Devlin B, Risch N, Roeder K
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, 15213, USA.
Genomics. 1996 Aug 15;36(1):1-16. doi: 10.1006/geno.1996.0419.
The pattern of linkage disequilibrium between a disease locus and a set of marker loci has been shown to be a useful tool for geneticists searching for disease genes. Several methods have been advanced to utilize the pairwise disequilibrium between the disease locus and each of a set of marker loci. However, none of the methods take into account the information from all pairs simultaneously while also modeling the variability in the disequilibrium values due to the evolutionary dynamics of the population. We propose a Composite Likelihood (CL) model that has these features when the physical distances between the marker loci are known or can be approximated. In this instance, and assuming that there is a single disease mutation, the CL model depends on only three parameters, the recombination fraction between the disease locus and an arbitrary marker locus, theta, the age of the mutation, and a variance parameter. When the CL is maximized over a grid of theta, it provides a graph that can direct the search for the disease locus. We also show how the CL model can be generalized to account for multiple disease mutations. Evolutionary simulations demonstrate the power of the analyses, as well as their potential weaknesses. Finally, we analyze the data from two mapped diseases, cystic fibrosis and diastrophic dysplasia, finding that the CL method performs well in both cases.
疾病位点与一组标记位点之间的连锁不平衡模式已被证明是遗传学家寻找疾病基因的有用工具。已经提出了几种方法来利用疾病位点与一组标记位点中每个位点之间的成对不平衡。然而，这些方法都没有同时考虑来自所有对的信息，也没有对由于群体进化动态导致的不平衡值的变异性进行建模。当标记位点之间的物理距离已知或可以近似时，我们提出了一种具有这些特征的复合似然（CL）模型。在这种情况下，并假设存在单个疾病突变，CL模型仅依赖于三个参数，疾病位点与任意标记位点之间的重组率θ、突变的年龄以及一个方差参数。当CL在θ的网格上最大化时，它会提供一个可以指导疾病位点搜索的图形。我们还展示了如何将CL模型推广以考虑多个疾病突变。进化模拟证明了分析的能力及其潜在弱点。最后，我们分析了两种已定位疾病（囊性纤维化和脊柱骨骺发育不良）的数据，发现CL方法在这两种情况下都表现良好。
