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保守蛋白-DNA复合物。在大多数人类细胞中，重复的远程远程DNA的初始长度随着年龄的增长而缩短，因此是增殖史和预先确定的细胞寿命的标志。端粒维持基因的突变导致过早衰老和许多与年龄有关的疾病。人类的平均端粒长度显示出很大的个体变异，并且似乎处于强大的遗传控制之下，但是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，我们建议识别和表征遗传因素，以建立塔利亚纳植物植物拟南芥中的端粒长度设定点。在我们的初步结果中，我们表明，与人类和酵母类似，天然拟南芥长度设定点显示出显着变化，并且我们确定了端粒长度QTL对5号染色体的主要效果。该提案的主要方法利用了拟南芥QTL的近期概述型近期的近期跨度型近期的技术突破性，利用了近期的技术突破性，以发现跨跨跨跨型杂志的近距离绘图，以发现近距离的近距离跨度跨度型近距离型近距离绘图。观点。 AIM 1利用了天然拟南芥种群的显着遗传多样性以及对端粒长度进行精确监测的简单测定。我们将继续使用候选基因方法和范围范围的比较序列和表达分析的组合来测量魔法人群中的端粒长度，并在魔法人群中进行端粒长度和精细地图。在AIM 2中，我们将利用多种遗传测定，例如敲除和转基因救援实验，在功能上表征候选基因并验证其在端粒生物学中的作用。我们的结果将使人们更好地了解遗传差异。天然拟南芥种群中的基本端粒长度多态性，也可能为人类中不同衰老率的分子基础提供重要的见解，并倾向于与衰老相关疾病。