Effects of advanced paternal age on germline genome stability

 描述（由申请人提供）：父亲年龄是精神病学关注的一个风险因素：40岁及以上父亲的后代患精神分裂症（SCZ）和自闭症谱系障碍（ASD）的风险增加2至3倍，这是一组异质性疾病，现在影响到在美国出生的88名儿童中的1名。虽然已知父亲年龄与某些孟德尔疾病基因的突变率呈正相关，但尚未证明父亲年龄会增加全基因组的突变率。与此同时，大量文献将基因拷贝数的自发变化（从头拷贝数变异，CNVs）与ASD和SCZ联系起来。此外，最近的研究表明，父亲的年龄与脑组织中表达的关键基因的表观遗传标记的改变有关。总之，这些观察结果提供了一种诱人的可能性，即通过增加生殖系突变和表位突变率，提高父亲年龄可能解释了工业化西方ASD发病率当代增加的部分原因。研究人类群体中父亲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，在其中估计年龄对男性遗传传递保真度的影响的大小和个体间变异性。这个Kirschstein-NRSA个人（F30）奖学金提案的目的是量化父系年龄效应（PAE）对雄性小鼠生殖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重要而及时的问题的见解。使用小鼠模型，我们将在三个水平上表征PAE：全染色体，DNA序列和染色质修饰。本研究的具体目标如下：（1）描述年龄对雄性生殖细胞减数分裂重组的速率和分布的影响，减数分裂重组是许多CNV产生的过程。 (2)使用下一代测序技术精确定量已知与神经精神疾病相关的一类特定突变（CNV）的突变率。 (3)表征PAE景观上的一类特定的表观遗传标记，甲基化。这些研究将揭示男性生殖细胞中基因组稳定性随年龄增长而保持的机制，并促进对一组常见神经精神疾病病因的理解。

 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.