Lamolle Guillermo, Marin Mónica, Alvarez-Valin Fernando
Sección Biomatemática, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo, Uruguay.
Mutat Res. 2006 Aug 30;600(1-2):102-12. doi: 10.1016/j.mrfmmm.2006.03.004. Epub 2006 May 2.
The last release of p53 somatic mutation database contains more than 20,000 of mutation among which 951 are silent (synonymous). This striking amount of silent mutations is much more than what would be expected if synonymous mutations were effectively neutral. The prevalent explanation to reconcile this vast amount of silent mutations with the neutral expectation is that they are just the subproduct of the hypermutability process that affect cancer cells. Some evidences have been presented in this direction, and the explanation has been taken as granted. Assuming that silent mutations are effectively neutral has major implication in the investigation of mutational processes that affect the gene encoding the p53 protein, since on the basis of this assumption they are considered the Null hypothesis, for instance for measuring and comparing among tissues the endogenous mutability. From this it follows that determining whether silent mutations in the p53 gene, and in all disease genes in general, are or not basically mutational noise, is of paramount importance. In this paper we readdress this topic by testing whether there is a relationship between the spatial distribution of silent mutations inside the p53 gene and functional significant features of the gene. For this purpose we divided the population of silent mutations in three groups: those that are found accompanied by other mutations (doublets and multiplest), those that were isolated as singlets, but the same mutation was also isolated as being part of a doublet (or multiplet) in another individual. And the last group is composed by those that were always found as singlets and never as being part of a doublet or a multiplet. This last group was expected to be enriched in functionally significant silent mutations. We found that all silent mutations, but particularly those of the last group, are preferentially located in conserved amino acid positions (i.e. functionally important amino acids) and also tend to be located inside suspected splicing enhancers. Noteworthy, this association remains even after eliminating the possible contribution of mutation hotspots. Besides, we present additional evidence in the direction that these putative splicing enhancers are real functional enhancers.
p53体细胞突变数据库的最新版本包含20000多个突变，其中951个是沉默（同义）突变。这一惊人数量的沉默突变远远超过了如果同义突变实际上是中性的情况下所预期的数量。将如此大量的沉默突变与中性预期相协调的普遍解释是，它们只是影响癌细胞的超突变过程的副产品。已经有一些证据支持这个方向，并且这个解释被认为是理所当然的。假设沉默突变实际上是中性的，这对影响p53蛋白编码基因的突变过程的研究有重大影响，因为基于这个假设，它们被视为零假设，例如用于测量和比较不同组织中的内源性突变率。由此可见，确定p53基因以及一般所有疾病基因中的沉默突变是否基本上是突变噪声至关重要。在本文中，我们通过测试p53基因内部沉默突变的空间分布与该基因的功能重要特征之间是否存在关系来重新探讨这个话题。为此，我们将沉默突变群体分为三组：那些与其他突变同时出现的（双重突变和多重突变），那些以单突变形式分离出来，但在另一个个体中该相同突变也作为双重突变（或多重突变）的一部分被分离出来的。最后一组由那些总是以单突变形式出现且从未作为双重突变或多重突变一部分的组成。预计最后一组富含功能重要的沉默突变。我们发现所有沉默突变，特别是最后一组的突变，优先位于保守氨基酸位置（即功能重要的氨基酸），并且也倾向于位于疑似剪接增强子内部。值得注意的是，即使消除了突变热点的可能贡献，这种关联仍然存在。此外，我们还提供了额外的证据表明这些假定的剪接增强子是真正的功能增强子。
