Exhaustive Analysis of Microsatellite Loci in the 1000 Genomes Project

千个基因组计划中微卫星位点的详尽分析

• 批准号: 8099068
• 负责人: HAROLD R GARNER
• 金额: $ 26.5万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-26 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099068
• 关键词: Area; Biological Markers; Characteristics; DNA; DNA Sequence; Data; Disease; Elements; Exhibits; Family; Forensic Medicine; Genes; Genetic Polymorphism; Genome; Genomics; Goals; Human; Human Genome; Individual; Instruction; Internet; Laboratories; Length; Measurement; Measures; Metadata; Methods; Microsatellite Repeats; Modeling; Ontology; Paternity testing; Principal Investigator; Process; Reagent; Repetitive Sequence; Research; Resources; Role; Single Nucleotide Polymorphism; Techniques; Variant; cohort; genome sequencing; genome-wide; pressure; trend; user-friendly

DESCRIPTION (provided by applicant): The study of repetitive DNA, microsatellites, a class of genomic variation which exhibits a 10,000 fold higher mutability than single nucleotide polymorphisms has been hampered by the lack of data at microsatellite- containing loci. That is, until now, with the emergence of data from the 1000 Genomes Project. We hypothesize that these hypervariable loci, once analyzed in depth will yield a new appreciation for their value and role in the genome as new biomarkers and functional elements. Baseline measurements of the variability at these loci in the substantial 1000 Genomes Project cohort will provide important information required to exploit these loci, both computationally and in the laboratory. The primary goal of the proposed research is to complete an exhaustive analysis and interpretation of the ~700,000 microsatellite loci using the -2,500 sets of genome sequence becoming available from the 1000 Genomes Project to measure their size, purity and motif dependent distributions and then overlay those data with metadata (gene ontologies, conservation and more) to create a resource where we an others can explore the significant, yet underappreciated role of microsatellite polymorphism in human variation and disease. We have demonstrated the techniques required and impactful preliminary results confirm feasibility and value and potential. Specific aims 1) align all 1000 Genomes Project sequence data to the microsatellite containing loci to measure the allelic distribution, polymorphism rate, characteristics, quality of the sequence in these repetitive regions; inspect and characterize groups of motif lengths and families (AAT,AAAT,AATT, etc.) to look for evidence for selection pressure, bias and genome wide trends; 2) compare the distributions with models for estimating polymorphism propensity as a function of specific sequence motifs, motif size, copies and purity (are there any SNPs), thus identifying any general replication or error correction mechanism bias, which we suspect; 3) annotate each locus with ontology, conservation and other positional data to identify any process, functional or disease propensity correlations; and 4) create a web resource to distribute our findings and other reagents derived from this study so others can investigate microsatellite sequence variability at individual loci or across the genome. RELEVANCE (See instructions): The human genome contains over 500,000 areas with repeated DNA sequence (e.g. CACACACACA) called microsatellites. They are extremely variable, cause numerous diseases, are used in forensics/ paternity testing and may alter many of our characteristics, but they are understudied and under- appreciated. The 1000 Genome Project data enables their thorough analysis en masse by our methods.

描述（由申请人提供）：重复DNA，微卫星，一类基因组变异，其变异性比单核苷酸多态性高10,000倍，由于缺乏含有微卫星的位点的数据，研究受到阻碍。也就是说，直到现在，随着1000基因组计划数据的出现。我们假设，一旦深入分析这些高变位点，将对它们作为新的生物标志物和功能元件在基因组中的价值和作用产生新的认识。在大量的1000基因组计划队列中，这些基因座的变异性基线测量将提供利用这些基因座所需的重要信息，无论是在计算上还是在实验室中。本研究的主要目标是利用1000基因组计划提供的2500组基因组序列，完成对约70万个微卫星位点的详尽分析和解释，以测量它们的大小、纯度和基序依赖分布，然后将这些数据与元数据（基因本体、保守性等）叠加，以创建一个资源，我们和其他人可以在其中探索重要的、然而，微卫星多态性在人类变异和疾病中的作用尚未得到充分认识。我们已经证明了所需的技术和有影响力的初步结果证实了可行性、价值和潜力。具体目标1)将所有1000个基因组计划序列数据与含有位点的微卫星进行比对，以测量这些重复区域的等位基因分布、多态性率、序列特征和质量；检查和表征基序长度和家族群（AAT，AAAT，AATT等），以寻找选择压力，偏差和全基因组趋势的证据；2)将分布与估计多态性倾向作为特定序列基序、基序大小、拷贝数和纯度（是否存在snp）的函数的模型进行比较，从而确定我们怀疑的任何一般复制或纠错机制偏差；3)用本体论、保守性和其他位置数据注释每个基因座，以识别任何过程、功能或疾病倾向的相关性；4)创建一个网络资源来发布我们的发现和从这项研究中获得的其他试剂，这样其他人就可以研究单个位点或整个基因组的微卫星序列变异性。相关性（见说明）：人类基因组包含超过50万个区域，这些区域具有重复的DNA序列（例如CACACACACA），称为微卫星。它们非常多变，会导致许多疾病，被用于法医/亲子鉴定，可能会改变我们的许多特征，但它们没有得到充分的研究和重视。1000基因组计划的数据使他们能够通过我们的方法进行全面的分析。

项目成果

Improved variation calling via an iterative backbone remapping and local assembly method for bacterial genomes.

通过细菌基因组的迭代主干重映射和局部组装方法改进了变异识别。

• DOI: 10.1016/j.ygeno.2012.07.015
• 发表时间: 2012
• 期刊: Genomics
• 影响因子: 4.4
• 作者: Tae,Hongseok;Settlage,RobertE;Shallom,Shamira;Bavarva,JasminH;Preston,Dale;Hawkins,GregoryN;Adams,LGarry;Garner,HaroldR
• 通讯作者: Garner,HaroldR

Population-scale analysis of human microsatellites reveals novel sources of exonic variation.

• DOI: 10.1016/j.gene.2012.12.068
• 发表时间: 2013-03-10
• 期刊: Gene
• 影响因子: 3.5
• 作者: McIver LJ;McCormick JF;Martin A;Fondon JW 3rd;Garner HR
• 通讯作者: Garner HR

Large scale comparison of non-human sequences in human sequencing data.

• DOI: 10.1016/j.ygeno.2014.08.009
• 发表时间: 2014-12
• 期刊: GENOMICS
• 影响因子: 4.4
• 作者: Tae, Hongseok;Karunasena, Enusha;Bavarva, Jasmin H.;McIver, Lauren J.;Garner, Harold R.
• 通讯作者: Garner, Harold R.