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

摘要

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.