A comparison of 100 human genes using an alu element-based instability model.
A comparison of 100 human genes using an alu element-based instability model.
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使用基于ALU元素的不稳定性模型比较100个人类基因。
DOI：
10.1371/journal.pone.0065188
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Batzer MA
中科院分区：
文献类型：
--
作者：
Cook GW;Konkel MK;Walker JA;Bourgeois MG;Fullerton ML;Fussell JT;Herbold HD;Batzer MA
拷贝数最高的人类逆转录转座子是Alu元素。人类基因组包含超过一百万个 Alu 元素，总共占我们 DNA 的百分之十以上。全长 Alu 元件以正向和反向随机分布在整个基因组中。然而，具有两个处于相同（正向）方向的Alus的全长宽间隔Alu对在统计上比具有两个处于相反（倒置）方向的Alu对更普遍。这种现象的原因尚不清楚。据推测，这种不平衡是异常反向 Alu 对相互作用的结果。一种提出的机制表明，反向 Alu 对可以异位相互作用，使组成该对的每个 Alu 元素的两端暴露于潜在的双链断裂或“撞击”。这种假设的每个 Alu 元素的“两次击中”（两次双链断裂）潜力被用来开发一个模型来比较人类基因的相对不稳定性。该模型结合了 1) Alu 元件的两次击中双链断裂潜力和 2) 从这些双链断裂延伸的外显子破坏性缺失的概率。该模型用于比较 50 个易于缺失的癌症基因和人类基因组中随机选择的 50 个基因的相对不稳定性。这里开发的基于 Alu 元件的基因组不稳定性模型的输出与观察到的易缺失癌症基因的不稳定性相一致。据估计，这 50 个癌症基因比使用该模型随机选择的基因不稳定 58%。七个容易缺失的癌症基因，ATM、BRCA1、FANCA、FANCD2、MSH2、NCOR1 和 PBRM1，是所分析的 100 个基因中最不稳定的 10% 之一。该算法可以为比较特定个人、家庭和人群特有的结构变异所带来的遗传风险奠定基础。
The human retrotransposon with the highest copy number is the Alu element. The human genome contains over one million Alu elements that collectively account for over ten percent of our DNA. Full-length Alu elements are randomly distributed throughout the genome in both forward and reverse orientations. However, full-length widely spaced Alu pairs having two Alus in the same (direct) orientation are statistically more prevalent than Alu pairs having two Alus in the opposite (inverted) orientation. The cause of this phenomenon is unknown. It has been hypothesized that this imbalance is the consequence of anomalous inverted Alu pair interactions. One proposed mechanism suggests that inverted Alu pairs can ectopically interact, exposing both ends of each Alu element making up the pair to a potential double-strand break, or “hit”. This hypothesized “two-hit” (two double-strand breaks) potential per Alu element was used to develop a model for comparing the relative instabilities of human genes. The model incorporates both 1) the two-hit double-strand break potential of Alu elements and 2) the probability of exon-damaging deletions extending from these double-strand breaks. This model was used to compare the relative instabilities of 50 deletion-prone cancer genes and 50 randomly selected genes from the human genome. The output of the Alu element-based genomic instability model developed here is shown to coincide with the observed instability of deletion-prone cancer genes. The 50 cancer genes are collectively estimated to be 58% more unstable than the randomly chosen genes using this model. Seven of the deletion-prone cancer genes, ATM, BRCA1, FANCA, FANCD2, MSH2, NCOR1 and PBRM1, were among the most unstable 10% of the 100 genes analyzed. This algorithm may lay the foundation for comparing genetic risks posed by structural variations that are unique to specific individuals, families and people groups.
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