Darvasi A, Kerem B
Department of Genetics, Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Israel.
Eur J Hum Genet. 1995;3(1):14-20. doi: 10.1159/000472269.
In vitro studies in bacterial, yeast and eukaryotic systems have demonstrated the existence of deletion and insertion 'hot-spots' involving repetitive sequences. Slipped-strand mispairing (SSM) has been suggested to be the mechanism involved. Progress in human molecular genetics has allowed the identification of many mutations causing diseases. Analysis of sequences involved in these mutations provides an opportunity to investigate the contribution of short tandem repeats to the naturally occurring mutations in coding regions of human genes. We have analyzed the sequences surrounding 625 disease-causing mutations in the coding regions of three genes: the cystic fibrosis transmembrane conductance regulator, beta globin and factor IX. Altogether, 134 (21%) insertion and deletion mutations of 4 base pairs or less were identified. In 47% of these mutations, the deletions and insertions occurred within a unit repeated tandemly 2- to 7-fold. These were classified as SSM mutations. The proportion of SSM mutations was significantly higher than expected by chance. The estimated net proportion of deletion and insertion mutations attributed to SSM was 27%. These results indicate that very short repetitive sequences contribute significantly to the generation of deletion and insertion mutations in human genes, and to the evolution of diversity of their coding regions.
在细菌、酵母和真核生物系统中进行的体外研究已证明存在涉及重复序列的缺失和插入“热点”。有人提出滑动链错配（SSM）是其中涉及的机制。人类分子遗传学的进展使得能够鉴定出许多导致疾病的突变。对这些突变所涉及序列的分析为研究短串联重复序列对人类基因编码区自然发生突变的贡献提供了机会。我们分析了三个基因（囊性纤维化跨膜传导调节因子、β珠蛋白和因子IX）编码区周围625个致病突变的序列。总共鉴定出134个（21%）4个碱基对或更少的插入和缺失突变。在这些突变中，47%的缺失和插入发生在2至7倍串联重复的单元内。这些被归类为SSM突变。SSM突变的比例显著高于偶然预期。归因于SSM的缺失和插入突变的估计净比例为27%。这些结果表明，非常短的重复序列对人类基因中缺失和插入突变的产生以及其编码区多样性的进化有显著贡献。
