背景:内含子代表了新microRNA(miRNA)进化的现有转录的潜在丰富来源。在Hox基因簇中,一个miRNA基因,miR-615位于Hoxc5基因的内含子内。这种miRNA具有有限的系统发育分布,提供了一个机会来检查发育重要的同源异型盒基因内含子内的新miRNA的起源和进化。
结果:比对和结构分析表明,该序列在Eutherian哺乳动物中高度保守,在非哺乳动物四足动物中不存在。有袋动物具有相似的序列,我们预测该序列不会被有效地加工为miRNA。我们的分析表明,在所有情况下,人类中HOXC5的转录都伴随着miR-615的表达,但是miRNA也可以通过使用基因内启动子独立于其宿主基因进行转录。我们提出了通过内含子exaptation的miR-615进化的方案,并推测独立转录调控的获得。靶标预测和转录组分析表明miR-615的显性产物参与生长和一系列发育过程的调节。
结论:miR-615基因在胎盘哺乳动物祖先的Hoxc5内含子内进化。使用miR-615作为案例研究,我们提出了一种模型,通过该模型,功能性miRNA可以逐渐出现在内含子中,通过选择二级结构,然后进化一个独立的miRNA启动子。Hox基因内含子内的位置特别令人感兴趣,因为miRNA对胎盘哺乳动物具有特异性,与其宿主基因共表达,可能具有互补功能。
BACKGROUND: Introns represent a potentially rich source of existing transcription for the evolution of novel microRNAs (miRNAs). Within the Hox gene clusters, a miRNA gene, miR-615, is located within the
intron of the Hoxc5 gene. This miRNA has a restricted phylogenetic distribution, providing an opportunity to examine the origin and evolution of a new miRNA within the
intron of a developmentally-important homeobox gene.
RESULTS: Alignment and structural analyses show that the sequence is highly conserved across eutherian mammals and absent in non-mammalian tetrapods. Marsupials possess a similar sequence which we predict will not be efficiently processed as a miRNA. Our analyses suggest that transcription of HOXC5 in humans is accompanied by expression of miR-615 in all cases, but that the miRNA can also be transcribed independently of its host gene through the use of an intragenic promoter. We present scenarios for the evolution of miR-615 through intronic exaptation, and speculate on the acquisition of independent transcriptional regulation. Target prediction and transcriptomic analyses suggest that the dominant product of miR-615 is involved in the regulation of growth and a range of developmental processes.
CONCLUSIONS: The miR-615 gene evolved within the
intron of Hoxc5 in the ancestor of placental mammals. Using miR-615 as a case
study, we propose a model by which a functional miRNA can emerge within an
intron gradually, by selection on secondary structure followed by evolution of an independent miRNA promoter. The location within a Hox gene
intron is of particular interest as the miRNA is specific to placental mammals, is co-expressed with its host gene and may share complementary functions.