THE GENETIC BASIS OF COMPLEX TRAITS

复杂性状的遗传基础

• 批准号: 7723454
• 负责人: SUDHA K IYENGAR
• 金额: $ 0.45万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723454
• 关键词: Accounting; Alleles; Biological; Biological Assay; Cloning; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Sequence; Disease; Disease susceptibility; Frequencies; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Goals; Grant; Human; Human Genome Project; Influentials; Institution; Maps; Methods; Mutation; Population; Predisposition; Range; Research; Research Personnel; Resources; Review Literature; Source; Therapeutic Intervention; Time; United States National Institutes of Health; Variant; Wages; base; clinical application; cost; design; human disease; positional cloning; prognostic; success; trait

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the Human Genome Project and the subsequent HapMap Project was to accelerate the pace at which genes for complex human traits were discovered. Elated by the early successes from cloning disease genes for monogenic disorders, the architects of the projects reasoned that complex human diseases were tractable to positional cloning methods. However, a schism emerged in the field, with hot debates regarding two competing hypotheses being publicly waged. These opposing hypotheses pertained to the anticipated allelic spectrum and frequency of disease variants associated with common, complex disease. The common disease, common variant hypothesis (CD/CV) stated that a few common allelic variants could account for the genetic variance in disease susceptibility, whereas the rare variant (CD/RV) hypothesis stated that DNA sequence variation at any gene causing disease could encompass a wide range of possibilities, with the most extreme being that each mutation is only found once in the population. The practical consequence of the debate can be broken into two parts. If the CD/CV hypothesis is true, then application of the positional cloning paradigm to map disease genes would be eminently more feasible, as a common allele would be easier to locate. Conversely, if rare variants cause common disease, then identifying these genetic susceptibility variants would be challenging. Whether a disease is caused by rare or common alleles will have an impact on clinical applications, such as designing prognostic assays, or planning therapeutic interventions; fewer susceptibility alleles will simplify assay design, and the associated reduction in costs would amortize if a universally applicable therapy can be deployed. A current review of the literature suggests that both these hypotheses are correct, depending on the gene and disease examined. Although the controversial debate is revived with the identification of each new disease gene, the time has come to integrate both hypotheses in a manner that best explains biological variation in natural populations. The allelic spectrum of variation in a particular gene may be better explained by one of the two hypotheses but, for a multifactorial trait, a composite encompassing all influential genes needs to be constructed.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 人类基因组项目和随后的HAPMAP项目的目标是加快发现复杂人类特征的基因的速度。由于克隆疾病基因对单基因疾病的早期成功，该项目的建筑师认为复杂的人类疾病是可以通过位置克隆方法处理的。但是，该领域出现了一个分裂，关于公开提出的两个相互竞争的假设的热门辩论。这些相反的假设与与常见的复杂疾病相关的预期等位基因谱和疾病变异的频率有关。常见疾病，常见的变体假设（CD/CV）指出，一些常见的等位基因变异可以解释疾病易感性的遗传差异，而稀有变体（CD/RV）假设表示，任何基因疾病的DNA序列变化都可以包括每种疾病的广泛范围，而每种疾病的范围都很广，并且只有一个人群是一个人群。辩论的实际结果可以分为两个部分。如果CD/CV假设是正确的，那么将位置克隆范式应用于绘制疾病基因的应用将更加可行，因为一个常见的等位基因将更容易定位。相反，如果罕见的变体引起常见疾病，那么确定这些遗传敏感性变异将具有挑战性。疾病是由罕见或普通等位基因引起的，会对临床应用产生影响，例如设计预后测定或计划治疗干预措施；较少的敏感性等位基因将简化测定设计，如果可以部署普遍适用的治疗，相关的成本降低将摊销。目前对文献的评论表明，这两个假设都是正确的，具体取决于所检查的基因和疾病。尽管有争议的辩论是通过鉴定出每个新疾病基因的鉴定而复兴的，但现在是时候以最好的方式将这两个假设整合到最能解释自然种群的生物学变化的方式。特定基因变异的等位基因谱可以通过两个假设之一来更好地解释，但是，对于多因素性状，需要构建包含所有有影响力基因的复合材料。