The X Chromosome plays an important role in human development and disease. However, functional genomic and disease association studies of X genes greatly lag behind autosomal gene studies, in part owing to the unique biology of X-Chromosome inactivation (XCI). Because of XCI, most genes are only expressed from one allele. Yet, ∼30% of X genes “escape” XCI and are transcribed from both alleles, many only in a proportion of the population. Such interindividual differences are likely to be disease relevant, particularly for sex-biased disorders. To understand the functional biology for X-linked genes, we developed X-Chromosome inactivation for RNA-seq (XCIR), a novel approach to identify escape genes using bulk RNA-seq data. Our method, available as an R package, is more powerful than alternative approaches and is computationally efficient to handle large population-scale data sets. Using annotated XCI states, we examined the contribution of X-linked genes to the disease heritability in the United Kingdom Biobank data set. We show that escape and variable escape genes explain the largest proportion of X heritability, which is in large part attributable to X genes with Y homology. Finally, we investigated the role of each XCI state in sex-biased diseases and found that although XY homologous gene pairs have a larger overall effect size, enrichment for variable escape genes is significantly increased in female-biased diseases. Our results, for the first time, quantitate the importance of variable escape genes for the etiology of sex-biased disease, and our pipeline allows analysis of larger data sets for a broad range of phenotypes.

中文翻译：

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推断逃避 X 染色体失活的基因揭示了可变逃避基因对性别偏见疾病的重要贡献

X染色体在人类发育和疾病中起着重要作用。然而，X 基因的功能基因组和疾病关联研究大大落后于常染色体基因研究，部分原因是 X 染色体失活 (XCI) 的独特生物学。由于 XCI，大多数基因仅由一个等位基因表达。然而，约 30% 的 X 基因“逃逸”了 XCI 并从两个等位基因转录，其中许多仅在一部分人群中。这种个体间差异可能与疾病有关，特别是对于性别偏见的疾病。为了了解 X 连锁基因的功能生物学，我们开发了用于 RNA-seq (XCIR) 的 X 染色体失活，这是一种使用大量 RNA-seq 数据识别逃逸基因的新方法。我们的方法，作为 R 包提供，比替代方法更强大，并且在处理大规模人口规模的数据集时计算效率更高。使用带注释的 XCI 状态，我们在英国生物银行数据集中检查了 X 连锁基因对疾病遗传力的贡献。我们表明逃逸和可变逃逸基因解释了 X 遗传力的最大比例，这在很大程度上归因于具有 Y 同源性的 X 基因。最后，我们研究了每种 XCI 状态在性别偏见疾病中的作用，发现尽管 XY 同源基因对具有更大的整体效应大小，但在女性偏见疾病中，可变逃逸基因的富集显着增加。我们的结果首次量化了可变逃逸基因对性别偏见疾病病因学的重要性，