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

基本信息

批准号：
8114533
负责人：
KATERYNA MAKOVA
金额：
$ 6.99万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114533
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 genomics egg environmental agent genome-wide human male insertion/deletion mutation interest male offspring programs repaired reproductive research study rhinoceros sperm cell tool trait

项目摘要

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，这一事实为测试突变是否由 DNA 复制错误引起提供了机会。如果这个假设成立，我们预计男性的突变率高于女性（男性突变偏差），年长男性的突变率高于年轻男性（父亲年龄效应）。在这里，我们将利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生成额外的数据来测试以下具体假设： 1. DNA 复制错误是插入和缺失 (indel) 的主要来源。 2. 核苷酸取代，特别是 CpG 二核苷酸，取决于种系数量细胞分裂。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. 微卫星重复扩张和收缩是由DNA复制错误引起的。这将通过观察不同年龄的人类男性单个精子的从头突变来进行测试。 4. 在哺乳动物中，雄性突变偏差的大小与世代时间呈正相关。为了研究这一点，我们将对长世代哺乳动物（鲸类和奇蹄类）中 X 和 Y 之间同源基因的内含子进行测序，并分析文献中的其他数据。拟议的研究与公共卫生和临床遗传学问题直接相关。引起人类遗传疾病的绝大多数突变是插入缺失、核苷酸取代和微卫星重复扩张/收缩。此外，单核苷酸多态性（SNP）（核苷酸取代的结果）和微卫星被广泛用于关联研究中绘制疾病和性状的标记。因此，了解这些位点的突变是由复制依赖性还是非复制依赖性因素（例如自由基等环境因素）驱动至关重要。此外，该项目的结论对于遗传咨询也很重要。也就是说，我们的结果将表明父亲在受孕时的年龄是否代表后代病理的危险因素。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gene survival and death on the human Y chromosome.

DOI：
10.1093/molbev/mss267
发表时间：
2013-04
期刊：
Molecular biology and evolution
影响因子：
10.7
作者：
Wilson Sayres MA;Makova KD
通讯作者：
Makova KD

Genome analyses substantiate male mutation bias in many species.

DOI：
10.1002/bies.201100091
发表时间：
2011-12
期刊：
BioEssays : news and reviews in molecular, cellular and developmental biology
影响因子：
0
作者：
Wilson Sayres MA;Makova KD
通讯作者：
Makova KD

Harnessing cloud computing with Galaxy Cloud.

DOI：
10.1038/nbt.2028
发表时间：
2011-11-08
期刊：
Nature biotechnology
影响因子：
46.9
作者：
通讯作者：

Using Galaxy to perform large-scale interactive data analyses.

DOI：
10.1002/0471250953.bi1005s38
发表时间：
2012-06
期刊：
Current protocols in bioinformatics
影响因子：
0
作者：
Hillman-Jackson, Jennifer;Clements, Dave;Blankenberg, Daniel;Taylor, James;Nekrutenko, Anton;Team, Galaxy
通讯作者：
Team, Galaxy

Evolution and survival on eutherian sex chromosomes.