Graphical modeling of the joint distribution of alleles at associated loci
Graphical modeling of the joint distribution of alleles at associated loci
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DOI：
10.1086/421249
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发表时间：
2004-06-01
影响因子：
9.8
通讯作者：
Camp, NJ
中科院分区：
文献类型：
--
作者：
Thomas, A;Camp, NJ
成对连锁不平衡，单倍型块，重组热点提供了一个在近端基因座的等位基因状态之间的依赖性和独立性的模式的部分描述。在总尺度上，重组和空间关系占主导地位，协会可以合理地描述这些条款。然而，在当前高密度地图的精细尺度上，突变过程也很重要，并且在基因座之间产生关联，这些关联独立于物理排序，并且不能用成对关联措施来概括。图形建模提供了一个标准的统计框架，用于精确描述这些复杂的随机数据。虽然图形模型通常用于假设自然导致特定模型的情况下，但不太为人所知的是，图形模型的估计也是一个发达的领域。我们展示了如何可分解的图形模型可以适合密集的遗传数据。目标函数是模型的对数似然最大化，惩罚模型的自由度的倍数。我们还描述了如何可以修改，将事先信息的轨迹位置。模拟退火用于找到好的解决方案。这种方法的部分吸引力在于，分类表型可以包括在同一分析中，并且与多态性的关联可以与基因座间关联联合评估。我们说明了我们的方法与ELAC2基因的25个位点的基因型数据。结果包含三阶和四阶位点的相互作用，并表明，在这个密度的标记，连锁不平衡是不是一个简单的函数的物理距离。图形模型提供了更多的灵活性来表达这些功能的等位基因的联合分布比单调函数连接物理和遗传图谱。
Pairwise linkage disequilibrium, haplotype blocks, and recombination hotspots provide only a partial description of the patterns of dependences and independences between the allelic states at proximal loci. On the gross scale, where recombination and spatial relationships dominate, the associations can be reasonably described in these terms. However, on the fine scale of current high-density maps, the mutation process is also important and creates associations between loci that are independent of the physical ordering and that can not be summarized with pairwise measures of association. Graphical modeling provides a standard statistical framework for characterizing precisely these sorts of complex stochastic data. Although graphical models are often used in situations in which assumptions lead naturally to specific models, it is less well known that estimation of graphical models is also a developed field. We show how decomposable graphical models can be fitted to dense genetic data. The objective function is the maximized log likelihood for the model penalized by a multiple of the model's degrees of freedom. We also describe how this can be modified to incorporate prior information of locus position. Simulated annealing is used to find good solutions. Part of the appeal of this approach is that categorical phenotypes can be included in the same analysis and association with polymorphisms can be assessed jointly with the interlocus associations. We illustrate our method with genotypic data from 25 loci in the ELAC2 gene. The results contain third- and fourth-order locus interactions and show that, at this density of markers, linkage disequilibrium is not a simple function of physical distance. Graphical models provide more flexibility to express these features of the joint distribution of alleles than do monotonic functions connecting physical and genetic maps.