Sex-specific contributions to genetic inheritance

生殖系突变可以导致遗传疾病，但也是进化辐射的驱动因素。雌性和雄性生殖系对从头开始的生殖系突变做出了不同的贡献。绝大多数新生的单核苷酸变异(SNV)或更严重的结构变异(SVS)是父系起源的。父母的年龄与配子中的遗传异常有关，在人类中，父亲的年龄与患自闭症和精神分裂症等神经发育障碍的风险增加相关。到目前为止，决定新生胚系突变的发生和遗传的机制仍然知之甚少。我们使用秀丽隐杆线虫模型研究了雌性和雄性生殖系中不同的基因组质量控制机制。我们已经建立了卵子发生过程中DNA损伤反应的调控机制，并在开创性工作中确定了线虫P53样蛋白CEP-1在介导基因组质量控制中的作用。最近，我们在雄性生殖细胞中发现了一种意想不到的DNA损伤后果。父亲暴露在辐射中是否以及如何影响后代，一直是辐射生物学中最长期存在的问题之一。主要的限制是缺乏对辐射损害的跨代影响的机械性洞察。利用线虫模型，我们确定特定成熟的精子容易受到辐射损伤，而辐射损伤是通过受精卵中容易出错的theta介导的末端连接(TMEJ)修复的。TMEJ介导的SVS导致子代基因组不稳定和跨代致死。我们进一步确定，这种跨代致死性是由H1连接子-组蛋白介导的异染色化引起的，在携带父性受损基因组的后代中。通过减少异染色化，同源重组修复(HRR)可以获得通路，修复遗传的DNA损伤，逆转跨代致死。在这里，我们提出了一个雄心勃勃的研究计划，以确定父亲DNA损伤的机制、影响和后果。我们将(1)研究母体TMEJ修复父本基因组的机制和(2)父系遗传DNA损伤如何触发异染色化导致子代修复受限的机制。我们将(3)在母体控制DNA修复机制的背景下讨论雄性胚系突变的机制和后果，以及(4)评估母系和父系老化在胚系突变发生中的作用。因此，我们将定义影响基因组进化的可遗传突变的性别特异性贡献的机制基础。鉴于我们已经确定的TMEJ修复结果也存在于自然线虫变体以及父系遗传的人类SVS中，我们的结果将为保守的遗传机制提供重要的新见解。

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.