A method for fine mapping quantitative trait loci in outbred animal stocks
A method for fine mapping quantitative trait loci in outbred animal stocks
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DOI：
10.1073/pnas.230304397
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发表时间：
2000-11-07
影响因子：
11.1
通讯作者：
Flint, J
中科院分区：
文献类型：
--
作者：
Mott, R;Talbot, CJ;Flint, J
动物数量性状基因座（QTL）的高分辨率定位一直是一个难题，因为在近交系间杂交中检测到的大效应值往往是由许多连锁的QTL引起的，而每个QTL的效应都很小。在一项关于小鼠恐惧的研究中，我们已经证明了在遗传异质性群体（HS）中精细定位小效应QTL是可能的。这一策略是一个强大的通用精细定位QTL的方法，只要在形成HS的自交系之间的杂交中检测到的QTL可以在HS中可靠地检测到。我们在这里表明，单标记关联分析确定只有两个五个QTL预计将在HS分离，显然限制了战略的实用性精细绘图。我们解决这个问题的多点分析，分配的概率，等位基因下降，从每个祖先在HS。该分析不使用谱系，而是需要有关HS创始人单倍型的信息。用这种方法，我们绘制了所有三个以前未检测到的基因座[染色体（Chr.）1 logP 4.9。10 logP 6.0，15 logP 4.0]。我们发现，单标记关联检测QTL失败的原因是它无法区分相反的表型效应时，他们发生在同一个标记等位基因。我们已经开发出一种强大的方法，精细定位QTL在遗传异质性动物，并建议它现在是具有成本效益的进行全基因组的高分辨率分析的复杂性状在同一组小鼠平行。
High-resolution mapping of quantitative trait loci (QTL) in animals has proved to be difficult because the large effect sizes detected in crosses between inbred strains are often caused by numerous linked QTLs, each of small effect. In a study of fearfulness in mice, we have shown it is possible to fine map small-effect QTLs in a genetically heterogeneous Stock (HS). This strategy is a powerful general method of fine mapping QTLs, provided QTLs detected in crosses between inbred strains that formed the HS can be reliably detected in the HS. We show here that single-marker association analysis identifies only two of five QTLs expected to be segregating in the HS and apparently limits the strategy's usefulness for fine mapping. We solve this problem with a multipoint analysis that assigns the probability that an allele descends from each progenitor in the HS. The analysis does not use pedigrees but instead requires information about the HS founder haplotypes. With this method we mapped all three previously undetected loci [chromosome (Chr.) 1 logP 4.9. Chr. 10 logP 6.0, Chr. 15 logP 4.0]. We show that the reason for the failure of single-marker association to detect QTLs is its inability to distinguish opposing phenotypic effects when they occur on the same marker allele. We have developed a robust method of fine mapping QTLs in genetically heterogeneous animals and suggest it is now cost effective to undertake genome-wide high-resolution analysis of complex traits in parallel on the same set of mice.