Assessing Mobile Element-based Mutagenic Recombination

描述(由申请人提供)：目前活跃的人类活动元素家族(L1、Alu和Sva)被公认为是遗传不稳定和相关遗传病(包括癌症)的重要贡献者。目前的估计将0.5%的人类遗传性疾病归因于移动元件插入和/或随后的突变重组的结果。虽然大多数关于可移动元件的诱变研究往往集中在破坏性插入事件上，但非等位可移动元件之间的重组可能会导致基因丢失、复制和/或重排，所有这些都会导致整体的体细胞突变负担。这些诱变事件在体细胞组织中发生的频率，以及调节该频率的因素，在很大程度上仍未得到研究。尽管在体细胞中发生的从头插入可移动元件的数量通常被认为是相当低的，但最近的证据表明，L1元件产生的双链断裂(DSB)比从头插入多几个数量级。由于已知双链断裂可以引发非等位基因重组，这些新的数据为我们提供了令人信服的理由来研究散布重复序列之间的突变重组以及L1内切酶引发这些事件的能力。

DESCRIPTION (provided by applicant): The currently active human mobile elements families (L1, Alu, and SVA) are well established as significant contributors to genetic instability and associated genetic diseases, including cancer. Current estimates attribute 0.5% of human inherited genetic disorders as having been the consequence of mobile element insertions and/or subsequent mutagenic recombinations. While most mutagenesis studies concerning mobile elements tend to focus on disruptive insertion events, recombinations between non-allelic mobile elements can result in genetic loss, duplication, and/or rearrangements, all of which contribute to the overall somatic mutation burden. The frequencies at which these mutagenic events occur in somatic tissues, as well as the factors that modulate that frequency, remain largely unexamined. Although the number of de novo mobile element insertions occurring in somatic cells is generally considered to be quite low, recent evidence indicates that L1 elements produce orders of magnitude more double-stranded breaks (DSBs) than de novo insertions. As double-stranded breaks are known to instigate non-allelic recombination, these new data offer us compelling reason to investigate mutagenic recombination between interspersed repeats and the ability of L1 endonuclease to instigate these events.