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

DNA修复机制对于维持基因组稳定和防止突变至关重要。虽然基因组畸变和突变在体细胞和人类中积累会导致癌症，但生殖细胞的基因组完整性被保存下来，这是物种维持所必需的。体细胞和生殖系之间的区别对从遗传性到衰老等概念具有根本的重要性。据认为，生殖系基因组受到Weismann屏障的保护，免受体细胞的影响。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细胞的影响。在这里，我们希望使用全基因组测序来鉴定由体细胞影响对生殖细胞DNA损伤反应引起的可遗传基因组改变。DNA修复基因的遗传性缺陷导致癌症易感性、发育失败和早衰。我们最近建立了秀丽隐杆线虫作为模型来研究引起核苷酸切除修复（NER）基因突变的疾病，并揭示了生殖细胞和体细胞中不同的DNA损伤反应（DDR）机制。有趣的是，我们发现生殖细胞中的DDR是由体细胞中的信号通路控制的。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种系基因组的稳定性和突变在世代中的积累。因此，我们将分析基因组构成和突变谱导致的异常体细胞成分的DDR。我们将重点关注(1)体细胞生态位细胞信号传导对原始生殖细胞DNA未修复后果的影响，(2)肠道应激信号传导对减数分裂粗线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。利用这三种实验范式，我们将使用全基因组测序（WGS）分析遗传基因组变异的后代。因此，我们将全面了解体细胞在调节生育和种系突变中的作用。我们的结果将影响我们对与人类遗传、生育和遗传疾病相关的生殖系突变发生和遗传机制的理解。

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.