Repetitive DNA structure of the human genome

人类基因组计划的最近完成给今天的科学家提供了一个特权的机会，第一次也是唯一一次，对人类DNA序列的结构进行了详细的全面描述。我们基因组的大部分仍然相对不足，特别是重复DNA片段，占我们总DNA序列的45%以上。许多重要的基因组更新机制导致了我们基因组中重复DNA的大量积累，包括基因组复制、转座、不平等交换和基因转换，这些机制对我们基因组的结构产生了巨大的影响。因此，我们建议通过开发新的计算机算法，基因组分析工具和严格的实验方法，对人类重复DNA的三个不同方面进行首次全基因组调查和分析。1)我们建议识别和表征人类反向DNA重复序列的完整目录，这些序列与许多重要的基因组功能，如DNA复制，减数分裂交叉和基因转换相关。我们的研究结果表明，人类X染色体含有大量的高度同源的反向重复序列，其中含有睾丸基因。2)我们建议调查新的类串联重复的“卫星”DNA，包含人类转座子。这些主要在染色体的着丝粒周围区域组织成多个大阵列，在那里发生快速的染色体进化。我们已经确定并表征了一个大的串联重复序列家族，该家族几乎完全由重排的MaLR LTR转座子组成，在8个不同的人类染色体上发现了70kb的阵列。3)我们建议进行人类转座因子（TE）的全基因组分析，通过分析大量的嵌套转座子簇，其中较新的TE已转座到旧的TE。我们已经开发出独特的方法和计算机算法，可以定位和索引人类基因组中的所有此类转座子簇，并可以推导出人类TE在进化过程中的相对时间顺序。这代表了一种全新的研究分子进化的方法，它不依赖于恒定突变率（分子钟）的假设。本申请中提出的研究将促进基因组学的计算和生物方法，并提供对我们DNA序列中较大且相对被忽视的部分的独特分析。

DESCRIPTION (provided by applicant): The repetitive DNA structure of the human genome The recent completion of the human genome project gives today's scientists the privileged opportunity to provide, for the first and only time, a detailed comprehensive description of the structure of the human DNA sequence. Large parts of our genome remain relatively understudied, especially the repetitive DNA fractions, which account for greater than 45% of our total DNA sequence. Many important genomic turnover mechanisms contribute to the large accumulation of repetitive DNA in our genome, including genomic duplication, transposition, unequal crossing over, and gene conversion, which have a huge impact on the structure of our genome over the course of evolution. Therefore, we propose to undertake the first genome- wide survey and analysis of three distinct aspects of human repetitive DNA, by developing novel computer algorithms, genome analysis tools, and rigourous experimental approaches. 1) We propose to identify and characterize the complete catalogue of human inverted DNA repeats, which have been associated with many important genome functions such as DNA replication, meiotic crossover, and gene conversion. Our results have shown that the human X chromosome contains a preponderance of large highly homologous inverted repeats that contain testes genes. 2) We propose to investigate novel classes of tandemly repeated "satellite" DNA that contain human transposons. These are organized in multiple large arrays primarily in the pericentromeric regions of chromosomes, where rapid chromosome evolution takes place. We have identified and characterized a large family of tandem repeats composed almost entirely of rearranged MaLR LTR transposons, found on 8 different human chromosomes in arrays as large as 70kb. 3) We propose to perform a genome-wide analysis of human transposable elements (TE's) by analyzing the large number of nested transposon clusters where newer TE's have transposed into older TE's. We have developed unique methodology and computer algorithms that can locate and index all such transposon clusters in the human genome, and can derive a relative chronological order of human TEs over the course of evolution. This represents a completely novel method of studying molecular evolution that is not dependent on the assumption of a constant mutation rate (molecular clock). The studies proposed in this application will facilitate both computational and biological approaches to genomics and provide a unique analysis of a large and relatively neglected portion of our DNA sequence.