From QTL to Gene for HDL Cholesterol

从 QTL 到 HDL 胆固醇基因

• 批准号: 6816607
• 负责人: Beverly J Paigen
• 金额: $ 42.25万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816607
• 关键词: atherosclerosis; bioinformatics; biotechnology; cholesterol; computer program /software; functional /structural genomics; gene expression; genetic mapping; genetic strain; high density lipoproteins; laboratory mouse; nucleic acid amplification techniques; nucleic acid sequence; quantitative trait loci; statistics /biometry

DESCRIPTION (provided by applicant): Epidemiological studies show that even small increases in high-density lipoprotein (HDL) cholesterol afford considerable protection against heart disease. Through quantitative trait locus (QTL) mapping in both mice and humans, many genomic regions have been found that contain genes affecting HDL levels. Combining data from our own laboratory with that from the literature shows that most HDL QTLs have been discovered many times, that the recently reported QTLs simply confirm previously reported ones, and that mouse and human QTLs are found in homologous chromosomal regions, suggesting that the same genes determine HDL in these species. We estimate that between 23 and 30 genes account for most population variation in HDL concentrations. Identifying these genes would increase our understanding of what factors cause an increase in HDL levels and may also provide therapeutic targets. Using mouse models, we aim to identify the genes underlying five HDL QTLs in the mouse chosen for further analysis because they are found in homologous regions of the human and mouse genomes; they have been found multiple times in different mouse crosses; and their effects are large enough to work with. For each QTL, we will test the hypothesis that increased HDL protects against atherosclerosis using congenic strains moving the allele causing increased HDL into the B6 genetic background. Using bioinformatics resources, we will narrow each QTL by combining statistical data from several crosses, comparing mouse and human homologies, applying haplotype analysis, and comparing sequence among mouse strains. Using genetic resources, we will further narrow each QTL with recombinant inbred strains, advanced intercross lines, and overlapping congenics. Candidate genes will be tested for expression and sequence differences; highly probable candidates will be proven by transgenic, knockout, and other technologies. Finally, we will build a public database of the raw QTL data that we and others have generated so that new techniques of analysis, such as determining the 95% confidence interval of a QTL, finding gene interactions, and analyzing combined cross data can be applied to published data.

描述（由申请人提供）：流行病学研究表明，即使是高密度脂蛋白（HDL）胆固醇的少量增加也可以对心脏病进行大量保护。通过小鼠和人类的定量性状基因座（QTL）映射，已经发现许多基因组区域包含影响HDL水平的基因。将我们自己的实验室的数据与文献相结合的数据表明，大多数HDL QTL已被发现很多次，最近报道的QTL只是简单地证实了先前报道的QTL，并且在同源染色体区域中发现了小鼠和人类QTL，这表明这些物种中的同一基因确定了HDL。我们估计23至30个基因占HDL浓度的大多数种群变化。识别这些基因将增加我们对哪些因素导致HDL水平增加的理解，并可能提供治疗靶标。使用小鼠模型，我们旨在确定所选小鼠中五个HDL QTL的基因进行进一步分析，因为它们是在人和小鼠基因组的同源区域中发现的。在不同的小鼠杂交中发现它们多次。它们的效果足够大，可以使用。对于每个QTL，我们将检验以下假设，即使用先天性菌株将HDL预防促进动脉粥样硬化的假设使等位基因将HDL增加到B6遗传背景。使用生物信息学资源，我们将通过结合几个十字的统计数据，比较小鼠和人类同源性，应用单倍型分析并比较小鼠菌株之间的序列来缩小每个QTL的范围。使用遗传资源，我们将通过重组近交菌株，高级间交叉线和重叠的友善者进一步缩小每个QTL。候选基因将进行表达和序列差异测试；高可能的候选人将通过转基因，淘汰和其他技术证明。最后，我们将构建一个我们和其他人生成的原始QTL数据的公共数据库，以便将新的分析技术（例如确定QTL的95％置信区间，查找基因相互作用以及分析组合的交叉数据可以应用于公开数据。