APPROACHES TO GENE MAPPING DEVELOPMENT AND APPLICATIONS

这项工作的主要重点是发展和 新的基因定位策略的应用， 人口遗传和进化的考虑。 了解这些 这些原则使我们能够扩大“可映射”基因的范围， 远远超出了目前正在绘制的特征。 我们尤其 使用这些分析模式来支持新的基因定位策略 从疾病的识别和定位， 疾病易感基因的关键功能定位研究 和人类主要基因的等位基因内的疾病相关基序 组织相容性复合体（MHC）。 传统上，映射集中在 传播遗传学的研究，以监测 反映联系的遗传模式。 我们的主要重点是 也一直在重组，但在重组水平（5 - 40 cM） 通常大于常规分析中处理的那些。 我们还利用种群遗传学和系统发育学原理， 处理低得多的重组水平（<1 cM），这是治疗 项目Z 01 BC 05680-06 LGD。 特别是，我们一直在改进 MALD（mapping by mixture linkage disequilibrium），混合连锁不平衡作图法， 以人群为基础的方法来定位基因是难治的， 传统的方法。 目前，参与癌症进展的基因 传染病（例如，艾滋病）和基因参与多因素 特征（例如，非BRCA乳腺癌基因）是特异性靶点 我们的分析。 该项目的工作主要是 理论上，但与其他经验项目密切相关， 实验室和其他使用MALD的地方。 理论的焦点 工作已经转向加速高通量基因分型，例如 微卫星分型，以及随之而来的数据考虑， 自然 在这方面特别重要的考虑是： 标记的共显性但阶段未知的基因型数据，但 潜在地疾病位点的所有类型的传播（显性， 共显性、隐性、多位点、不完全显性）; 群组收集的优化（例如，相对大小 患者/对照样品与其他策略）;缺乏 由于微卫星基因座的高突变率而导致的血统同一性; 高效检测高度多等位基因基因座的畸变。 此外，我们工作的一个主要组成部分是增加基因 基因组学实验室其他成员的绘图研究 多样性

The primary focus of this work has been on the development and application of novel gene mapping strategies that incorporate population genetic and evolutionary considerations. Awareness of these principles has allowed us to expand the range of "mappable" genes and traits well beyond those currently being mapped. In particular, we are using these modes of analysis to underpin novel gene mapping strategies that range 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 (MHC). Classically, mapping has focussed on transmission genetics in pedigrees to monitor distortions in inheritance patterns that reflect linkage. Our principal focus has also been on recombination, but on levels of recombination (5 - 40 cM) that are generally greater than those treated in conventional analyses. We have also used population genetic and phylogenetic principles to deal with much lower levels of recombination ( <1 cM), which is treated in project Z01 BC 05680-06 LGD. In particular, we have been refining MALD (mapping by admixture linkage disequilibrium), as a population-based approach toward mapping genes that are refractory to conventional approaches. Right now, genes involved in progression of infectious disease (e.g., AIDS) and genes involved in multifactorial traits (e.g., the non-BRCA breast cancer genes) are specific targets of our analyses. Work within this project remains primarily theoretical, but is closely allied to other empirical projects in this laboratory and elsewhere that are using MALD. Focus of the theoretical work has shifted to expediting high throughput genotyping, such as microsatellite typing, and the attendant considerations of data of that nature. Especially important considerations for this context are: co-dominant but phase-unknown genotypic data for markers, but potentially all types of transmission for disease loci (dominant, co-dominant, recessive, multiple loci, incomplete penetrance); optimization of cohort collection (e.g., relative size of patient/control samples vs. other strategies); lack of identity-by-descent due to high mutation rates at microsatellite loci; efficient detection of distortions for highly multi-allelic loci. Additionally, a major component of our work is to augment the gene mapping research by other members of the Laboratory of Genomic Diversity.