Cross-Mapping Events in miRNAs Reveal Potential miRNA-Mimics and Evolutionary Implications

MicroRNAs (miRNAs) have important roles in various biological processes. miRNA cross-mapping is a prevalent phenomenon where miRNA sequence originating from one genomic region is mapped to another location. To have a better understanding of this phenomenon in the human genome, we performed a detailed analysis in this paper using public miRNA high-throughput sequencing data and all known human miRNAs. We observed widespread cross-mapping events between miRNA precursors (pre-miRNAs), other non-coding RNAs (ncRNAs) and the opposite strands of pre-miRNAs by analyzing the high-throughput sequencing data. Computational analysis on all known human miRNAs also confirmed that many of them could be involved in cross-mapping events. The processing or decay of both ncRNAs and pre-miRNA opposite strand transcripts may contribute to miRNA enrichment, although some might be miRNA-mimics due to miRNA mis-annotation. Comparing to canonical miRNAs, miRNAs involved in cross-mapping events between pre-miRNAs and other ncRNAs normally had shorter lengths (17–19 nt), lower prediction scores and were classified as pseudo miRNA precursors. Notably, 4.9% of all human miRNAs could be accurately mapped to the opposite strands of pre-miRNAs, which showed that both strands of the same genomic region had the potential to produce mature miRNAs and simultaneously implied some potential miRNA precursors. We proposed that the cross-mapping events are more complex than we previously thought. Sequence similarity between other ncRNAs and pre-miRNAs and the specific stem-loop structures of pre-miRNAs may provide evolutionary implications.

微小核糖核酸（microRNAs，miRNAs）在诸多生物学过程中发挥关键作用。miRNA交叉比对（miRNA cross-mapping）是一种普遍存在的现象，即源自某一基因组区域的miRNA序列被比对至另一基因组位置。为深入解析人类基因组中的该现象，本文依托公开的miRNA高通量测序数据与所有已知人类miRNA开展了详尽分析。通过分析高通量测序数据，我们发现miRNA前体（pre-miRNAs）、其他非编码RNA（non-coding RNAs，ncRNAs）与miRNA前体反义链之间存在广泛的交叉比对事件。对所有已知人类miRNA的计算分析亦证实，其中诸多序列可能参与交叉比对事件。非编码RNA与miRNA前体反义链转录本的加工或降解过程可能促进miRNA的富集，不过其中部分序列可能因miRNA注释错误而成为miRNA模拟物。与经典miRNA相比，参与miRNA前体与其他非编码RNA之间交叉比对事件的miRNA通常长度更短（17~19 nt）、预测得分更低，且被归类为假miRNA前体。值得注意的是，所有人类miRNA中有4.9%可精准比对至miRNA前体的反义链，这表明同一基因组区域的两条链均具备产生成熟miRNA的潜力，同时也暗示了部分潜在的miRNA前体。我们提出，交叉比对事件的复杂程度远超此前认知。其他非编码RNA与miRNA前体之间的序列相似性，以及miRNA前体特有的茎环结构，或可为进化研究提供新的启示。