GENETIC, EVOLUTIONARY, AND PHYLOGENETIC ANALYSIS OF HUMAN ALLELES AND HAPLOTYPES

在基因组区域中观察到的连锁不平衡模式是突变（以及基因转换等罕见事件）、亚种群迁移、重组和选择历史的残留物。实际上，在寻找遗传变异和疾病易感性之间的联系时，连锁不平衡可能是一种混淆因素，使一组基因中的哪一组对疾病效应负责，或者是一种必要的工具，如通过混合连锁不平衡进行制图，使我们能够将未知的疾病基因定位到一个小的染色体区域。我们目前正在应用与连锁不平衡的产生和持续有关的过程的知识来开发工具，以支持寻找与疾病相关的基因。我们的实验室吗?我们对艾滋病候选基因多态性的研究已经发现了一些具有2到9个多态性位点的基因。由于单个基因内的所有位点在重组上非常接近，因此强烈的连锁不平衡是规则，因此考虑单倍型以及单个位点变异与疾病进展的关联是特别有趣的。在已经观察到疾病关联的情况下，但相关多态性可能只是一种尚未确定的多态性的标记，我们可以通过缩小与特定单倍型的关联来更好地集中搜索功能多态性。因此，我们开发了一个单倍型估计程序，其输出包括计算机程序SAS中的生存分析代码，允许以单倍型作为解释变量进行快速生存分析。在基因组尺度上，我们在CEPH图谱系谱的同质人群中完成了5048个常染色体短串联重复位点的研究，试图测量？背景联动不平衡？存在于流感人群中的。距离小于4 cM的位点对中约有4%存在连锁不平衡，这种不平衡与标记间的重组距离成反比。对22个常染色体进行5cM滑动窗口分析，发现10个基因组片段（2.2-6.4 cM）存在多位点连锁不平衡。这些片段，包括6号染色体上的HLA，可能是近期进化史中选择性扫描的指标，突出了特定进化后果的基因组片段。艾滋病抵抗和艾滋病进展-疾病关联，法医，遗传分化，遗传多样性，主要组织相容性复合体，微卫星，多态性，重组，-既不是人类受试者也不是人类组织

The pattern of linkage disequilibrium observed in a region of the genome is the residue of the history of mutation (and rarer events such as gene conversion), migration of subpopulations, recombination, and selection. Practically, in the search for associations between genetic variants and susceptibility to disease, linkage disequilibrium may be either a confounding factor obscuring which of a group of genes is responsible for the disease effect, or an essential tool, as in mapping by admixture linkage disequilibrium, enabling us to localize unknown disease genes to a small chromosomal region. We are currently involved in applying knowledge of the processes involved in the creation and persistance of linkage disequilibrium to develop tools to support the search for disease assocated genes. Our lab?s search for polymorphisms in AIDS candidate genes has uncovered several cases of genes with between two and nine polymorphic loci. Since all loci within a single gene will be recombinationally very close, strong linkage disequilibrium is the rule, and it is particularly interesting to consider the association of haplotypes, as well as of individual locus variants, on disease progression. In cases where a disease association has been observed, but the associated polymorphism may be only a marker for an as yet unidentified polymorphism, we can better focus the search for the functional polymorphism by narrowing down the association to specific haplotypes. Therefore we have developed a haplotype estimation program whose output includes code for survival analysis in the computer program, SAS, allowing rapid survival analysis with haplotypes as explanatory variables. On the genomic scale, we completed a study of 5048 autosomal short tandem repeat loci in homogeneous populations in the CEPH mapping pedigree, in an attempt to measure the ?background linkage disequilibrium? present in a panmictic human population. Approximately 4% of pairs of loci separated by less than 4 cM showed linkage disequilibrium, with the disequilibrium being proportional to the inverse of the recombination distance between the markers. A locus by locus 5cM sliding window analysis across 22 autosomes revealed 10 genomic segments (2.2-6.4 cM), of elevated multilocus linkage disequilibrium. These segments, which include HLA on chromosome 6, may be indicators of selective sweeps in recent evolutionary history, highlighting genome segments of particular evolutionary consequence. AIDS Resistance and Progression to AIDS - disease association, forensics, genetic differentiation, Genetic Diversity, Major histocompatibility Complex, microsatellites, Polymorphism, recombination, - Neither Human Subjects nor Human Tissues