APPROACHES TO GENE MAPPING DEVELOPMENT AND APPLICATIONS

群体遗传学和相关学科的方法是阐明遗传对人类疾病影响的武器库的有力补充。这个项目的目标是将现有的和新的群体遗传学理论提炼成适用于LGD疾病基因发现工作的策略和算法。我们正在将这些方法应用于艾滋病、前列腺癌、高血压、肾脏疾病和病毒性肝炎的研究。一个主要的焦点一直是混合物连锁不平衡（MALD）的方法来映射疾病基因，其可行性，我们以前证明了计算和模拟研究的映射的发展。我们已经完成了一项使用FY（达菲）基因座作为疾病基因替代物的原理验证研究。对FY周围80 cM范围内的26个STR位点进行连锁不平衡检测，结果表明，FY组内35 cM范围内的STR位点均存在连锁不平衡，所有5 cM范围内的STR位点均存在显著连锁不平衡。 我们早期的MALD可行性研究已经引发了对非裔美国人前列腺癌的全面研究。这项研究采用了数百个STR标记，在整个基因组中以约10 cM的间隔分布，正如可行性研究所建议的那样。认识到在非理想情况下（例如，疾病病因学涉及几个低表达率的疾病基因），疾病关联的MALD信号可能很弱，我们继续改进检测MALD关联的方法。STR标记的使用提出了一个特定的数学挑战，因为许多最初为MALD开发的计算方法假设双等位基因位点，而STR可能有12个或更多的等位基因。我们已经开发出一种新的方法，具体的多等位基因位点，使用祖先群体之间的等位基因频率的差异（与非洲等位基因频率在这种情况下是从非裔美国人的频率外推），以估计疾病和对照组的祖先。这种方法已在FY（Duffy）位点周围的标记上进行了测试，在那里它能够以比列联表分析更高的灵敏度检测与FY的连锁。基因图谱和艾滋病-混合，疾病关联，进化，连锁不平衡，主要组织相容性复合体，微卫星，重组，-人类组织，液体，细胞等。

The approaches of population genetics and related disciplines are a powerful addition to the arsenal of weapons available for elucidating genetic influences on human diseases. The objective of this project is to distill existing and new theory in population genetics into strategies and algorithms applicable to the disease gene discovery effort of the LGD. We are applying these methods to studies of AIDS, prostate cancer, hypertension, kidney disease, and viral hepatitis. A principal focus has been the development of the mapping by admixture linkage disequilibrium (MALD) approach to mapping disease genes, whose feasibility we previously demonstrated by calculations and simulation studies. We have completed a proof-of principle study using the FY (duffy) locus as a surrogate for a disease gene. A test of 26 short tandem repeat (STR) loci in an 80 cM interval around FY showed linkage disequilibrium, detetectible by a contingency table analysis of different FY groups, for markers as far as 35 cM from FY, with all STR markers within 5 cM showing significant linkage disequilibrium. Our earlier MALD feasiblity studies have led to a full scale study of prostate cancer in African Americans. This study employs several hundred STR markers spaced at approximately 10 cM intervals across the genome, as suggested by the feasibility studies. Recognizing that in non-ideal circumstances (e.g., a disease etiology involving several low penetrance disease genes) the MALD signal for disease association may be weak, we have continued to refine methods for detecting MALD associations. The use of STR markers presents a specific mathematical challenge since many of the calculational methods originally developed for MALD assumed diallelic loci, while the STRs may have twelve or more alleles. We have developed a new method specific for multiallelic loci which uses allele frequency differences between the ancestral groups (with the African allele frequencies in this case being extrapolated from African American frequencies) to estimate ancestry in disease and control groups. This approach has been tested on markers around the FY (Duffy) locus, where it is able to detect linkage with FY with greater sensitivity than the contingency table analysis. Gene Mapping and AIDS - admixture, disease association, Evolution, linkage disequilibrium, Major histocompatibility Complex, microsatellites, recombination, - Human Tissues, Fluids, Cells, etc.