PDF(Pubmed)
Abstract：
Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole-blood bulk RNA sequencing samples from INTERVAL study blood donors. We found that while individual misexpression events occur rarely, in aggregate they were found in almost all samples and a third of inactive protein-coding genes. Using 2,821 paired whole-genome and RNA sequencing samples, we identified that misexpression events are enriched in cis for rare structural variants. We established putative mechanisms through which a subset of SVs lead to gene misexpression, including transcriptional readthrough, transcript fusions, and gene inversion. Overall, we develop misexpression as a type of transcriptomic outlier analysis and extend our understanding of the variety of mechanisms by which genetic variants can influence gene expression.
摘要：
基因错误表达是在通常无活性的情况下基因的异常转录。尽管已知其在特定罕见疾病中的病理后果，我们对其在人类中的广泛流行和机制了解有限。为了解决这个问题，我们分析了来自INTERVAL研究献血者的4,568份全血批量RNA测序样本中的基因错误表达.我们发现，虽然个别错误表达事件很少发生，总的来说，它们存在于几乎所有的样本和三分之一的无活性蛋白质编码基因中。使用2,821个配对的全基因组和RNA测序样本，我们发现,对于罕见的结构变异体,错误表达事件富含顺式.我们建立了推测的机制，通过这些机制，SVs的一个子集导致基因错误表达，包括转录通读，转录融合，和基因倒位。总的来说,我们开发了错误表达作为转录组异常分析的一种类型，并扩展了我们对遗传变异影响基因表达的各种机制的理解。
