Taylor J F, Abbitt B, Walter J P, Davis S K, Jaques J T, Ochoa R F
Department of Animal Science, Texas A&M University, College Station 77843.
Genetics. 1993 Nov;135(3):855-68. doi: 10.1093/genetics/135.3.855.
beta-Mannosidosis is a lethal lysosomal storage disease inherited as an autosomal recessive in man, cattle and goats. Laboratory assay data of plasma beta-mannosidase activity represent a mixture of homozygous normal and carrier genotype distributions in a proportion determined by genotype frequency. A maximum likelihood approach employing data transformations for each genotype distribution and assuming a diallelic model of inheritance is described. Estimates of the transformation and genotype distribution parameters, gene frequency, genotype fitness and carrier probability were obtained simultaneously from a sample of 2,812 observations on U.S. purebred Salers cattle with enzyme activity, age, gender, month of pregnancy, month of testing, and parents identified. Transformations to normality were not required, estimated gene and carrier genotype frequencies of 0.074 and 0.148 were high, and the estimated relative fitness of heterozygotes was 1.36. The apparent overdominance in fitness may be due to a nonrandom sampling of progeny genotypes within families. The mean of plasma enzyme activity was higher for males than females, higher in winter months, lower in summer months and decreased with increased age. Estimates of carrier probabilities indicate that the test is most effective when animals are sampled as calves, although effectiveness of the plasma assay was less for males than females. Test effectiveness was enhanced through averaging repeated assays of enzyme activity on each animal. Our approach contributes to medical diagnostics in several ways. Rather than assume underlying normality for the distributions comprising the mixture, we estimate transformations to normality for each genotype distribution simultaneously with all other model parameters. This process also excludes potential biases due to data preadjustment for systematic effects. We also provide a method for partitioning phenotypic variation within each genotypic distribution which allows an assessment of the value of repeat measurements of the predictive variable for genotype assignment.
β-甘露糖苷贮积症是一种致死性溶酶体贮积病，在人类、牛和山羊中以常染色体隐性方式遗传。血浆β-甘露糖苷酶活性的实验室检测数据代表了纯合正常和携带者基因型分布的混合，其比例由基因型频率决定。本文描述了一种最大似然法，该方法对每种基因型分布采用数据转换，并假设为双等位基因遗传模型。从2812例具有酶活性、年龄、性别、怀孕月份、检测月份且已确定亲本的美国纯种萨勒斯牛样本中，同时获得了转换和基因型分布参数、基因频率、基因型适合度和携带者概率的估计值。无需进行正态转换，估计的基因频率和携带者基因型频率分别为0.074和0.148，较高，估计的杂合子相对适合度为1.36。适合度方面明显的超显性可能是由于家系内子代基因型的非随机抽样所致。血浆酶活性的平均值男性高于女性，冬季较高，夏季较低，且随年龄增长而降低。携带者概率的估计表明，当动物作为犊牛进行采样时，该检测最为有效，尽管血浆检测对雄性动物的有效性低于雌性动物。通过对每只动物的酶活性重复检测进行平均，提高了检测的有效性。我们的方法在几个方面有助于医学诊断。我们不是假设构成混合物的分布具有潜在的正态性，而是与所有其他模型参数同时估计每种基因型分布的正态转换。这个过程还排除了由于对系统效应进行数据预调整而产生的潜在偏差。我们还提供了一种方法，用于划分每个基因型分布内的表型变异，这使得能够评估预测变量的重复测量对于基因型分配的价值。
