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胚系中积累。父母，尤指母亲出生时的年龄 一直在增加。然而，除了一些出生缺陷的风险外，这一趋势对 后代的基因组稳定性尚不清楚。转座元件(TES)是一种公认的 胚系中的基因组不稳定性，长穿插元件-1(L1)反转录转座子是驱动因素 所有由TE引起的人类基因组损伤。L1可以通过以下途径引入基因组不稳定性 逆转录转座和DNA双链断裂的产生。L1诱导的势 DSB引入结构基因组变异尚不清楚，但可能比L1的影响更大 逆转位。我们的初步数据支持L1诱导的DSB引入了结构基因组 已知的变异会随着年龄的增长而在哺乳动物基因组中积累。即使L1可以引入可遗传的 亲本胚系DNA损伤、亲本出生年龄与L1-DNA含量的关系 后代基因组中的相关基因组不稳定性尚不清楚。也不知道这两个人是否 母亲和父亲的年龄起着一定的作用。这一知识很重要，因为由于他们可能 继承含有更多L1诱导的DNA损伤的基因组，年长父母的后代可能有不同的 与年轻父母的子女相比，他们更容易患上与年龄相关的疾病。我们的初步调查结果， 使用携带活性L1转基因的转基因小鼠模型产生的，支持 年龄较大的小鼠的后代在出生时拥有更多的从头L1插入，而不是它们的兄弟姐妹的基因组产生的 同样的繁殖配对在更小的年龄。这项提案的目标是测试父母出生时的年龄 L1逆转录转座和双链断裂对后代基因组不稳定性的影响 基因组。拟议项目的结果可能是L1逆转位和DSB具有纵向 对亲代，进而对后代体内基因组稳定性的影响。这一发现将为 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，以及测试是否在人类人口中发生同样的现象。

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.