Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders of Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Cell Rep. 2021 Jul 27;36(4):109439. doi: 10.1016/j.celrep.2021.109439.
Ubiquitous in eukaryotes, circular RNAs (circRNAs) comprise a large class of mostly non-coding RNAs produced by back-splicing. Although some circRNAs have demonstrated biochemical activities, whether most circRNAs are functional is unknown. Here, we test the hypothesis that circRNA production primarily results from splicing error and so is deleterious instead of beneficial. In support of the error hypothesis, our analysis of RNA sequencing data from 11 shared tissues of humans, macaques, and mice finds that (1) back-splicing is much rarer than linear-splicing, (2) the rate of back-splicing diminishes with the splicing amount, (3) the overall prevalence of back-splicing in a species declines with its effective population size, and (4) circRNAs are overall evolutionarily unconserved. We estimate that more than 97% of the observed circRNA production is deleterious. We identify a small number of functional circRNA candidates, and the genome-wide trend strongly suggests that circRNAs are largely non-functional products of splicing errors.
环状 RNA（circRNA）普遍存在于真核生物中，它们是一类主要由反向剪接产生的非编码 RNA 分子。虽然一些 circRNA 已经表现出了生化活性，但大多数 circRNA 是否具有功能仍不清楚。在这里，我们检验了这样一个假设，即 circRNA 的产生主要是由于剪接错误，因此是有害的，而不是有益的。为了支持错误假说，我们分析了来自人类、猕猴和小鼠 11 个共享组织的 RNA 测序数据，发现：（1）反向剪接比线性剪接罕见得多；（2）反向剪接的速率随着剪接量的减少而减少；（3）在一个物种中，反向剪接的总体普遍性随着其有效种群大小的减少而下降；（4）circRNA 在总体上进化上是没有保守性的。我们估计，超过 97%的观察到的 circRNA 产生是有害的。我们鉴定出少数具有功能的 circRNA 候选物，全基因组的趋势强烈表明 circRNA 主要是剪接错误的非功能性产物。
