Identification and analysis of genetic determinants of natural telomere length variation

自然端粒长度变异遗传决定因素的鉴定和分析

基本信息

批准号：
9262152
负责人：
Eugene V Shakirov
金额：
$ 7.83万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262152
关键词：
Affect Age Aging Arabidopsis Biological Biological Assay Biological Models Biology Biology of Aging Birth Candidate Disease Gene Cell Aging Cell Proliferation Cells Chromosomes Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 5 Complex DNA Data Set Disease Eukaryota Foundations Future Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Variation Genetic study Genome Genomics Goals Heritability Homeostasis Human Inbreeding Individual Knock-out Lead Length Longevity Maintenance Malignant Neoplasms Maps Measurement Measures Minor Modeling Molecular Monitor Mouse-ear Cress Mutation Nature Normal Cell Orthologous Gene Phenotype Plant Model Plants Population Positioning Attribute Predisposition Premature aging syndrome Proliferation Marker Proteins Quantitative Trait Loci Recombinants Recording of previous events Research Resources Role Telomere Maintenance Telomere Maintenance Gene Telomere Shortening Transgenic Organisms Variant Yeasts age related cell growth regulation comparative experimental study genetic analysis genetic variant insight inter-individual variation novel public health relevance telomere tool

项目摘要

DESCRIPTION (provided by applicant) Telomeres are evolutionarily conserved protein-DNA complexes at the physical ends of linear eukaryotic chromosomes. The initial length of the repetitive telomeric DNA set at birth shortens with age in most human cells, thus serving as a marker of proliferation history and pre-determining cellular lifespan. Mutations in telomere maintenance genes lead to premature aging and a number of age-related disorders. Mean telomere length in humans shows considerable inter-individual variation and appears to be under strong genetic control, but the exact nature of factors establishing telomere length set point remains elusive. Here we propose to identify and characterize genetic factors establishing telomere length set point in the model plant Arabidopsis thaliana. In our preliminary results, we show that, similar to humans and yeast, natural Arabidopsis populations display significant variation in telomere length set point, and we identify a major effect telomere length QTL on chromosome 5. The main approach of this proposal takes advantage of the major recent technical breakthroughs in Arabidopsis QTL mapping using genetically advanced Recombinant Inbred MAGIC Lines to discover genetic factors establishing population-specific telomere length set point. Aim 1 takes advantage of the remarkable genetic diversity of natural Arabidopsis populations and the easy assays for precise monitoring of telomere length. We will continue measuring telomere length in the MAGIC population and fine-map one major and several minor QTL using a combination of candidate gene approach and population- wide comparative sequence and expression analysis. In Aim 2, we will utilize multiple genetic assays, such as knock-out and transgenic rescue experiments, to functionally characterize candidate genes and validate their role in telomere biology. Our results will lead to better understanding of genetic differences underlying telomere length polymorphism in natural Arabidopsis populations, and may also provide important insights into the molecular basis for different rates of aging among humans and predisposition to aging-associated diseases.

描述（由申请人提供）端粒是线性真核染色体物理末端的进化上保守的蛋白质-DNA 复合物，在大多数人类细胞中，出生时重复端粒 DNA 的初始长度随着年龄的增长而缩短，因此可以作为增殖历史和预先确定细胞寿命的标志。端粒维持基因的突变导致过早衰老和许多与年龄相关的疾病，人类的平均端粒长度显示出相当大的个体间差异，并且似乎受到强烈的遗传影响。控制，但建立端粒长度设定点的因素的确切性质仍然难以捉摸。在这里，我们建议在模型拟南芥植物中识别和表征建立端粒长度设定点的遗传因素，我们的初步结果表明，与人类相似。酵母、天然拟南芥群体在端粒长度设定点上表现出显着的变化，我们确定了第 5 号染色体上的一个主要影响端粒长度的 QTL。该提案的主要方法利用了最近在使用遗传先进的重组近交系 MAGIC 进行拟南芥 QTL 定位，以发现建立群体特异性端粒长度设定点的遗传因素，目标 1 利用自然拟南芥群体的显着遗传多样性和精确监测端粒长度的简单分析。结合候选基因方法和群体比较宽序列和表达分析，测量 MAGIC 群体中的端粒长度并精细定位一个主要和几个次要 QTL。 2，我们将利用多种遗传学，例如敲除和转基因救援实验，对候选基因进行功能表征并验证它们在端粒生物学中的作用，我们的结果将有助于更好地了解自然拟南芥群体中端粒长度多态性的遗传差异，它还可能为人类不同衰老速度和衰老相关疾病易感性的分子基础提供重要见解。