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: 8451365
• 负责人: Fernando Pardo-Manuel de Villena
• 金额: $ 17.76万
• 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/8451365
• 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; next generation sequencing; 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.

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很大的意义，其中三种最严重的疾病（自闭症，精神分裂症和躁郁症）都显示出PAE。这些疾病的可能性大约是40岁> 40岁的父亲的两倍，而父亲> 50岁的可能性是20-25岁的父亲的三倍。在过去的25年中，男性> 40岁的出生率增加了50％（现在是美国所有分娩的10％），因此这已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从头拷贝数变体（CNV）的负担增加，支持自发突变参与严重精神疾病，并有可能帮助解释这些疾病的PAE。但是，尚未明确证明父亲的年龄增加了任何生物体中后代的突变负担。由于在CNV和人类的点突变负担上对PAE进行高度的搜索是由于后代数量少而难以评估，因此我们建议使用实验室鼠标回答这个问题。我们已经手头上有DNA样品来通过下一代测序进行此实验，并请求资金计算突变负担的PAE。此外，我们在老年男性和年轻男性中收集了一系列与生育力相关的表型，以及在年轻人和老年父亲的后代中与精神病相关的行为表型，从而可以直接比较基因型与表型。我们已经收集了所有DNA样品和相关表型，并准备进行高通量测序，以计算与生物医学的突变率。在AIM 1中，我们专注于CNV，由于我们为此目的选择了小鼠，因此在低覆盖范围测序中很容易检测到，在AIM 2中，我们专注于需要更高覆盖率的点突变。显然，该项目的潜在奖励是巨大的。我们知道，PAE是多种神经精神疾病的危险因素，但是尚不清楚的机制尚不清楚。总之，如果该项目成功，它将为人类精神病样本扩展基础，并在下一代小鼠系统生物学平台（协作十字架）内进行详细的机械研究。