Structural basis for triplet repeat disorders: a computational analysis
Structural basis for triplet repeat disorders: a computational analysis
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DOI：
10.1093/bioinformatics/15.11.918
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发表时间：
1999-11-01
期刊：
影响因子：
5.8
通讯作者：
Pedersen, AG
中科院分区：
文献类型：
--
作者：
Baldi, P;Brunak, S;Pedersen, AG
动机：十几种主要的退行性疾病，包括肌强直性营养不良症、亨廷顿氏病和脆性X综合征，都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，与已知的病理性扩张有关。为什么特别的三胞胎似乎被挑出来？它们膨胀的机制是什么？它是如何依赖于三重态本身的？其他三胞胎或更长的重复序列是否与其他疾病有关？结果如下：使用几种不同的计算模型的DNA结构，我们表明，三胞胎参与的病理重复一般属于极端类。因此，CAG/CTG重复是特别灵活的，而GCC，CGG和GAA重复似乎显示出灵活和刚性（但弯曲）的特性，这取决于分析方法。事实上，（1）当三核苷酸重复超过大约50个重复时，它们经常变得越来越不稳定，和（2）重复的12-mer在超过13个重复时显示出类似的不稳定性增加，这表明大约150 bp是重复不稳定性的一般阈值长度。因为这大约是包裹在单个核小体护理颗粒中的DNA的长度，我们推测染色质结构可能在扩增机制中起重要作用。我们还认为，我们预测具有非常高的灵活性的十二聚体的扩张可能在神经退行性疾病多系统萎缩（MSA）的发病机制中发挥作用。联系方式：pfbaldi@ics.uci.edu，yves@netid.com，brunak@tbs.dtu.dk，gorm@cbs.dtu.dk。
Motivation: 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 singed 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?Results: 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 repents often become increasingly unstable when they exceed a length of approximately 50 repeats, and (2) repented 12-mers display a similar increase in instability above 13 repeats, together suggest that approximately 150 bp is a general threshold length far repeat instability Since this is about the length of DNA wrapped up in a single nucleosome care particle, we speculate that chromatin structure may play an important role in the expansion mechanism. We furthermore suggest that expansion afa dodecamer repent, which we predict to have very high flexibility, may play a role in the pathogenesis of the neurodegenerative disorder multiple system atrophy (MSA).Contact: pfbaldi@ics.uci.edu, yves@netid.com, brunak@tbs.dtu.dk, gorm@cbs.dtu.dk.