Sex-specific contributions to genetic inheritance

点击翻译按钮获取中文摘要

Germline mutations can result in genetic disorders but are also the driver of evolutionary radiation. The female and male germlines make distinct contributions to de novo germline mutations. The vast majority of germline de novo single nucleotide variants (SNVs) or the more severe structural variants (SVs) are of paternal origin. Parental age correlates with genetic aberrations in the gametes and in humans, the age of the father correlates with increased risk of neurodevelopmental disorders such as autism and schizophrenia. The mechanisms determining the occurrence and inheritance of de novo germline mutations have thus far remained poorly understood. We have investigated the distinct genome quality control mechanisms in the female and male germlines using the Caenorhabditis elegans model. We have established regulatory mechanisms of the DNA damage response during oogenesis and, in seminal works, determined the role of C. elegans p53-like, CEP-1, in mediating the genome quality control. Most recently, we identified an unexpected consequence of DNA damage in male germ cells. Whether and how paternal exposure to radiation affects the offspring has been one of the longest standing questions in radiation biology. The major limitation has been the lack of mechanistic insight into transgenerational effects of radiation damage. Using the C. elegans model, we determined that specifically mature sperm is vulnerable to radiation damage that is repaired by the error prone theta-mediated endjoining (TMEJ) in the zygote. The TMEJ-mediated SVs lead to genome instability in the offspring and transgenerational lethality. We further determined that the transgenerational lethality is caused by H1 linker histone-mediated heterochromatization in the germline of the offspring carrying paternally damaged genomes. By reducing the heterochromatization, homologous recombination repair (HRR) could gain access, repair the inherited DNA damage and reverse the transgenerational lethality. Here, we set forth a highly ambitious research program to determine the mechanisms, influences and consequences of paternal DNA damage. We will (1) investigate the mechanisms of maternal TMEJ repair of paternal genomes and (2) address the mechanisms how the paternally inherited DNA damage triggers the heterochromatization leading to repair restriction in the offspring. We will (3) address the mechanisms and consequences of the male germline mutagenesis in the context of the maternal control of the DNA repair mechanisms and (4) assess the role of maternal and paternal aging in the occurrence of germline mutations. We will thus define mechanistic underpinnings of the sex-specific contributions to heritable mutations that affect genome evolution. Given that the TMEJ repair outcomes that we have identified are also present in natural C. elegans variants as well as in paternally inherited human SVs, our results will provide important new insights into conserved mechanisms of inheritance.