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，基因组的不稳定性在生殖系中积累。父母，特别是母亲的出生年龄 一直在增加然而，除了一些出生缺陷的风险外，这一趋势对婴儿的影响也很大。 后代的基因组稳定性仍然未知。转座因子（Transposable elements，TE）是转座因子的一个来源。 生殖系中的基因组不稳定性，长散布元件-1（L1）反转录转座子是驱动因子 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 DSB引入结构基因组变异的情况尚不清楚，但可能大于L1的影响 反转录转位我们的初步数据支持L1诱导的DSB引入了结构基因组 已知哺乳动物基因组中的变异会随着年龄的增长而积累。尽管L1可以引入遗传的 父母生殖细胞系中的DNA损伤，父母出生时年龄与L1- 后代基因组中相关的基因组不稳定性尚不清楚。也不知道两人是否 母亲和父亲的年龄发挥作用。这些知识很重要，因为他们可能 遗传基因组中含有更多的L1诱导的DNA损伤，年长父母的后代可能有不同的 与年轻父母的后代相比，年轻父母的后代患年龄相关疾病的风险更高。我们的初步发现， 使用携带活性L1转基因的转基因小鼠模型产生，支持 年长小鼠的后代在出生时携带更多的从头L1插入物，而不是它们的兄弟姐妹的基因组， 同样的繁殖后代在年轻时配对。这项提案的目的是测试父母出生时的年龄是否 影响后代中由L1反转录转座和DSB引起的基因组不稳定性的量 基因组拟议项目的结果可能是L1逆转录和DSB具有纵向 对亲本和后代体内基因组稳定性的影响。这一发现将为以下方面提供依据： 分析这种损伤对老年人所生后代年龄相关健康参数的影响， 父母，以及测试是否同样的现象发生在人类群体。

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.