Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases.
Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases.
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DOI：
10.1101/gr.275677.121
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发表时间：
2021-09
期刊：
影响因子：
7
通讯作者：
Liu DJ
中科院分区：
文献类型：
--
作者：
Sauteraud R;Stahl JM;James J;Englebright M;Chen F;Zhan X;Carrel L;Liu DJ
X染色体在人类发育和疾病中起着重要作用。然而，X基因的功能基因组学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，大多数基因仅从一个等位基因表达。然而，大约30%的X基因“逃脱”XCI，并从两个等位基因转录，许多人只在一部分人口中。这种个体间的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X染色体失活RNA-seq（XCIR），这是一种使用批量RNA-seq数据识别逃逸基因的新方法。我们的方法，作为一个R包，比其他方法更强大，是计算效率高，以处理大型人口规模的数据集。使用注释的XCI状态，我们研究了X连锁基因对英国生物银行数据集中疾病遗传力的贡献。我们发现，逃逸和可变逃逸基因解释了最大比例的X遗传，这在很大程度上是由于X基因与Y同源性。最后，我们研究了每个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著增加。我们的研究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，我们的管道允许分析更大的数据集，用于广泛的表型。
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.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
64.8
作者：
通讯作者：
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.1806811115
发表时间：
2018-12-18
影响因子：
11.1
作者：
Garieri, Marco;Stamoulis, Georgios;Antonarakis, Stylianos E.
通讯作者：
Antonarakis, Stylianos E.