Buard J, Bourdet A, Yardley J, Dubrova Y, Jeffreys A J
Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
EMBO J. 1998 Jun 15;17(12):3495-502. doi: 10.1093/emboj/17.12.3495.
Unstable minisatellites display high frequencies of spontaneous gain and loss of repeats in the human germline. Most length changes arise through complex recombination events including intra-allelic duplications/deletions and inter-allelic transfers of repeats. Definition of the factors modulating instability requires both measurement of mutation rate and detailed analysis of mutant structures at the level of individual alleles. We have measured mutation rates in sperm for a wide range of alleles of the highly unstable human minisatellite CEB1. Instability varies by three orders of magnitude between alleles and increases steadily with the size of the tandem array. Structural analysis of mutant molecules derived from six alleles revealed that it is the rate of intra-allelic rearrangements which increases with array size and that intra-allelic duplication events tend to cluster within homogeneous segments of alleles; both phenomena resemble features of trinucleotide repeat instability. In contrast, inter-allelic transfers occur at a fairly constant rate, irrespective of array length, and show a mild polarity towards one end of the minisatellite, suggesting the possible influence of flanking DNA on these conversion-like events.
不稳定的微卫星在人类生殖系中显示出高频的自发重复序列增减。大多数长度变化是通过复杂的重组事件产生的，包括等位基因内的重复序列复制/缺失以及等位基因间的重复序列转移。确定调节不稳定性的因素既需要测量突变率，也需要在单个等位基因水平上对突变结构进行详细分析。我们已经测量了高度不稳定的人类微卫星CEB1的多种等位基因在精子中的突变率。等位基因之间的不稳定性相差三个数量级，并且随着串联阵列大小的增加而稳步上升。对来自六个等位基因的突变分子进行的结构分析表明，等位基因内重排率随阵列大小增加，并且等位基因内重复事件倾向于聚集在等位基因的同源区段内；这两种现象都类似于三核苷酸重复序列不稳定性的特征。相比之下，等位基因间转移以相当恒定的速率发生，与阵列长度无关，并且显示出朝向微卫星一端的轻微极性，这表明侧翼DNA可能对这些类似转换的事件产生影响。
