APPROACHES TO GENE MAPPING DEVELOPMENT AND APPLICATIONS

种群遗传学、分子进化和系统发育 重建是一个连续的学科统一体，它提供了不同的 对人类遗传学中一些更有趣问题的看法 疾病。在理论和应用上的改进 有了精致而详细的理解，学科现在是可能的 人类和其他正在出现的基因组。的研究目标 该项目主要涉及到的开发和应用。 人口统计、遗传和系统发育分析。特别是，我们正在 使用这些分析模式来支持新的基因图谱策略 这一范围，就它们的基因组规模而言，从鉴定和 疾病和疾病易感基因的定位研究 绘制关键功能和与疾病相关的主题图 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支撑各种 LGD在艾滋病、乳腺癌、前列腺癌方面的合作中的病因 癌症、高血压和肾脏疾病。与这些相伴而生 关于人类分子模式的相关分子研究 短(等位基因)和长(单倍型和多基因座)的变异 基因类型)基因组范围。 我们在混合连锁不平衡(MALD)作图方面的早期工作 论证了其作为一种映射策略的可行性 混合群体中连锁不平衡的检测。这项工作 MALD实现最近已经扩展到包括不同的 传播方式(例如，隐性、显性和共显性 疾病表型)，患者和对照的优化抽样， 不完全外显和疾病遗传异质性。此外， 现在对连锁性的测试要容易得多，也更容易接受高- 临床环境中的吞吐量分析。明确的结果是 通过i)求解由于以下原因而产生的预期不平衡水平(D 混合体；ii)将D转换为可测量的效果(在这种情况下， 患者和正常对照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；以及三)确定患者/对照样本量 需要在统计上检测效果。

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.