Male Mutation Bias and Paternal Age Effect in Mammals

哺乳动物中的雄性突变偏差和父亲年龄效应

• 批准号: 7913976
• 负责人: KATERYNA MAKOVA
• 金额: $ 8.71万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-09 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913976
• 关键词: Age; Bioinformatics; Birth; Cell division; Cetacea; Clinical; Conceptions; CpG dinucleotide; DNA; DNA biosynthesis; Data; Disease; Dolphins; Equus caballus; Fathers; Female; Free Radicals; Generations; Genes; Genetic; Genetic Counseling; Genetic Variation; Genome; Genomics; Hand; Hereditary Disease; Homologous Gene; Human; Human Genetics; Interspersed Repetitive Sequences; Introns; Laboratories; Life; Literature; Macaca; Mammals; Maps; Meiosis; Microsatellite Repeats; Molecular; Molecular Evolution; Mus; Mutagenesis; Mutation; Nucleotides; Outcome; Pan Genus; Paternal Age; Pathology; Perissodactyla; Population; Primates; Pseudogenes; Public Health; Rattus; Replication Error; Research; Research Personnel; Risk Factors; Rodent; Sex Bias; Sex Chromosomes; Single Nucleotide Polymorphism; Site; Source; Testing; Time; Whales; age effect; autosome; comparative; egg; environmental agent; genome-wide; human male; insertion/deletion mutation; interest; male; offspring; programs; repaired; reproductive; research study; rhinoceros; sperm cell; tool; trait

DESCRIPTION (provided by applicant): Mutations are the cause of many human genetic diseases and the main source of genetic variation in natural populations. Thus, elucidating the mechanisms of mutagenesis is of great significance. The fact that, in mammals, the number of germline cell divisions (and of DNA replications) is higher in males than in females provides an opportunity to test whether mutations result from errors in DNA replication. If this hypothesis is true, we expect higher mutation rate in males than in females (male mutation bias) and higher mutation rate in older males than in younger males (paternal age effect). Here we will employ the tools of comparative genomics and bioinformatics to analyze available mammalian genomic sequences and generate additional data experimentally to test the following specific hypotheses: 1. Errors in DNA replication are the primary sources of insertions and deletions (indels). 2. Nucleotide substitutions, particularly at CpG dinucleotides, depend on the number of germline cell divisions. To test these first two hypotheses we will estimate mutation rates from mammalian whole-genome alignments and compare these rates between sex chromosomes and autosomes. 3. Microsatellite repeat expansions and contractions are caused by errors in DNA replication. This will be tested by observing de novo mutations in single sperm of human males of different ages. 4. The magnitude of male mutation bias and generation time are positively correlated in mammals. To investigate this, we will sequence introns of genes homologous between X and Y in mammals with long generation time (Cetacea and Perissodactyla) and analyze additional data from the literature. The proposed research has direct relevance to issues of public health and clinical genetics. The overwhelming majority of mutations causing human genetic diseases are indels, nucleotide substitutions, and microsatellite repeat expansions/contractions. Moreover, single nucleotide polymorphisms (SNPs), an outcome of nucleotide substitutions, and microsatellites are widely used markers for mapping diseases and traits in association studies. Thus, it is critical to know whether mutations at these loci are driven by replication-dependent or by replication-independent factors (e.g., environmental agents such as free radicals). Additionally, the conclusions of this project will be important for genetic counseling. Namely, our results will indicate whether the age of a father at the time of conception represents a risk factor for pathology in the offspring.

描述（申请人提供）：突变是许多人类遗传疾病的原因，也是自然群体遗传变异的主要来源。因此，阐明诱变机制具有重要意义。在哺乳动物中，雄性生殖细胞分裂（和DNA复制）的数量高于雌性，这一事实提供了一个测试突变是否由DNA复制错误引起的机会。如果这一假设是正确的，我们预计男性的突变率高于女性（男性突变偏倚），老年男性的突变率高于年轻男性（父亲年龄效应）。 在这里，我们将采用比较基因组学和生物信息学的工具来分析现有的哺乳动物基因组序列，并通过实验产生额外的数据来测试以下特定假设： 1. DNA复制中的错误是插入和缺失（indels）的主要来源。 2.核苷酸取代，特别是在CpG二核苷酸处，取决于种系突变的数量。 细胞分裂为了验证前两个假设，我们将估计哺乳动物的突变率。 全基因组比对，并比较性染色体和常染色体之间的这些比率。 3.微卫星重复序列的扩展和收缩是由DNA复制错误引起的。这将通过观察不同年龄的人类男性的单个精子中的从头突变来测试。 4.在哺乳动物中，雄性突变偏好的大小与世代时间呈正相关。 为了研究这一点，我们将测序X和Y之间同源的基因内含子在哺乳动物与长世代的时间（鲸目和奇蹄目），并分析来自文献的其他数据。 拟议的研究与公共卫生和临床遗传学问题直接相关。绝大多数导致人类遗传疾病的突变是插入缺失、核苷酸取代和微卫星重复序列扩增/收缩。此外，单核苷酸多态性（SNPs），核苷酸取代的结果，和微卫星被广泛使用的标记，用于映射疾病和性状的关联研究。因此，了解这些基因座的突变是由复制依赖性因素还是由复制非依赖性因素（例如，环境因素如自由基）。此外，该项目的结论将是重要的遗传咨询。也就是说，我们的研究结果将表明父亲在受孕时的年龄是否代表后代病理学的风险因素。