The impact of advanced parental age on genomic instability in offspring associated with retrotransposon-induced DNA damage

摘要 随着年龄的增长，基因组不稳定性在种系中积累。父母，尤其是母亲的出生年龄 一直在增加。然而，除了某些出生缺陷的风险之外，这种趋势对 后代的基因组稳定性仍然未知。转座因子 (TE) 是已知的来源 种系中的基因组不稳定，长散布的 element-1 (L1) 反转录转座子是驱动因素 人类基因组中所有 TE 引起的损伤。 L1 可以通过以下方式引入基因组不稳定性 逆转录转座和 DNA 双链断裂 (DSB) 的产生。 L1诱导的潜力 DSB 引入结构基因组变异的效果尚不清楚，但可能比 L1 的影响更大 逆转录转座。我们的初步数据支持 L1 诱导的 DSB 引入结构基因组 已知哺乳动物基因组中随着年龄的增长而积累的变异。尽管L1可以引入遗传 亲代种系中的 DNA 损伤、亲代出生年龄与 L1- 数量之间的关系 后代基因组中相关的基因组不稳定性尚不清楚。也不知道两者是否 母亲和父亲的年龄发挥着一定作用。这些知识很重要，因为他们可能 由于继承的基因组含有更多 L1 诱导的 DNA 损伤，年长父母的后代可能有不同的情况 与年轻父母的后代相比，其患年龄相关疾病的风险更高。我们的初步发现， 使用含有活性 L1 转基因的转基因小鼠模型生成，支持 年长小鼠的后代在出生时比它们的兄弟姐妹产生的基因组含有更多的 de novo L1 插入片段 年轻时的相同繁殖对。该提案的目的是测试父母的出生年龄是否 影响后代中 L1 逆转录转座和 DSB 导致的基因组不稳定性的程度 基因组。拟议项目的结果可能是 L1 逆转录和 DSB 具有纵向 对亲本以及后代基因组体内稳定性的影响。这一发现将为 分析这种损害对老年人所生后代与年龄相关的健康参数的影响 父母，以及测试同样的现象是否发生在人群中。

Abstract Genomic instability accumulates in the germ line with age. Parental, particularly maternal, age at birth has been increasing. However, apart from the risk for some birth defects, the impact of this trend on the genome stability of offspring remains unknown. Transposable elements (TEs) are an established source of genomic instability in the germ line, with the long interspersed element-1 (L1) retrotransposon being the driver of all TE-induced damage in the human genome. L1 can introduce genomic instability through retrotransposition and the generation of DNA double-strand breaks (DSBs). The potential of the L1-induced DSBs to introduce structural genomic variations is not known, but could be greater than the impact of L1 retrotransposition. Our preliminary data support that the L1-induced DSBs introduce structural genomic variations known to accumulate with age in mammalian genomes. Even though L1 can introduce heritable DNA damage in the parental germ line, the relationship between parental age at birth and the amount of L1- associated genomic instability in the genomes of offspring is not known. It is also not known whether both maternal and paternal age play a role. This knowledge is important because due to the fact that they may inherit genomes harboring more L1-induced DNA damage, the offspring of older parents may have different risks for developing age-associated diseases than the offspring of younger parents. Our preliminary findings, generated using a transgenic mouse model harboring an active L1 transgene, support that the genomes of offspring of older mice harbor more de novo L1 inserts at birth than the genomes of their siblings produced by the same breeding pairs at younger ages. The goal of this proposal is to test whether parental age at birth influences the amount of genomic instability resulting from L1 retrotransposition and DSBs in offspring genomes. The outcome of the proposed project may be that L1 retrotransposition and DSBs have longitudinal impact on parental, and by extension offspring, genome stability in vivo. This finding will provide a rationale for analyzing the effect of this damage on the age-associated health parameters of offspring produced by older parents, as well as for testing whether the same phenomenon occurs in the human population.