maternal allele, while females express maternal and paternal alleles in a mosaic manner. An additional complication is the existence of genes that escape X inactivation and thus are ubiquitously expressed from both alleles in females. The mosaic nature of X-linked gene expression and the potential for escape can vary between individuals, tissues, cell types and stages of life. Our understanding of the specialized nature of X-linked genes and of the multilayer epigenetic regulation that influence their expression throughout the organism has been helped by molecular studies conducted by tissue-specific and single-cell-specific approaches. In turn, the definition of molecular events that control X silencing has helped develop new approaches for the treatment of some X-linked disorders. This review focuses on the peculiarities of the X chromosome genetic content and epigenetic regulation in shaping the manifestation of congenital and acquired X-linked disorders in a sex-specific manner.

中文翻译：

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人类疾病中的 X 因素：基因含量和剂量调节的影响

X 和 Y 染色体的基因含量在进化过程中发生了显着差异。随之而来的男性和女性基因组内的剂量不平衡导致了独特的全染色体调控机制，对 X 连锁基因表达具有显着和性别特异性的影响。在女性中随机选择的一条 X 染色体上的大多数基因的 X 失活或沉默对 X 连锁疾病的表现产生了深远的影响，因为男性继承了一个母体等位基因，而女性则以镶嵌方式表达母体和父系等位基因。另一个复杂因素是存在逃避 X 失活的基因，因此在女性的两个等位基因中普遍表达。X连锁基因表达的镶嵌性质和逃逸的可能性可能因个体、组织、细胞类型和生命阶段而异。通过组织特异性和单细胞特异性方法进行的分子研究有助于我们了解 X 连锁基因的特殊性质和影响其在整个生物体中表达的多层表观遗传调控。反过来，控制 X 沉默的分子事件的定义有助于开发治疗某些 X 连锁疾病的新方法。本综述侧重于 X 染色体遗传内容的特殊性和表观遗传调控在以性别特异性方式塑造先天性和获得性 X 连锁疾病的表现。反过来，控制 X 沉默的分子事件的定义有助于开发治疗某些 X 连锁疾病的新方法。本综述侧重于 X 染色体遗传内容的特殊性和表观遗传调控在以性别特异性方式塑造先天性和获得性 X 连锁疾病的表现。反过来，控制 X 沉默的分子事件的定义有助于开发治疗某些 X 连锁疾病的新方法。本综述侧重于 X 染色体遗传内容的特殊性和表观遗传调控在以性别特异性方式塑造先天性和获得性 X 连锁疾病的表现。