DELETION AND INSERTION MUTATIONS IN SHORT TANDEM REPEATS IN THE CODING REGIONS OF HUMAN GENES

In vitro studies in bacterial, yeast and eukaryotic systems have demon strated the existence of deletion and insertion 'hotspots' involving r epetitive sequences. Slipped-strand mispairing (SSM) has been suggeste d to be the mechanism involved. Progress in human molecular genetics h as allowed the identification of many mutations causing diseases. Anal ysis of sequences involved in these mutations provides an opportunity to investigate the contribution of short tandem repeats to the natural ly occurring mutations in coding regions of human genes. We have analy zed the sequences surrounding 625 disease-causing mutations in the cod ing regions of three genes: the cystic fibrosis transmembrane conducta nce regulator, beta globin and factor IX. Altogether, 134 (21%) insert ion 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 mu tations. The proportion of SSM mutations was significantly higher than expected by chance. The estimated net proportion of deletion and inse rtion mutations attributed to SSM was 27%. These results indicate that very short repetitive sequences contribute significantly to the gener ation of deletion and insertion mutations in human genes, and to the e volution of diversity of their coding regions.