英国威康桑格研究所Raheleh Rahbari团队取得一项新突破。他们的最新研究探明了精子测序显示，男性生殖系存在广泛的正向选择。这一研究成果于2025年10月8日发表在国际顶尖学术期刊《自然》上。

本研究采用双工测序方法NanoSeq4对来自24-75岁个体的81份大精子样本进行测序。他们的发现揭示了由与人类衰老相关的两个突变特征驱动的每个单倍体基因组每年1.67个（95%置信区间为1.41-1.92）突变的线性累积。精子样本的深度靶向和外显子组NanoSeq5鉴定了超过35000个种系编码突变。课题组人员在雄性种系中发现了40个基因（其中31个是新发现的），这些基因具有激活或功能丧失机制，并参与多种细胞途径。大多数正选择的基因与儿童的发育或癌症易感性疾病有关，而其中一些基因在健康人群中显示出蛋白质截断变异的频率增加。

该课题组人员发现，精子发生过程中的积极选择导致已知疾病导管突变的风险增加2-3倍，这导致3-5%的中年至老年个体的精子在整个外显子组中具有致病性突变。这些发现揭示了生殖系选择动力学，并强调了高龄父亲所生孩子的疾病风险比之前所认识到的要大得多。

据介绍，发生在精子或卵子细胞系中的突变可以遗传给后代。在人类中，精子发生过程中驱动突变的正选择可以增加某些发育障碍的出生患病率。直到最近，对精子中这种选择程度的描述一直受到测序技术错误率的限制。

附：英文原文

Title: Sperm sequencing reveals extensive positive selection in the male germline

Author: Neville, Matthew D. C., Lawson, Andrew R. J., Sanghvi, Rashesh, Abascal, Federico, Pham, My H., Cagan, Alex, Nicola, Pantelis A., Bayzetinova, Tetyana, Baez-Ortega, Adrian, Roberts, Kirsty, Lensing, Stefanie V., Widaa, Sara, Alcantara, Raul E., Garca, Mara Paz, Wadge, Sam, Stratton, Michael R., Campbell, Peter J., Small, Kerrin, Martincorena, Iigo, Hurles, Matthew E., Rahbari, Raheleh

Issue&Volume: 2025-10-08

Abstract: Mutations that occur in the cell lineages of sperm or eggs can be transmitted to offspring. In humans, positive selection of driver mutations during spermatogenesis can increase the birth prevalence of certain developmental disorders1,2,3. Until recently, characterizing the extent of this selection in sperm has been limited by the error rates of sequencing technologies. Here we used the duplex sequencing method NanoSeq4 to sequence 81 bulk sperm samples from individuals aged 24–75years. Our findings revealed a linear accumulation of 1.67 (95% confidence interval of 1.41–1.92) mutations per year per haploid genome driven by two mutational signatures associated with human ageing. Deep targeted and exome NanoSeq5 of sperm samples identified more than 35,000 germline coding mutations. We detected 40 genes (31 newly identified) under significant positive selection in the male germline that have activating or loss-of-function mechanisms and are involved in diverse cellular pathways. Most of the positively selected genes are associated with developmental or cancer predisposition disorders in children, whereas four of the genes exhibited increased frequencies of protein-truncating variants in healthy populations. We show that positive selection during spermatogenesis drives a 2–3-fold increased risk of known disease-causing mutations, which results in 3–5% of sperm from middle-aged to older individuals with a pathogenic mutation across the exome. These findings shed light on germline selection dynamics and highlight a broader increased disease risk for children born to fathers of advanced age than previously appreciated.

DOI: 10.1038/s41586-025-09448-3

Source: https://www.nature.com/articles/s41586-025-09448-3