THE GENETIC BASIS OF COMPLEX TRAITS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类基因组计划和随后的HapMap计划的目标是加快发现复杂人类特征基因的速度。对克隆单基因疾病疾病基因的早期成功感到高兴，这些项目的设计者们推理说，复杂的人类疾病可以通过位置克隆方法解决。然而，该领域出现了分歧，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预期等位基因谱和疾病变异的频率。常见疾病，常见变异假说(CD/CV)指出，少数常见等位基因变异可以解释疾病易感性的遗传差异，而罕见变异(CD/RV)假说指出，任何致病基因的DNA序列变异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。这场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，那么应用位置克隆范例来绘制疾病基因图谱将明显更可行，因为共同的等位基因将更容易定位。相反，如果罕见的变异导致常见疾病，那么识别这些遗传易感变异将是具有挑战性的。无论疾病是由罕见的还是常见的等位基因引起的，都将对临床应用产生影响，如设计预后分析或计划治疗干预措施；较少的易感等位基因将简化分析设计，如果能够部署普遍适用的治疗方法，相关成本的降低将摊销。目前对文献的回顾表明，根据所检查的基因和疾病，这两种假说都是正确的。尽管随着每一种新疾病基因的确定，这场有争议的辩论重新燃起，但现在是时候以最好地解释自然种群中的生物变异的方式整合这两种假说了。一个特定基因的等位基因变异谱可能可以用两个假设中的一个更好地解释，但对于一个多因素性状，需要构建一个包含所有有影响的基因的复合体。

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.