APPROACHES TO GENE MAPPING DEVELOPMENT AND APPLICATIONS

基因图谱开发和应用的方法

• 批准号: 6160949
• 负责人: J C STEPHENS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160949
• 关键词: animal genetic material tag; disease /disorder proneness /risk; family genetics; genetic mapping; genetic markers; genetic recombination; human genetic material tag; human population genetics; immunogenetics; linkage disequilibriums; neoplasm /cancer genetics; population genetics

Population genetics, molecular evolution, and phylogenetic reconstruction are a continuum of disciplines that provide different perspectives on some of the more interesting questions of human genetic disease. Refinements in both the theory and the application of these disciplines are now possible with the exquisitely detailed understanding of human and other genomes that is emerging. The research objectives of this project primarily concern the development and application of demographic, genetic, and phylogenetic analyses. In particular, we are using these modes of analysis to underpin novel gene mapping strategies that range, in terms of their genomic scale, from the identification and localization of disease and disease susceptibility genes to studies mapping the critical functional and disease-related motifs within alleles of the human major histocompatibility complex. These strategies are currently being applied to find genes underpinning various etiologies in LGD collaborations on AIDS, breast cancer, prostate cancer, hypertension, and kidney disease. Concomittant with these studies are related molecular studies on patterns of human molecular variation at both short (allelic) and long (haplotypes and multi-locus genotypes) genomic ranges. Our early work on mapping by admixture linkage disequilibrium (MALD) demonstrated its feasibility as a mapping strategy by the direct detection of linkage disequilibrium in admixed populations. The work on MALD implementation has recently been expanded to include different transmission modalities (e.g., recessive, dominant, and codominant disease phenotypes), optimized sampling of patients and controls, incomplete penetrance, and disease genetic heterogeneity. Furthermore, now the tests for linkage are much easier and more amenable to high- throughput analysis in a clinical setting. Explicit results were obtained by i) solving for expected levels of disequilibrium (D) due to admixture; ii) translating D into a measurable effect (in this case, an allele frequency difference between patients and appropriate controls) under different models of admixture, transmission modality, and allele frequency; and iii) determination of patient/control sample sizes required to statistically detect the effect.

群体遗传学、分子进化和系统发育 重建是一个学科的连续体，提供不同的 对人类遗传学中一些更有趣的问题的看法 疾病这些理论和应用的完善 现在，通过细致入微的理解， 人类和其他正在出现的基因组。的研究目标 该项目主要涉及开发和应用 人口统计学遗传学和系统发育分析我们尤其 使用这些分析模式来支持新的基因定位策略 从它们的基因组规模来看， 疾病和疾病易感基因的定位研究 映射关键功能和疾病相关的基序， 人类主要组织相容性复合体的等位基因。这些策略 目前正被应用于寻找基因基础上的各种 艾滋病、乳腺癌、前列腺癌、乳腺癌、前列腺癌、 癌症、高血压和肾病。与此同时， 研究是关于人类分子模式的相关分子研究， 短（等位基因）和长（单倍型和多位点）的变异 基因型）基因组范围。 利用混合连锁不平衡（MALD）作图的早期工作 证明了其作为映射策略的可行性， 混合群体中连锁不平衡的检测。的工作 MALD的实施最近已经扩展到包括不同的 传输模态（例如，隐性、显性和共显性 疾病表型），患者和对照的优化取样， 不完全遗传和疾病遗传异质性。此外，委员会认为， 现在，连锁反应的测试要容易得多，也更容易接受高- 临床环境中的通量分析。明确的结果是 通过i）求解由于以下原因而导致的预期不均衡水平（D）获得 ii）将D转化为可测量的效果（在这种情况下， 患者和适当对照之间的等位基因频率差异） 在不同的混合模式、传播方式和等位基因下， 频率;和iii）确定患者/对照样本量 需要统计检测效果。