Nature，Nature子刊两篇文章解析选择性拼接

　　

生物通报道：选择性拼接是指一个RNA转录本通过对一些外显子和内含子的选择性剪切、连接而形成不同的mRNA分子的过程，如果选择性拼接过程出错，会引发癌症、神经系统疾病。在本期的《Nature》和《Nature Genetics》杂志上，两个研究小组又获得了选择性拼接的新研究成果。

肌体中的所有细胞都使用同一套基因编码指令，脑细胞特别依赖于选择性拼接过程去产生其功能所需的特异蛋白。选择转录得到的零碎的RNA片段，并且拼接起来成为一个可以编码目的蛋白的模板，这种过程在从果蝇到人类的所有细胞中都存在。利用选择性拼接过程形成不同的蛋白翻译模板，单一基因能够产生各种形式的有时可达上千的蛋白。

选择性拼接过程成为研究热点，部分原因在于这种现象能够用于解释：为何与果蝇、线虫等低等生物有相似规模基因组的人类却是如此复杂。同时越来越多的实验显示选择性拼接在神经系统疾病等疾病中扮演重要角色。比如，选择性拼接出错会导致囊肿性纤维化，以及共济性失调、孤独症等神经系统疾病。

在第一篇文章中，来自麻省理工的研究人员对15个不同的人类组织和细胞系的转录本进行了深入研究，发现大约94%的人类基因会制造出同一蛋白的不同形态，但同一蛋白质的不同形态，会有不同甚至是完全相反的功能。

而在第二篇文章中，来自加拿大多伦多大学的研究人员则第一次利用mRNA序列数据进行人类组织可变剪接复杂性分析。并且研究人员通过比较mRNA-Seq和EST-cDNA序列数据，发现至95％的multiexon基因的转录都有可变拼接。

（生物通：万纹）

原文摘要：

Alternative isoform regulation in human tissue transcriptomes

Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon–exon junctions indicated that 92–94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.

Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing

We carried out the first analysis of alternative splicing complexity in human tissues using mRNA-Seq data. New splice junctions were detected in 20% of multiexon genes, many of which are tissue specific. By combining mRNA-Seq and EST-cDNA sequence data, we estimate that transcripts from 95% of multiexon genes undergo alternative splicing and that there are 100,000 intermediate- to high-abundance alternative splicing events in major human tissues. From a comparison with quantitative alternative splicing microarray profiling data, we also show that mRNA-Seq data provide reliable measurements for exon inclusion levels.