Approaches to Gene Mapping Development and Applications

基因图谱开发和应用的方法

• 批准号: 6558947
• 负责人: STEPHEN J O'BRIEN
• 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/6558947
• 关键词: Asians; European; animal genetic material tag; disease /disorder proneness /risk; family genetics; gene frequency; genetic mapping; genetic markers; genetic polymorphism; genetic recombination; human genetic material tag; human population genetics; immunogenetics; linkage disequilibriums; neoplasm /cancer genetics; population genetics; quantitative trait loci

A large number of heritable traits are not amenable to pedigree analysis because of incomplete penetrance, the requirement for a environmental factor, or the infeasibility of collecting genotypic data from relatives of affected individuals. Such traits must be localized by population-genetic-association studies. However, the detection of polymorphic genes that influence quantitative traits, disease states, and other characters by association analysis depends on the persistence of measurable linkage disequilibrium (i.e., haplotype-allele association). An approach to the maximization of the linkage-disequilibrium for gene-localization studies involves mapping by admixture linkage disequilibrium (MALD), whereby populations composed of recently mixed ethnic groups display transient linkage disequilibrium over longer centimorgan (cM) intervals for at least 20 generations as compared to the panmictic founder populations from which the admixed ethnic group was derived. Theoretical and simulation studies that predict the limits of population parameters influencing MALD assessment have been described by this and other laboratories. A MALD map was produced for 744 short tandem repeat polymorphisms (STR) distributed throughout the human genome containing assessments of allele frequencies in African Americans, Asians, European Americans, and Hispanics. This allele frequency data was used to compute differences in composite delta, log-likelihood ratios, and I* between ethnic groups. This should allow the selection of markers suitable for case-control disease association studies in admixed populations such as African Americans or Hispanics since high values of these measures increase the likelihood of detecting association between a marker and a disease locus. We have observed linkage disequilibrium (LD) in African Americans between the FY locus on chromosome 1 and flanking STR markers as well as with AT3, a diallelic polymorphism located over 20 cM from FY. The sign of the disequilibrium coefficient between the FY and AT3 was consistent with admixture LD since the alleles found to be in positive association (i.e., the corresponding haplotypes occurred at a frequency significantly greater than the product of the corresponding allele frequencies) were from the same ancestral populations. We now have found linkage disequilibrium in African Americans between the GC locus on chromosome 4 and flanking STRs demonstrating that admixture LD is a general phenomenon.

由于外显率不完全、需要环境因素或无法从受影响个体的亲属收集基因型数据，大量遗传性状不适合进行谱系分析。这些特征必须通过群体遗传关联研究来定位。然而，通过关联分析检测影响数量性状、疾病状态和其他性状的多态性基因取决于可测量的连锁不平衡（即单倍型-等位基因关联）的持续存在。基因定位研究中连锁不平衡最大化的一种方法涉及通过混合连锁不平衡 (MALD) 进行绘图，其中由最近混合的种族群体组成的种群在较长的厘摩 (cM) 间隔内表现出短暂的连锁不平衡至少 20 代，如下所示与混杂族群所源自的恐慌始祖人群相比。本实验室和其他实验室已经描述了预测影响 MALD 评估的总体参数限制的理论和模拟研究。 针对分布在整个人类基因组中的 744 个短串联重复多态性 (STR) 生成了 MALD 图谱，其中包含对非裔美国人、亚洲人、欧洲裔美国人和西班牙裔美国人等位基因频率的评估。该等位基因频率数据用于计算种族组之间复合增量、对数似然比和 I* 的差异。这应该允许选择适合混合人群（例如非裔美国人或西班牙裔）的病例对照疾病关联研究的标记，因为这些测量值的高值增加了检测标记与疾病位点之间关联的可能性。 我们在非裔美国人中观察到 1 号染色体上的 FY 基因座与侧翼 STR 标记以及 AT3（距离 FY 超过 20 cM 的双等位基因多态性）之间存在连锁不平衡 (LD)。 FY 和 AT3 之间的不平衡系数的符号与混合物 LD 一致，因为发现正相关的等位基因（即，相应的单倍型出现的频率显着大于相应等位基因频率的乘积）来自相同的祖先人群。我们现在发现非裔美国人中 4 号染色体上的 GC 位点和侧翼 STR 之间存在连锁不平衡，这表明混合 LD 是一种普遍现象。