Peier Andrea M, Nelson David L
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Genomics. 2002 Oct;80(4):423-32. doi: 10.1006/geno.2002.6849.
Fragile X syndrome results from the massive expansion of a CGG repeat in the 5' untranslated region of the gene FMR1. Data suggest that the hyperexpansion properties of FMR1 CGG repeats may depend on flanking cis-acting elements. We have therefore used homologous recombination in yeast to introduce an in situ CGG expansion corresponding to a premutation-sized allele into a human YAC carrying the FMR1 locus. Several transgenic lines were generated that carried repeats of varying lengths and amounts of flanking sequence. Length-dependent instability in the form of small expansions and contractions was observed in both male and female transmissions over five generations. No parent-of-origin effect or somatic instability was observed. Alterations in tract length were found to occur exclusively in the 3' uninterrupted CGG tract. Large expansion events indicative of a transition from a premutation to a full mutation were not observed. Overall, our results indicate both similarities and differences between the behavior of a premutation-sized repeat in mouse and that in human.
脆性X综合征是由基因FMR1的5'非翻译区中CGG重复序列的大量扩增引起的。数据表明，FMR1 CGG重复序列的超扩增特性可能取决于侧翼顺式作用元件。因此，我们利用酵母中的同源重组，将对应于前突变大小等位基因的原位CGG扩增引入携带FMR1基因座的人类酵母人工染色体（YAC）中。产生了几个转基因系，它们携带了不同长度和侧翼序列量的重复序列。在五代的雄性和雌性传递中均观察到了以小扩增和收缩形式出现的长度依赖性不稳定性。未观察到亲本来源效应或体细胞不稳定性。发现序列长度的改变仅发生在3'不间断的CGG序列中。未观察到表明从前突变向全突变转变的大扩增事件。总体而言，我们的结果表明，前突变大小的重复序列在小鼠和人类中的行为既有相似之处，也有不同之处。
