Mapping RNA splicing variations in clinically accessible and nonaccessible tissues to facilitate Mendelian disease diagnosis using RNA-seq
Mapping RNA splicing variations in clinically accessible and nonaccessible tissues to facilitate Mendelian disease diagnosis using RNA-seq
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DOI：
10.1038/s41436-020-0780-y
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发表时间：
2020-03-30
影响因子：
8.8
通讯作者：
Bhoj, Elizabeth J.
中科院分区：
文献类型：
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作者：
Aicher, Joseph K.;Jewell, Paul;Bhoj, Elizabeth J.
目的RNA-seq是一种很有前途的方法，通过检测DNA测序遗漏的RNA剪接中的致病性畸变来提高诊断水平。RNA-seq通常在来自血液和皮肤的临床可及组织（CAT）上进行。RNA组织特异性使得难以识别相关但不可接近的组织（非CAT）中的畸变。我们确定了来自CAT的RNA-seq如何代表基因和非CAT之间的剪接。方法我们从基因型-组织表达项目（GTEx）和ArrayExpress的56个不同成人和胎儿组织中定量了801个RNA-seq样本的RNA剪接。我们鉴定了每种非CAT中的基因和剪接事件，并确定了每种CAT中的RNA-seq何时不能充分代表它们。我们开发了一个在线资源MAJIQ-CAT，用于探索我们对特定基因和组织的分析。结果在非CAT基因中，40.2%的基因存在至少一个CAT不能充分代表的剪接，6.3%的基因存在所有CAT不能充分代表的剪接。大多数（52.1%）代表性不足的基因在CAT中低表达（每百万转录本（TPM）< 1），但5.8%的基因尽管表达良好（TPM > 10），但代表性不足。结论利用来自CAT的RNA-seq不能充分评估非CAT中的许多剪接事件。MAJIQ-CAT允许用户探索哪些可访问的组织（如果有的话）最能代表感兴趣的基因和组织中的剪接。
Purpose RNA-seq is a promising approach to improve diagnoses by detecting pathogenic aberrations in RNA splicing that are missed by DNA sequencing. RNA-seq is typically performed on clinically accessible tissues (CATs) from blood and skin. RNA tissue specificity makes it difficult to identify aberrations in relevant but nonaccessible tissues (non-CATs). We determined how RNA-seq from CATs represent splicing in and across genes and non-CATs. Methods We quantified RNA splicing in 801 RNA-seq samples from 56 different adult and fetal tissues from Genotype-Tissue Expression Project (GTEx) and ArrayExpress. We identified genes and splicing events in each non-CAT and determined when RNA-seq in each CAT would inadequately represent them. We developed an online resource, MAJIQ-CAT, for exploring our analysis for specific genes and tissues. Results In non-CATs, 40.2% of genes have splicing that is inadequately represented by at least one CAT; 6.3% of genes have splicing inadequately represented by all CATs. A majority (52.1%) of inadequately represented genes are lowly expressed in CATs (transcripts per million (TPM) < 1), but 5.8% are inadequately represented despite being well expressed (TPM > 10). Conclusion Many splicing events in non-CATs are inadequately evaluated using RNA-seq from CATs. MAJIQ-CAT allows users to explore which accessible tissues, if any, best represent splicing in genes and tissues of interest.