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)指的是随着父亲年龄的增长，患某一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，在精神病学中，三种最严重的疾病(自闭症、精神分裂症和双相情感障碍)都显示出PAE。与20-25岁的父亲相比，40岁的父亲患这些疾病的可能性大约是前者的两倍，而50岁的父亲患这种疾病的可能性是后者的三倍。在过去的25年里，40岁男性的出生率增加了50%(现在占美国所有出生人口的10%)，因此这正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)的负担增加，支持严重精神疾病中的自发突变，并可能有助于解释这些疾病的PAE。然而，父亲的年龄并没有明确地表明会增加任何生物体中后代的突变负担。由于后代数量少，很难评估在CNV上对PAE的高功率搜索和人类的点突变负担，我们建议使用实验室小鼠来回答这个问题。我们已经有了DNA样本，可以通过下一代测序来进行这项实验，并申请资金来计算突变负担的PAE。此外，我们收集了一系列老年和年轻男性的生育相关表型，以及年轻和老年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和表型。我们已经收集了所有的DNA样本和相关的表型，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，我们专注于CNV，由于我们为此选择了小鼠，因此在低覆盖率测序中很容易检测到CNV，而在目标2中，我们专注于点突变，这需要更高的覆盖率。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。总而言之，如果这个项目成功，它将为扩展到人类精神样本和在下一代小鼠系统生物学平台Collaborative Cross内进行详细的机械研究奠定基础。 公共卫生相关性： 8.40岁以上父亲的后代项目显示，自闭症和精神分裂症的风险增加，这表明新的DNA突变在一些人的这些疾病中起到了作用。然而，还没有明确的证据表明，父亲年龄的增加会导致后代基因组水平上的突变增加。由于在人类身上测试这一点非常困难和昂贵，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。