Classical microRNA (miRNA) has been so far believed as a single sequence, but it indeed contains multiple miRNA isoforms (isomiR) with various sequences and expression patterns. It is not clear whether these diverse isomiRs have potential relationships and whether they contribute to miRNA:mRNA interactions. Here, we aimed to reveal the potential evolutionary and functional relationships of multiple isomiRs based on let-7 and miR-10 gene families that are prone to clustering together on chromosomes. Multiple isomiRs within gene families showed similar functions to their canonical miRNAs, indicating selection of the predominant sequence. IsomiRs containing novel seed regions showed increased/decreased biological function depending on whether they had more/less specific target mRNAs than their annotated seed. Few gene ontology(GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were shared among the target genes of the annotated seeds and the novel seeds. Various let-7 isomiRs with novel seed regions may cause opposing drug responses despite the fact that they are generated from the same miRNA locus and have highly similar sequences. IsomiRs, especially the dominant isomiRs with shifted seeds, may disturb the coding-non-coding RNA regulatory network. These findings provide insight into the multiple isomiRs and isomiR-mediated control of gene expression in the pathogenesis of cancer.

迄今为止，经典的microRNA（miRNA）被认为是单个序列，但实际上它包含具有不同序列和表达模式的多种miRNA亚型（isomiR）。目前尚不清楚这些多样化的isomiR是否具有潜在的关系，以及它们是否有助于miRNA：mRNA相互作用。在这里，我们旨在揭示基于let-7和miR-10基因家族的多个isoomiRs的潜在进化和功能关系，这些家族易于在染色体上聚集在一起。基因家族中的多个isomiRs显示出与其规范的miRNA类似的功能，表明选择了主要序列。包含新种子区域的IsomiRs表现出增加/减少的生物学功能，这取决于它们是否比注释种子具有更多/更少的特异性靶标mRNA。注释种子和新种子的靶基因之间几乎没有基因本体论（GO）术语和《京都基因与基因组百科全书》（KEGG）途径。尽管具有相同种子区的各种let-7 isomiRs可能会产生相反的药物反应，尽管它们是从相同的miRNA基因座产生的，并且具有高度相似的序列。IsomiRs，尤其是种子转移的优势isomiRs，可能会扰乱编码非编码RNA调控网络。这些发现为癌症的发病机理中多种isomiRs和isomiR介导的基因表达控制提供了见识。尽管具有相同种子区的各种let-7 isomiRs可能会产生相反的药物反应，尽管它们是从相同的miRNA基因座产生的，并且具有高度相似的序列。IsomiRs，尤其是种子转移的优势isomiRs，可能会扰乱编码非编码RNA调控网络。这些发现为癌症的发病机理中多种isomiRs和isomiR介导的基因表达控制提供了见识。尽管具有相同种子区的各种let-7 isomiRs可能会产生相反的药物反应，尽管它们是从相同的miRNA基因座产生的，并且具有高度相似的序列。IsomiRs，尤其是种子转移的显性isomiRs，可能会扰乱编码非编码RNA调控网络。这些发现为癌症的发病机理中多种isomiRs和isomiR介导的基因表达控制提供了见识。