Department of Biology, University of North Carolina, Chapel Hill, NC, 27599, USA.
Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Hum Genet. 2022 Oct;141(10):1659-1672. doi: 10.1007/s00439-021-02395-9. Epub 2021 Nov 6.
Disease-associated variants (DAVs) are commonly considered either through a genomic lens that describes variant function at the DNA level, or at the protein function level if the variant is translated. Although the genomic and proteomic effects of variation are well-characterized, genetic variants disrupting post-transcriptional regulation is another mechanism of disease that remains understudied. Specific RNA sequence motifs mediate post-transcriptional regulation both in the nucleus and cytoplasm of eukaryotic cells, often by binding to RNA-binding proteins or other RNAs. However, many DAVs map far from these motifs, which suggests deeper layers of post-transcriptional mechanistic control. Here, we consider a transcriptomic framework to outline the importance of post-transcriptional regulation as a mechanism of disease-causing single-nucleotide variation in the human genome. We first describe the composition of the human transcriptome and the importance of abundant yet overlooked components such as introns and untranslated regions (UTRs) of messenger RNAs (mRNAs). We present an analysis of Human Gene Mutation Database variants mapping to mRNAs and examine the distribution of causative disease-associated variation across the transcriptome. Although our analysis confirms the importance of post-transcriptional regulatory motifs, a majority of DAVs do not directly map to known regulatory motifs. Therefore, we review evidence that regions outside these well-characterized motifs can regulate function by RNA structure-mediated mechanisms in all four elements of an mRNA: exons, introns, 5' and 3' UTRs. To this end, we review published examples of riboSNitches, which are single-nucleotide variants that result in a change in RNA structure that is causative of the disease phenotype. In this review, we present the current state of knowledge of how DAVs act at the transcriptome level, both through altering post-transcriptional regulatory motifs and by the effects of RNA structure.
疾病相关变异（DAV）通常通过描述 DNA 水平变异功能的基因组视角，或者在变异被翻译时通过描述蛋白质功能水平来考虑。尽管变异的基因组和蛋白质组效应已经得到很好的描述，但破坏转录后调控的遗传变异是另一种未得到充分研究的疾病机制。特定的 RNA 序列基序在真核细胞的核和细胞质中都介导转录后调控，通常通过与 RNA 结合蛋白或其他 RNA 结合。然而，许多 DAV 远不在这些基序上，这表明转录后机制控制有更深层次。在这里，我们考虑一个转录组学框架来概述转录后调控作为人类基因组中单核苷酸变异引起疾病的机制的重要性。我们首先描述人类转录组的组成以及内含子和信使 RNA（mRNA）的非翻译区（UTR）等丰富但被忽视的成分的重要性。我们对映射到 mRNA 的人类基因突变数据库变体进行了分析，并检查了转录组中致病相关变异的分布。虽然我们的分析证实了转录后调控基序的重要性，但大多数 DAV 并不直接映射到已知的调控基序。因此，我们回顾了证据，证明这些特征基序之外的区域可以通过 RNA 结构介导的机制在 mRNA 的四个元件（外显子、内含子、5' 和 3'UTR）中调节功能。为此，我们回顾了已发表的核糖开关的例子，核糖开关是导致疾病表型的 RNA 结构变化的单核苷酸变异。在这篇综述中，我们展示了 DAV 在转录组水平上作用的现有知识状态，包括通过改变转录后调控基序和 RNA 结构的影响。
