SUP: an extension to SLINK to allow a larger number of marker loci to be simulated in pedigrees conditional on trait values
SUP: an extension to SLINK to allow a larger number of marker loci to be simulated in pedigrees conditional on trait values
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DOI：
10.1186/1471-2156-7-40
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发表时间：
2006-07-03
期刊：
影响因子：
2.9
通讯作者：
Lemire, Mathieu
中科院分区：
文献类型：
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作者：
Lemire, Mathieu
工作背景：随着近年来高通量基因分型技术的发展，使得人类复杂性状的大规模关联作图成为可能，有前途的统计设计和方法已经出现。高效的模拟软件是评估新统计检验性能的关键要素。SLINK是一个灵活的模拟工具，已被广泛用于产生分离和重组过程的标记连锁，并可能与，一个性状基因座，条件性状值在任意系谱。在实践中，它最严重的限制是可以模拟的位点数量很少，因为算法的复杂性与这个数量呈指数关系。我描述了一个两步算法的实现，该算法将与SLINK结合使用，以使大量的标记基因座的模拟与一个性状基因座相连，并以家庭中的性状值为条件，这些位点可能处于连锁不平衡状态。SLINK在第一步中用于以观察到的性状值为条件来模拟性状基因座处的基因型，并且还用于生成模拟等位基因的下降路径的指标。在第二步中，以第一步中模拟的性状基因座基因型为条件，在创始者中产生标记等位基因或单倍型。然后，标记基因座之间的重组过程在遗传路径和性状基因座基因型上有条件地发生。这种两步实现通常比其他设计用于生成与性状基因座相关或可能相关的标记数据的软件在计算上更快。结论：由于所提出的方法使用SLINK来模拟分离过程，因此它受益于其灵活性：这一特点可能是定性的，有可能界定不同的责任类别（其允许模拟基因-环境相互作用或甚至模拟非连锁易感区域之间的多位点效应），或者其可以是定量的和正态分布的。特别是，这个实现是唯一一个可用的，可以产生大量的标记基因座的条件下观察到的数量性状值的一组系谱。
Background: With the recent advances in high-throughput genotyping technologies that allow for large-scale association mapping of human complex traits, promising statistical designs and methods have been emerging. Efficient simulation software are key elements for the evaluation of the properties of new statistical tests. SLINK is a flexible simulation tool that has been widely used to generate the segregation and recombination processes of markers linked to, and possibly associated with, a trait locus, conditional on trait values in arbitrary pedigrees. In practice, its most serious limitation is the small number of loci that can be simulated, since the complexity of the algorithm scales exponentially with this number.Results: I describe the implementation of a two-step algorithm to be used in conjunction with SLINK to enable the simulation of a large number of marker loci linked to a trait locus and conditional on trait values in families, with the possibility for the loci to be in linkage disequilibrium. SLINK is used in the first step to simulate genotypes at the trait locus conditional on the observed trait values, and also to generate an indicator of the descent path of the simulated alleles. In the second step, marker alleles or haplotypes are generated in the founders, conditional on the trait locus genotypes simulated in the first step. Then the recombination process between the marker loci takes place conditionally on the descent path and on the trait locus genotypes. This two-step implementation is often computationally faster than other software that are designed to generate marker data linked to, and possibly associated with, a trait locus.Conclusion: Because the proposed method uses SLINK to simulate the segregation process, it benefits from its flexibility: the trait may be qualitative with the possibility of defining different liability classes (which allows for the simulation of gene-environment interactions or even the simulation of multi-locus effects between unlinked susceptibility regions) or it may be quantitative and normally distributed. In particular, this implementation is the only one available that can generate a large number of marker loci conditional on the set of observed quantitative trait values in pedigrees.