Evolutionary dynamics of gene and isoform regulation in mammalian tissues

Most mammalian genes produce multiple distinct mRNAs through alternative splicing, but the extent of splicing conservation is not clear. To assess tissue-specific transcriptome variation across mammals, we sequenced cDNA from 9 tissues from 4 mammals and one bird in biological triplicate, at unprecedented depth. We find that while tissue-specific gene expression programs are largely conserved, alternative splicing is well conserved in only a subset of tissues and is frequently lineage-specific. Thousands of novel, lineage-specific and conserved alternative exons were identified; widely conserved alternative exons had signatures of binding by MBNL, PTB, RBFOX, STAR and TIA family splicing factors, implicating them as ancestral mammalian splicing regulators. Our data also indicates that alternative splicing is often used to alter protein phosphorylatability, delimiting the scope of kinase signaling.绝大多数哺乳动物基因可通过可变剪接产生多种不同的信使RNA（messenger RNA, mRNA），但可变剪接的保守程度尚未得到清晰阐明。为评估不同哺乳动物中组织特异性转录组的变异情况，本研究以空前的测序深度，对4种哺乳动物和1种鸟类的9种组织的互补DNA（complementary DNA, cDNA）开展了三次生物学重复测序。研究结果显示，尽管组织特异性基因表达程序整体上较为保守，但可变剪接仅在部分组织中呈现高度保守性，且常表现为谱系特异性。本研究共鉴定出数千个新型、谱系特异性及保守型可变外显子；广泛保守的可变外显子存在MBNL、PTB、RBFOX、STAR及TIA家族剪接因子的结合特征，提示这些因子为哺乳动物祖先的剪接调控因子。本研究数据同时表明，可变剪接常被用于改变蛋白质的磷酸化潜能，从而限定激酶信号通路的作用范围。