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

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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.