Effect of paternal age on mutational burden and behavior in mice

父亲年龄对小鼠突变负荷和行为的影响

• 批准号: 8229344
• 负责人: Fernando Pardo-Manuel de Villena
• 金额: $ 22.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8229344
• 关键词: Age; Age-Years; Anxiety; Area; Autistic Disorder; Behavior; Behavioral; Biological Models; Bipolar Disorder; Birth; Birth Rate; Competence; Complex; DNA; Data; Data Set; Disease; Epididymis; Etiology; Exploratory/Developmental Grant; Fathers; Fertility; Fostering; Foundations; Funding; Gene Mutation; Genome; Genotype; Germ-Line Mutation; Hand; Histology; Human; Laboratory mice; Lead; Learning; Malignant Neoplasms; Measures; Memory; Morphology; Mus; Mutation; NIH Program Announcements; Organ Weight; Organism; Paternal Age; Phenotype; Point Mutation; Population; Process; Psychiatry; Public Health; Quality Control; Reading; Rewards; Risk; Risk Factors; Role; Sampling; Schizophrenia; Science; Seminal Vesicles; Sperm Count Procedure; Staging; Systems Biology; Technology; Testing; Testis; Time; Variant; age effect; cell motility; design; genome sequencing; male; men; morris water maze; neuropsychiatry; next generation; novel; offspring; preference; pup; reproductive; research study; severe mental illness; social

DESCRIPTION (provided by applicant): The paternal age effect (PAE) refers to an increased risk for a particular phenotype or mutation with increasing age of the father. This is of major relevance in psychiatry where three of the most severe disorders (autism, schizophrenia, and bipolar disorder) all show a PAE. These disorders are roughly twice as likely with fathers >40 years of age and three times more likely with fathers >50, compared with 20-25 year old fathers. The birth rate for males >40 has increased by 50% in the past 25 years (now 10% of all US births), so this is becoming a significant public health issue. Recent discoveries show an increased burden of de novo copy number variants (CNVs) in autism and schizophrenia, supporting the involvement of spontaneous mutations in severe mental illness and potentially helping to explain the PAE for these disorders. However, paternal age has not been explicitly shown to increase the mutational burden of offspring in any organism. Since a highly-powered search for a PAE on CNV and point mutation burden in humans is difficult to assess because of low numbers of offspring, we propose to use the laboratory mouse to answer this question. We already have DNA samples in hand to perform this experiment via next-generation sequencing and request funds to calculate the PAE on mutational burden. Furthermore, we have collected a range of fertility-related phenotypes in old and young males and psychiatrically-related behavioral phenotypes in the offspring of young and old fathers, allowing a direct comparison of genotype to phenotypes. We have collected all of the DNA samples and relevant phenotypes, and are ready to proceed with high-throughput sequencing in order to calculate mutation rates of great relevance to biomedicine. In Aim 1 we focus on CNVs, which are readily detected at low coverage sequencing due to our selection of mice for this purpose, and in Aim 2 we focus on point mutations, which require higher coverage. Clearly, the potential reward of this project is substantial. We know that PAE is a risk factor for multiple neuropsychiatric disorders but the mechanism underlying risk is unknown. In conclusion, if this project is successful, it would lay the foundation for extension to human psychiatric samples and detailed mechanistic studies within a next-generation mouse systems biology platform, the Collaborative Cross. PUBLIC HEALTH RELEVANCE: 8. PROJECT NARRATIVE Offspring of fathers over the age of 40 show an increased risk of autism and schizophrenia, suggesting a role for new DNA mutations in causing these diseases in some people. However, it has not been explicitly shown that increased paternal age leads to an increase in mutations in offspring, on the level of the genome. Since testing this in humans is very difficult and expensive, we propose to use the laboratory mouse to answer this question and see if having older fathers alters behavior of offspring in mice.

描述（由申请人提供）： 父亲年龄效应（PAE）是指随着父亲年龄的增加，特定表型或突变的风险增加。这在精神病学中具有重要意义，其中三种最严重的疾病（自闭症、精神分裂症和双相情感障碍）都表现出 PAE。与 20-25 岁的父亲相比，40 岁以上的父亲患这些疾病的可能性大约是 20 岁以上的父亲的两倍，50 岁以上的父亲患这些疾病的可能性大约是 20-25 岁的父亲的三倍。过去 25 年中，40 岁以上男性的出生率增加了 50%（目前占美国出生人口总数的 10%），因此这正在成为一个重大的公共卫生问题。最近的发现表明，自闭症和精神分裂症中的从头拷贝数变异 (CNV) 负担增加，支持自发突变与严重精神疾病有关，并可能有助于解释这些疾病的 PAE。然而，尚未明确表明父亲年龄会增加任何生物体后代的突变负担。由于后代数量较少，很难评估人类 CNV 和点突变负担的 PAE 的高效搜索，因此我们建议使用实验室小鼠来回答这个问题。我们手头已经有 DNA 样本，可以通过下一代测序进行这项实验，并请求资金来计算突变负担的 PAE。此外，我们还收集了老年和年轻男性的一系列与生育相关的表型，以及年轻和年老父亲的后代的精神相关行为表型，从而可以直接比较基因型与表型。我们已经收集了所有的DNA样本和相关表型，并准备进行高通量测序，以计算与生物医学密切相关的突变率。在目标 1 中，我们重点关注 CNV，由于我们为此目的选择了小鼠，因此在低覆盖率测序中很容易检测到 CNV；在目标 2 中，我们重点关注需要更高覆盖率的点突变。显然，这个项目的潜在回报是巨大的。我们知道 PAE 是多种神经精神疾病的危险因素，但潜在风险的机制尚不清楚。总之，如果该项目成功，它将为下一代小鼠系统生物学平台 Collaborative Cross 中扩展到人类精神病学样本和详细机制研究奠定基础。 公共卫生相关性： 8. 项目叙述 40 岁以上父亲的后代患自闭症和精神分裂症的风险增加，这表明新的 DNA 突变在导致某些人患这些疾病方面发挥了作用。然而，尚未明确表明父亲年龄的增加会导致后代基因组水平上突变的增加。由于在人类身上进行测试非常困难且昂贵，因此我们建议使用实验室小鼠来回答这个问题，看看年长的父亲是否会改变小鼠后代的行为。