Kaplan N L, Hill W G, Weir B S
Statistics and Biomathematics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Am J Hum Genet. 1995 Jan;56(1):18-32.
Until recently, attempts to map disease genes on the basis of population associations with linked markers have been based on expected values of linkage disequilibrium. These methods suffer from the large variances imposed on disequilibrium measures by the evolutionary process, but a more serious problem for many diseases is that they assume an equilibrium population. For diseases that arose only a few hundred generations ago, it is more appropriate to concentrate on the initial growth phase of the disease. We invoke a Poisson branching process for this early growth, and estimate the likelihood for the recombination fraction between marker and disease loci, on the basis of simulated disease populations. The limits of the resulting support intervals for the recombination fraction vary inversely with the age of the disease in generations. We illustrate the procedure with data on cystic fibrosis and diastrophic dysplasia, for which the method appears appropriate, and for Friedreich ataxia and Huntington disease, for which it does not. A valuable aspect of the method is the ability in some cases to compare likelihoods of the three orders for a disease locus and two linked marker loci.
直到最近，基于与连锁标记的群体关联来定位疾病基因的尝试都是基于连锁不平衡的期望值。这些方法受到进化过程给不平衡测量带来的巨大方差的影响，但对许多疾病来说，更严重的问题是它们假定群体处于平衡状态。对于仅在几百代之前出现的疾病，关注疾病的初始增长阶段更为合适。我们针对这种早期增长引入泊松分支过程，并基于模拟的疾病群体估计标记与疾病位点之间重组率的似然性。所得重组率支持区间的界限与以代计的疾病年龄成反比。我们用囊性纤维化和肢端发育不良的数据说明了该程序，该方法似乎适用于这些疾病，而对于弗里德赖希共济失调和亨廷顿病则不适用。该方法的一个有价值的方面是在某些情况下能够比较疾病位点和两个连锁标记位点的三种排序的似然性。
