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实验杂交中的顺序数量性状基因座定位

Sequential quantitative trait locus mapping in experimental crosses.

作者信息

Satagopan Jaya M, Sen Saunak, Churchill Gary A

机构信息

Memorial Sloan-Kettering Cancer Center, USA.

出版信息

Stat Appl Genet Mol Biol. 2007;6:Article12. doi: 10.2202/1544-6115.1264. Epub 2007 Apr 17.

Abstract

The etiology of complex diseases is heterogeneous. The presence of risk alleles in one or more genetic loci affects the function of a variety of intermediate biological pathways, resulting in the overt expression of disease. Hence, there is an increasing focus on identifying the genetic basis of disease by systematically studying phenotypic traits pertaining to the underlying biological functions. In this paper we focus on identifying genetic loci linked to quantitative phenotypic traits in experimental crosses. Such genetic mapping methods often use a one stage design by genotyping all the markers of interest on the available subjects. A genome scan based on single locus or multi-locus models is used to identify the putative loci. Since the number of quantitative trait loci (QTLs) is very likely to be small relative to the number of markers genotyped, a one-stage selective genotyping approach is commonly used to reduce the genotyping burden, whereby markers are genotyped solely on individuals with extreme trait values. This approach is powerful in the presence of a single quantitative trait locus (QTL) but may result in substantial loss of information in the presence of multiple QTLs. Here we investigate the efficiency of sequential two stage designs to identify QTLs in experimental populations. Our investigations for backcross and F2 crosses suggest that genotyping all the markers on 60% of the subjects in Stage 1 and genotyping the chromosomes significant at 20% level using additional subjects in Stage 2 and testing using all the subjects provides an efficient approach to identify the QTLs and utilizes only 70% of the genotyping burden relative to a one stage design, regardless of the heritability and genotyping density. Complex traits are a consequence of multiple QTLs conferring main effects as well as epistatic interactions. We propose a two-stage analytic approach where a single-locus genome scan is conducted in Stage 1 to identify promising chromosomes, and interactions are examined using the loci on these chromosomes in Stage 2. We examine settings under which the two-stage analytic approach provides sufficient power to detect the putative QTLs.

摘要

复杂疾病的病因具有异质性。一个或多个基因座中风险等位基因的存在会影响多种中间生物学途径的功能,从而导致疾病的明显表现。因此,通过系统研究与潜在生物学功能相关的表型特征来确定疾病的遗传基础,受到了越来越多的关注。在本文中,我们专注于在实验杂交中识别与数量表型特征相关的基因座。此类基因定位方法通常采用单阶段设计,即对所有可用受试者上感兴趣的标记进行基因分型。基于单基因座或多基因座模型的基因组扫描用于识别假定的基因座。由于数量性状基因座(QTL)的数量相对于已基因分型的标记数量很可能较少,因此通常采用单阶段选择性基因分型方法来减轻基因分型负担,即仅对具有极端性状值的个体进行标记基因分型。这种方法在存在单个数量性状基因座(QTL)时很有效,但在存在多个QTL时可能会导致大量信息丢失。在这里,我们研究了顺序两阶段设计在实验群体中识别QTL的效率。我们对回交和F2杂交的研究表明,在第一阶段对60%的受试者进行所有标记的基因分型,在第二阶段使用额外的受试者对在20%水平上显著的染色体进行基因分型,并对所有受试者进行测试,提供了一种识别QTL的有效方法,相对于单阶段设计,仅使用70%的基因分型负担,而与遗传力和基因分型密度无关。复杂性状是多个QTL产生主效应以及上位性相互作用的结果。我们提出了一种两阶段分析方法,即在第一阶段进行单基因座基因组扫描以识别有前景的染色体,并在第二阶段使用这些染色体上的基因座检查相互作用。我们研究了两阶段分析方法在何种情况下具有足够的能力来检测假定的QTL。

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