Baldi P, Brunak S, Chauvin Y, Pedersen A G
Department of Information and Computer Science, College of Medicine, University of California, Irvine 92697-3425, USA.
Bioinformatics. 1999 Nov;15(11):918-29. doi: 10.1093/bioinformatics/15.11.918.
Over a dozen major degenerative disorders, including myotonic distrophy, Huntington's disease and fragile X syndrome, result from unstable expansions of particular trinucleotides. Remarkably, only some of all the possible triplets, namely CAG/CTG, CGG/CCG and GAA/TTC, have been associated with the known pathological expansions. This raises some basic questions at the DNA level. Why do particular triplets seem to be singled out? What is the mechanism for their expansion and how does it depend on the triplet itself? Could other triplets or longer repeats be involved in other diseases?
Using several different computational models of DNA structure, we show that the triplets involved in the pathological repeats generally fall into extreme classes. Thus, CAG/CTG repeats are particularly flexible, whereas GCC, CGG and GAA repeats appear to display both flexible and rigid (but curved) characteristics depending on the method of analysis. The fact that (1) trinucleotide repeats often become increasingly unstable when they exceed a length of approximately 50 repeats, and (2) repeated 12-mers display a similar increase in instability above 13 repeats, together suggest that approximately 150 bp is a general threshold length for repeat instability. Since this is about the length of DNA wrapped up in a single nucleosome core particle, we speculate that chromatin structure may play an important role in the expansion mechanism. We furthermore suggest that expansion of a dodecamer repeat, which we predict to have very high flexibility, may play a role in the pathogenesis of the neurodegenerative disorder multiple system atrophy (MSA).
pfbaldi@ics.uci.edu, yves@netid.com, brunak@cbs.dtu.dk, gorm@cbs.dtu.dk.
包括强直性肌营养不良、亨廷顿舞蹈症和脆性X综合征在内的十几种主要退行性疾病，是由特定三核苷酸的不稳定扩增引起的。值得注意的是，在所有可能的三联体中，只有一些，即CAG/CTG、CGG/CCG和GAA/TTC，与已知的病理性扩增有关。这在DNA层面引发了一些基本问题。为什么特定的三联体似乎被挑选出来了？它们扩增的机制是什么，以及它如何依赖于三联体本身？其他三联体或更长的重复序列会涉及其他疾病吗？
使用几种不同的DNA结构计算模型，我们表明参与病理性重复的三联体通常属于极端类别。因此，CAG/CTG重复序列特别灵活，而GCC、CGG和GAA重复序列根据分析方法似乎既显示出灵活又显示出刚性（但弯曲）的特征。（1）三核苷酸重复序列在超过大约50个重复序列的长度时通常会变得越来越不稳定，以及（2）重复的12聚体在超过13个重复序列时显示出类似的不稳定性增加，这两个事实共同表明大约150 bp是重复序列不稳定性的一般阈值长度。由于这大约是包裹在单个核小体核心颗粒中的DNA长度，我们推测染色质结构可能在扩增机制中起重要作用。我们还提出，我们预测具有非常高灵活性的十二聚体重复序列的扩增可能在神经退行性疾病多系统萎缩（MSA）的发病机制中起作用。
pfbaldi@ics.uci.edu，yves@netid.com，brunak@cbs.dtu.dk，gorm@cbs.dtu.dk。
