Effects of advanced paternal age on germline genome stability

 描述(由申请人提供)：父亲的年龄是精神病学感兴趣的一个风险因素：父亲40岁及以上的子女患精神分裂症(SCZ)和自闭症谱系障碍(ASD)的风险增加两到三倍，这是一组不同的疾病，现在影响到美国出生的88名儿童中就有一名。虽然已知父亲的年龄与某些孟德尔病基因的突变率呈正相关，但尚未证明父亲的年龄会增加全基因组的突变率。与此同时，迅速增长的文献将基因拷贝数的自发变化(从头拷贝数变体，CNV)与ASD和SCZ联系起来。此外，父亲的年龄最近被证明与脑组织中表达的关键基因的表观遗传标记改变有关。综上所述，这些观察结果提出了一种诱人的可能性，即通过增加生殖系突变和表观突变率来提高父亲的年龄，可能解释了当代西方工业化国家自闭症发病率增加的部分原因。在人类群体中研究父系年龄的影响是相当困难的，但实验室小鼠提供了一个理想的系统，可以用来估计年龄对通过男性进行遗传传播的保真度的影响的大小和个体间的变异性。这项Kirschstein-NRSA个体(F30)联谊会建议的目的是量化父亲年龄效应(PAE)对雄性小鼠种系基因组稳定性的影响，从而提供对基本生物学过程和精神病学中一个重要和及时的问题的见解。使用小鼠模型，我们将在三个水平上表征PAE：完整染色体、DNA序列和染色质修饰。这项建议的具体目的如下：(1)描述年龄对减数分裂重组的速度和分布的影响--许多CNV的产生过程--在男性生殖系中。(2)使用下一代测序技术精确量化一种特定类型的突变的PAE，CNV已知与神经精神障碍有关。(3)在一类特定的表观遗传标记甲基化的景观上表征PAE。这些研究将阐明男性生殖细胞中基因组随年龄增长保持稳定的机制，并促进对一组常见神经精神障碍的病因学的理解。

 DESCRIPTION (provided by applicant): Paternal age is a risk factor of interest in psychiatry: offspring of fathers 40 years of age and older are at two- to three-fold increased risk for schizophrenia (SCZ) and for autism-spectrum disorders (ASD), a heterogeneous group of disorders which now affects as many 1 in 88 children born in the United States. Although paternal age is known to be positively associated with mutation rate at certain Mendelian disease genes, paternal age has not yet been demonstrated to increase mutation rate genome-wide. Meanwhile a rapidly-growing body of literature links spontaneous changes in gene copy number (de novo copy-number variants, CNVs) to both ASD and SCZ. Furthermore, paternal age has recently been shown to be associated with altered epigenetic marks at key genes expressed in brain tissue. Taken together, these observations hold out the enticing possibility that advancing paternal age, by increasing germline mutation and epi-mutation rate, may explain some portion of the contemporary increase in ASD incidence in the industrialized West. Studying the effect of paternal age in human populations is quite difficult, but laboratory mice provide an ideal system in which to estimate both the magnitude and inter-individual variability of the effects of age on the fidelity of genetic transmission through males. The objective of this Kirschstein-NRSA individual (F30) fellowship proposal is to quantify the paternal-age effect (PAE) on genome stability in the germline of male mice, thus providing insight both on fundamental biological processes and an important and timely question in psychiatry. Using a mouse model, we will characterize the PAE at three levels: whole chromosomes, DNA sequence, and chromatin modifications. The specific aims of this proposal are as follows: (1) Characterize the effect of age on the rate and distribution of meiotic recombination - the process by which many CNVs arise - in the male germline. (2) Use next-generation sequencing to precisely quantify the PAE on mutation rate for one specific class of mutations, CNVs, known to be associated with neuropsychiatric disorders. (3) Characterize the PAE on the landscape of one specific class of epigenetic marks, methylation. These studies will shed light on the mechanisms by which the stability of the genome is maintained with age in male germ cells, as well as advance understanding of the etiology of a group of common neuropsychiatric disorders.