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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人类基因组计划和随后的人类基因组单体型图计划的目标是加快发现复杂人类特征基因的步伐。这些项目的设计师们被克隆单基因疾病的疾病基因的早期成功所鼓舞，认为复杂的人类疾病可以通过定位克隆方法来控制。然而，该领域出现了分裂，关于两个相互竞争的假设的激烈辩论正在公开进行。这些相反的假设涉及与常见的复杂疾病相关的疾病变异的预期等位基因谱和频率。常见疾病，常见变异假说（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变异，而罕见变异（CD/RV）假说指出，任何导致疾病的基因的DNA序列变异都可能包含广泛的可能性，最极端的是每个突变在人群中只发现一次。辩论的实际结果可以分为两部分。如果CD/CV假说是正确的，那么应用定位克隆模式来定位疾病基因将是非常可行的，因为一个共同的等位基因将更容易定位。相反，如果罕见变异导致常见疾病，那么识别这些遗传易感性变异将具有挑战性。疾病是由罕见还是常见等位基因引起的将对临床应用产生影响，例如设计预后测定或规划治疗干预;较少的易感性等位基因将简化测定设计，并且如果可以部署普遍适用的疗法，则相关的成本降低将被摊销。目前的文献综述表明，这两种假设都是正确的，这取决于所检查的基因和疾病。虽然随着每一个新的疾病基因的鉴定，有争议的辩论又重新开始，但现在是时候以最好的方式解释自然人群中的生物变异来整合这两种假设了。在一个特定的基因的等位基因谱的变化可能会更好地解释了两个假设之一，但对于一个多因子性状，一个复合材料，包括所有有影响力的基因需要构建。