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）：