Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Am J Psychiatry. 2013 Jun;170(6):599-608. doi: 10.1176/appi.ajp.2013.12101352.
There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications.
有大量来自流行病学研究的证据表明，年长父亲的后代患神经发育障碍的风险增加，例如精神分裂症和自闭症。作者提出了一种可能与之相关的新机制。由于男性生殖细胞在生殖年龄范围内经历了更多的细胞分裂，因此发生在父系生殖细胞中的复制错误与年长男性后代的新生突变有关。最近人们认识到，通过 RAS 蛋白途径失调改变增殖的男性生殖细胞中的体细胞突变可导致突变克隆系在睾丸内的扩张。首次在与与父龄相关的罕见疾病（例如 Apert 综合征、软骨发育不全）相关的研究中发现，该过程被称为“自私精原细胞选择”。这种机制有利于携带致病突变的生殖细胞的繁殖，随着男性年龄的增长，精子的突变谱越来越偏斜，并丰富了年长父亲后代的新生突变，这些突变优先影响特定的细胞信号通路。这种机制不仅为父龄较大与各种神经发育障碍之间的关联提供了一种简洁的解释，而且还深入了解了这些疾病的遗传结构（新生突变的作用）、神经生物学相关性（改变的细胞周期）和一些流行病学特征。作者概述了测试该模型的假设。鉴于大多数社会中晚育的世俗变化，这一假设具有重要的公共卫生意义。
