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: 7075345
• 负责人: KATERYNA MAKOVA
• 金额: $ 21.09万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7075345
• 关键词: Cetacea; CpG islands; DNA replication; Ungulate; animal genetic material tag; autosome; bioinformatics; clinical research; comparative genomic hybridization; gender difference; gene deletion mutation; gene mutation; human genetic material tag; human tissue; nucleic acid repetitive sequence; sex chromosomes; sperm

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病的原因，也是自然种群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，这一事实为测试突变是否源于DNA复制错误提供了机会。如果这一假设属实，我们预计男性的突变率高于女性(男性突变倾向)，老年男性的突变率高于年轻男性(父系年龄效应)。 在这里，我们将使用比较基因组学和生物信息学的工具来分析可用的哺乳动物基因组序列，并通过实验产生额外的数据来检验以下特定的假设： 1.DNA复制错误是插入和缺失(INDELs)的主要来源。 2.核苷酸替换，特别是CpG二核苷酸的替换，取决于生殖系的数量 细胞分裂。为了检验前两个假设，我们将估计哺乳动物的突变率。 进行全基因组比对，并比较性染色体和常染色体之间的比率。 3.微卫星重复序列的扩增和收缩是由DNA复制错误引起的。这将通过观察不同年龄的男性单个精子的从头突变来检验。 4.哺乳动物雄性突变偏向的大小与世代时间呈正相关。 为了研究这一点，我们将对具有长世代时间的哺乳动物(鲸目和腹足目)的X和Y同源基因的内含子进行测序，并分析来自文献的其他数据。这项拟议的研究与公共卫生和临床遗传学问题直接相关。导致人类遗传病的绝大多数突变是INDELS、核苷酸替换和微卫星重复扩增/收缩。此外，单核苷酸多态(SNPs)是核苷酸替换的结果，微卫星是关联研究中广泛用于定位疾病和性状的标记。因此，了解这些基因座的突变是由复制依赖的因素还是复制无关的因素(例如，环境因素，如自由基)驱动的是至关重要的。此外，该项目的结论将对遗传咨询具有重要意义。也就是说，我们的结果将表明，怀孕时父亲的年龄是否代表着后代患病的风险因素。