Kim Eddo, Goren Amir, Ast Gil
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
RNA Biol. 2008 Jan-Mar;5(1):17-9. doi: 10.4161/rna.5.1.5944. Epub 2008 Mar 22.
Splicing is a molecular mechanism, by which introns are removed from an mRNA precursor and exons are ligated to form a mature mRNA. Mutations that cause defects in the splicing mechanism are known to be responsible for many diseases, including cystic fibrosis and familial dysautonomia. If mutations that cause defects in splicing are responsible for such severe deleterious phenotypic differences, it is possible that mutations in splicing are also responsible for mildly deleterious phenotypic differences. Although deleterious mutations are rapidly eliminated from the population by purifying selection, the selection against mild deleterious effects is not as strong. Since mildly deleterious mutations have a chance of surviving natural selection, we might be mistakenly referring to these mutations as neutral variation between individuals. Splicing has also been shown to be seriously affected in cancer. Examination of cancerous tissues revealed alterations in expression levels of genes involved in mRNA processing and also a slight reduction in the level of exon skipping--the most common form of alternative splicing in humans. This implies that defects in genes involved in the regulation of splicing in cancerous tissues affect the delicate regulation of the inclusion level of alternatively skipped exons, shifting their mode of splicing back to constitutive. It may be that splicing silencers play a more prominent role in alternative splicing regulation than previously anticipated.
剪接是一种分子机制，通过该机制，内含子从mRNA前体中被去除，外显子被连接以形成成熟的mRNA。已知导致剪接机制缺陷的突变是许多疾病的病因，包括囊性纤维化和家族性自主神经功能异常。如果导致剪接缺陷的突变是造成如此严重有害表型差异的原因，那么剪接突变也可能是造成轻度有害表型差异的原因。尽管有害突变通过纯化选择迅速从种群中消除，但针对轻度有害效应的选择并不那么强烈。由于轻度有害突变有机会在自然选择中存活下来，我们可能会错误地将这些突变称为个体间的中性变异。剪接在癌症中也被证明受到严重影响。对癌组织的检查发现，参与mRNA加工的基因表达水平发生了改变，并且外显子跳跃水平略有降低——外显子跳跃是人类最常见的可变剪接形式。这意味着癌组织中参与剪接调控的基因缺陷会影响可变跳跃外显子包含水平的精细调控，使其剪接模式转变回组成型。可能剪接沉默子在可变剪接调控中发挥着比之前预期更突出的作用。
