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

高龄父母对逆转录转座子诱导的 DNA 损伤相关后代基因组不稳定性的影响

• 批准号: 9277878
• 负责人: Victoria Perepelitsa Belancio
• 金额: $ 18.81万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277878
• 关键词: Age; Age-Months; Aging; Animal Model; Bioinformatics; Biology; Birth; Breeding; Congenital Abnormality; Custom; DNA Damage; DNA Double Strand Break; DNA Transposable Elements; Data; Data Analyses; Developed Countries; Development; Disease; Elderly; Elements; Embryonic Development; Event; Female; Frequencies; Generations; Genome; Genome Stability; Genomic Instability; Genomics; Germ Lines; Goals; Health; Heritability; Human; Human Genome; Individual; Inherited; Knowledge; Lead; Link; Location; Long Interspersed Elements; Malignant Neoplasms; Maternal Age; Medical; Methods; Mothers; Mus; Mutation; Outcome; Parasites; Parental Ages; Parents; Partner in relationship; Paste substance; Paternal Age; Play; Population; Reporting; Retrotransposition; Retrotransposon; Risk; Role; Siblings; Source; Testing; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Variant; Viral; advanced maternal age; design; genomic variation; in vivo; male; mammalian genome; mouse model; next generation sequencing; offspring; repaired; socioeconomics; structural genomics; trend

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.

抽象的 基因组不稳定性随着年龄的增长而积累。父母，尤其是母亲，出生时的年龄 一直在增加。但是，除了出现某些先天缺陷的风险外，这种趋势对 后代的基因组稳定性仍然未知。转座元素（TES）是既定来源 种系中的基因组不稳定性，长长的散布元素-1（L1）逆转座子是驱动器 在人类基因组中所有TE诱导的损害中。 L1可以通过 逆转录和DNA双链断裂的产生（DSB）。 L1诱导的潜力 DSB引入结构基因组变异尚不清楚，但可能大于L1的影响 逆转录。我们的初步数据支持L1诱导的DSB引入结构基因组 哺乳动物基因组中已知随着年龄而累积的变异。即使L1可以引入可遗传的 父母种系中的DNA损伤，出生时父母的年龄与L1-的数量之间的关系 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 母亲和父亲时代起着作用。这些知识很重要，因为由于他们可能 继承具有更多L1引起的DNA损伤的基因组，年长父母的后代可能有不同的 与年轻父母的后代相比，患上与年龄相关的疾病的风险。我们的初步发现， 使用具有活性L1转基因的转基因小鼠模型生成，支持的基因组 年长的老鼠的后代出生时藏有更多的从头插入物，而不是其兄弟姐妹的基因组。 年轻时相同的育种对。该提议的目的是测试父母出生时的年龄 影响后代L1逆转录和DSB产生的基因组不稳定性量 基因组。拟议项目的结果可能是L1逆转录和DSB具有纵向 对父母的影响，以及扩展后代，体内基因组稳定性。这一发现将为 分析这种损害对老年人产生的后代与年龄相关的健康参数的影响 父母，以及测试是否在人口中发生相同的现象。