Fertility Labs of Colorado, Lone Tree, CO, USA.
Fertility Genetics, Lone Tree, CO, USA.
Aging Cell. 2020 Aug;19(8):e13178. doi: 10.1111/acel.13178. Epub 2020 Jul 1.
Paternal aging and the prevalence of neurodevelopmental disorders in offspring are well documented. Yet, the underlying mechanism and the mode of inheritance have not been conclusively established. Advancing paternal age is a subtle and varying phenotype. As such, it is likely that a threshold for cumulative risk may exist that, if surpassed, culminates in a predisposition to disease and ultimately an observed phenotype in offspring. Epigenetic regulation provides a plausible explanation for the nongenetic paternal transmission of disease susceptibility. With the use of whole-genome methylation sequencing, the data described herein substantiate an increasingly compromised DNA methylation profile as sperm ages and, for the first time, also demonstrate a generational correlation in sperm and blastocyst of an altered methylome associated with advanced paternal age. Methylation alterations are not randomly distributed across the genome, but appear clustered at certain chromosomal locations, and significantly colocalize with regions of nucleosome retention. Genes associated with autism spectrum disorder, schizophrenia, and bipolar disorder are significantly enriched with causative methylation aberrations in both sperm and embryos from aged fathers. The long-term health burden and societal economic impact of these conditions are substantial and will continue with increasingly prevalent diagnosis. This work provides a mechanistic link between the paternal age effect and offspring neurodevelopmental disorders leading to a better understanding of causation and investigation into potential future therapy.
父系衰老与后代神经发育障碍的患病率已有充分记录。然而，其潜在机制和遗传模式尚未得到明确确立。父系年龄的增长是一种微妙且多变的表型。因此，可能存在一个累积风险的阈值，如果超过这个阈值，就会导致疾病易感性，并最终在后代中观察到表型。表观遗传调控为疾病易感性的非遗传父系传递提供了合理的解释。使用全基因组甲基化测序，本文所述的数据证实了随着精子老化，DNA 甲基化图谱越来越受到损害，并且首次还证明了与高龄父亲相关的甲基化组改变与精子和胚泡之间存在世代相关性。甲基化改变不是随机分布在整个基因组中，而是似乎集中在某些染色体位置，并且与核小体保留区域显著共定位。与自闭症谱系障碍、精神分裂症和双相情感障碍相关的基因在高龄父亲的精子和胚胎中都存在导致疾病的甲基化异常，显著富集。这些疾病的长期健康负担和社会经济影响是巨大的，并且随着越来越普遍的诊断，这种情况将继续存在。这项工作在父系年龄效应与后代神经发育障碍之间建立了一种机制联系，从而更好地理解了病因，并为未来的潜在治疗方法提供了研究方向。
