Evolutionary Conserved Sequences in the Human Genome

人类基因组中的进化保守序列

• 批准号: 6549176
• 负责人: KELLY A FRAZER
• 金额: $ 10万
• 依托单位: PERLEGEN SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549176
• 关键词: Rodentias; animal genetic material tag; biochemical evolution; cats; chromosome 21; computer program /software; computer system design /evaluation; cow; dogs; functional /structural genomics; genome; human genetic material tag; microarray technology; molecular biology information system; nucleic acid sequence; oligonucleotides; open reading frames; polymerase chain reaction; swine

DESCRIPTION (provided by applicant): The present technical ability to sequence entire mammalian genomes outpaces current computational and experimental abilities to decode the information contained within these sequences. Cross-species sequence comparisons are a powerful method for decoding genomic information due to the fact that functional elements are conserved through evolution whereas nonfunctional sequences drift. Because the rate of evolution varies widely in different regions of a genome within a species as well as for orthologous sequences between species, a comprehensive comparative analysis of the human genome will require that it be compared with the genomic sequences of multiple mammals. At the current cost of sequencing mammalian genomes it is too expensive to obtain in-depth sequence coverage of more than a few mammals. Thus, we are left with the choice of forgoing the information that would be obtained by multi-species comparisons or employing a high-resolution scanning approach, such as described in this proposal, for comparing human sequences with the DNA of multiple mammals. In phase I of the proposed research, we will analyze the data from a pilot study in which a 300-kb region of human chromosome 21 has been compared with the DNA of five mammals using oligonucleotide high-density arrays. We will improve the current algorithms employed for detecting and characterizing evolutionarily conserved sequences using high-density arrays. In addition, we will demonstrate that multi-species comparative analysis using high-density arrays combined with targeted dideoxy-sequencing can obtain the homologous sequences of biologically interesting conserved elements across multiple mammals. During phase II of this proposal, we will screen approximately 32 Mb of human chromosome 21 for conserved sequences by hybridizing high-density arrays with orthologous dog, cat, cow, pig, and horse DNA. The goal of this proposal is to demonstrate the feasibility and cost-effectiveness of the high-density array approach for identifying conserved human elements by comparative analysis with multiple mammals across the entire human genome.

描述（由申请人提供）：目前对整个哺乳动物基因组进行测序的技术能力超过了目前解码这些序列中所含信息的计算和实验能力。跨物种序列比较是解码基因组信息的有力方法，因为功能元件在进化过程中是保守的，而非功能序列是漂移的。由于进化速率在一个物种内基因组的不同区域以及物种之间的直系同源序列中变化很大，因此对人类基因组的全面比较分析将需要将其与多种哺乳动物的基因组序列进行比较。以目前哺乳动物基因组测序的成本，要获得超过几种哺乳动物的深度序列覆盖率太昂贵了。因此，我们只能选择放弃通过多物种比较获得的信息，或者采用高分辨率扫描方法，如本提案所述，将人类序列与多种哺乳动物的DNA进行比较。在拟议研究的第一阶段，我们将分析来自一项试点研究的数据，其中使用寡核苷酸高密度阵列将人类21号染色体的300 kb区域与5种哺乳动物的DNA进行比较。我们将改进目前的算法用于检测和表征进化保守序列使用高密度阵列。此外，我们将证明，使用高密度阵列结合靶向双脱氧测序的多物种比较分析可以获得跨多种哺乳动物的生物学上感兴趣的保守元件的同源序列。在第二阶段的建议，我们将筛选约32 Mb的人类21号染色体的保守序列，通过杂交高密度阵列与orthopathic狗，猫，牛，猪和马的DNA。该提案的目标是通过与整个人类基因组中的多种哺乳动物进行比较分析来证明高密度阵列方法用于识别保守的人类元件的可行性和成本效益。