Contribution of retrotransposition to developmental disorders
Contribution of retrotransposition to developmental disorders
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DOI：
10.1038/s41467-019-12520-y
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发表时间：
2019-10-11
影响因子：
16.6
通讯作者：
Hurles, Matthew E.
中科院分区：
文献类型：
--
作者：
Gardner, Eugene J.;Prigmore, Elena;Hurles, Matthew E.
移动的遗传元件（Mobile genetic Elements，ME）是DNA的一个片段，它可以通过反转录转座（retrotranslocation，RT）过程复制自身和其他转录序列。在人类中，几种疾病已归因于RT，但RT在严重发育障碍（DD）中的作用尚未探讨。在这里，我们确定RT衍生的事件在9738外显子组测序的三重奏与DD影响的先证者。我们确定了9个新生ME，其中4个可能导致患者的症状（0.04%），以及2个新生基因逆转录重复。除了确定可能的诊断RT事件，我们估计全基因组的种系ME突变率和选择性约束，并证明编码RT事件的纯化选择等同于截断突变的签名。总的来说，我们的分析代表了对反转录转座对蛋白质编码基因的影响的全面询问，并为未来的进化和疾病研究提供了框架。
Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient's symptoms (0.04%), as well as 2 de novo gene retro-duplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.