Assessing Mobile Element-based Mutagenic Recombination

评估基于移动元件的诱变重组

• 批准号: 7155693
• 负责人: Dale James Hedges
• 金额: $ 4.6万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155693
• 关键词: animal genetic material tag; biochemical evolution; chemical stability; cytosine nucleotides; gene rearrangement; genetic disorder; genetic susceptibility; human genetic material tag; methylation; molecular genetics; mutagen testing; mutagens; phosphoester ligase; postdoctoral investigator; reporter genes; tissue /cell culture; transfection; transposon /insertion element; animal genetic material tag; biochemical evolution; chemical stability; cytosine nucleotides; gene rearrangement; genetic disorder; genetic susceptibility; human genetic material tag; methylation; molecular genetics; mutagen testing; mutagens; phosphoester ligase; postdoctoral investigator; reporter genes; tissue /cell culture; transfection; transposon /insertion element

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.

描述（由申请人提供）：当前活跃的人类移动元件家族（L1，ALU和SVA）已被良好确定为遗传不稳定性和相关遗传疾病（包括癌症）的重要贡献者。当前的估计将0.5％的人遗传遗传疾病归因于移动元件插入和/或随后的诱变重组的结果。尽管有关移动元件的大多数诱变研究倾向于集中于颠覆性插入事件，但非平行性移动元件之间的重组可能导致遗传丧失，重复和/或重排，这所有这些都会导致整体躯体突变负担。这些诱变事件发生在体细胞组织中的频率，以及调节该频率的因素，在很大程度上仍未受到检查。尽管通常认为在体细胞中发生的从头移动元件插入的数量被认为是很低，但最近的证据表明，L1元素产生的数量级比从头插入的多双链断裂（DSB）多。由于已知双链断裂会激发非平行性重组，因此这些新数据为我们提供了令人信服的理由来研究散布的重复序列之间的诱变重组以及L1核酸内切核酸酶启动这些事件的能力。