Paternal age effects on sperm epigenome and the resultant offspring.

流行病学研究提供的证据表明，父亲的年龄对后代患某些疾病的流行有影响，包括自闭症和癌症。全基因组测序技术显示，老年男性的后代携带更多的基因突变。众所周知，男性生殖细胞分裂的数量随着年龄的增长而增加;因此，年长父亲的后代中较高的从头突变率可能起源于精子。我们推测，除了基因突变数量的增加，与年轻男性相比，老年男性的精子含有更多的表观遗传扰动。精子特异性表型突变的遗传可能有助于疾病的病因学表现出“父亲年龄效应”。为了探索这种可能性，我们将对老年男性和年轻男性的精子样本进行全基因组甲基化（Illumina 450 K阵列）分析。将通过深度亚硫酸氢盐测序额外测量精心选择的候选基因的甲基化，以检测罕见的表突变。作为后续，我们将分析胎儿脐带血甲基化的后代，以评估父亲的年龄是否有表观遗传的影响下一代。该项目的目的是提供关于父亲衰老对精子的表观遗传影响以及老年父亲后代某些疾病发作的见解。

Epidemiological studies provide evidence for an influence of paternal age on the prevalence of certain diseases in the offspring, including autism and cancer. Genome-wide sequencing techniques revealed that the offspring of older men carry more genetic mutations. It is well known that the number of germ cell divisions in males increase with age; therefore, the higher de novo mutation rate in the offspring of older fathers may have originated in sperm. We speculate that in addition to an increased number of genetic mutations, the sperm of older males contain more epigenetic perturbations when compared to their younger counterparts. The inheritance of spermspecific epimutations may contribute to the etiology of disorders showing a “paternal age effect”. To explore this possibility we will perform genome-wide methylation (Illumina 450K arrays) analysis with sperm samples of old versus young males. The methylation of well selected candidate genes will be additionally measured via deep bisulfite sequencing to detect rare epimutations. As a followup, we will analyze the fetal cord blood methylome of the resultant offspring to assess whether paternal age has an epigenetic influence on the next generation. The aim of this project is to provide insight on the epigenetic effect of paternal aging on sperm and on the onset of certain disorders in the offspring of older fathers.