Mutation analysis of somatic signalling modifiers of the DNA damage response in germ cells

生殖细胞 DNA 损伤反应体细胞信号修饰因子的突变分析

• 批准号: 418036758
• 负责人: Professor Dr. Björn Schumacher
• 金额: --
• 依托单位: Institute for Genome Stability in Ageing and Disease
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418036758?language=en
• 关键词: Mutation; analysis; somatic; signalling; modifiers

DNA repair mechanisms are essential for maintaining genome stability and prevent mutations. While genomic aberrations and mutations accumulate in somatic cells and in humans cause cancer, genome integrity of germ cells is preserved and required for species maintenance. The distinction between soma and germline is of fundamental importance for concepts ranging from heritability to aging. It is thought that the germline genomes are protected by the Weismann barrier from influences by the soma. Our recent work has challenged this barrier and suggests that the quality control of heritable genomes is influenced by the soma. Here we wish to use whole genome sequencing to identify heritable genomic alterations caused by somatic influences on the DNA damage response in germ cells.Heritable defects in DNA repair genes cause cancer susceptibility, developmental failure and premature aging. We have recently established C. elegans as model for studying disease causing mutations in nucleotide excision repair (NER) genes and uncovered distinct DNA damage response (DDR) mechanisms in germ cells and the soma. Interestingly, we observed that the DDR in germ cells is controlled by signaling pathways functioning in somatic cells. We found that somatic tissues can modulate the quality control of heritable genomes and thus exert intergenerational effects on genome stability. We wish to explore how somatic signaling mechanisms affect the stability of germline genomes and the accumulation of mutations through the generations. We will therefore analyse the genomic constitution and the mutation spectra resulting from aberrant somatic components of the DDR. We will focus (1) on the impact of somatic niche cell signaling on the consequences of unrepaired DNA in primordial germ cells, (2) on the influence of intestinal stress signaling on the genome quality control in meiotic pachytene cells, and (3) on how environmental influences affect germline genomes. Using those three experimental paradigms, we will analyse the progeny for inherited genome variants using whole genome sequencing (WGS). We will thus gain comprehensive insight into the role of the soma in regulating fertility and germline mutations. Our results will impact our understanding of the mechanisms governing germline mutation occurrence and inheritance relevant for human inheritance, fertility, and genetic diseases.

DNA修复机制是维持基因组稳定和防止突变的关键。虽然基因组异常和突变在体细胞和人类体内积累会导致癌症，但生殖细胞的基因组完整性得到保护，是物种维持所必需的。体细胞和生殖系之间的区别对于从遗传性到衰老的各种概念都是至关重要的。有人认为，生殖系基因组受到魏斯曼屏障的保护，不受胞体的影响。我们最近的工作挑战了这一障碍，并表明可遗传基因组的质量控制受到体节的影响。在这里，我们希望使用全基因组测序来识别由于体细胞对生殖细胞DNA损伤反应的影响而引起的可遗传的基因组改变。DNA修复基因的可遗传缺陷会导致癌症易感性、发育失败和过早衰老。我们最近建立了线虫模型，用于研究核苷酸切除修复(NER)基因的致病突变，并在生殖细胞和胞体中发现了不同的DNA损伤反应(DDR)机制。有趣的是，我们观察到生殖细胞中的DDR是由体细胞中起作用的信号通路控制的。我们发现，体细胞组织可以调节可遗传基因组的质量控制，从而对基因组稳定性产生代际影响。我们希望探索体细胞信号机制如何影响生殖系基因组的稳定性和突变在世代中的积累。因此，我们将分析DDR的基因组组成和突变谱，这些突变是由DDR的异常体细胞成分引起的。我们将集中于(1)体细胞生态位信号对原始生殖细胞中未修复DNA后果的影响，(2)肠道应激信号对减数分裂粗线期细胞基因组质量控制的影响，以及(3)环境影响如何影响生殖系基因组。使用这三种实验范式，我们将使用全基因组测序(WGS)来分析遗传基因组变异的后代。因此，我们将全面了解SOMA在调节生育和生殖系突变方面的作用。我们的结果将影响我们对与人类遗传、生育和遗传病相关的生殖系突变发生和遗传的机制的理解。