MODEL MISSPECIFICATION AND MULTIPOINT LINKAGE ANALYSIS
MODEL MISSPECIFICATION AND MULTIPOINT LINKAGE ANALYSIS
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DOI：
10.1159/000154047
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发表时间：
1992-01-01
期刊：
影响因子：
1.8
通讯作者：
GIUFFRA, L
中科院分区：
文献类型：
--
作者：
RISCH, N;GIUFFRA, L
成对连锁分析是强大的遗传模型误指定的优势是正确指定的，主要影响是通货膨胀的重组分数。 相比之下，我们表明，多点分析下错误指定的模型是不强大的，当一个假定的疾病位点之间的紧密侧翼标记，潜在的虚假负多点lod分数产生。 这个问题是由于疾病等位基因的分离的不正确归因以及随之而来的侧翼标记之间的（不太可能的）双交换的结论。 作为一种可能的解决方案，我们建议使用高疾病等位基因频率，因为这允许概率为nonsegregation（通过父母纯合性或双交配）。 我们通过分析和分析的系谱数据模拟下的两个位点的异质性模型，使用疾病等位基因频率为0.05的显性情况下和0.25的隐性情况下，是相当强大的生产积极的多点lod分数与近侧翼标记在广泛的条件，包括不同的等位基因频率，上位性，遗传异质性和表型。
Pairwise linkage analysis is robust to genetic model misspecification provided dominance is correctly specified, the primary effect being inflation of the recombination fraction. By contrast, we show that multipoint analysis under misspecified models is not robust when a putative disease locus is placed between close flanking markers, with potentially spuriously negative multipoint lod scores being produced. The problem is due to incorrect attribution of segregation of a disease allele and the consequent conclusion of (unlikely) double crossovers between flanking markers. As a possible solution, we propose the use of high disease allele frequencies, as this allows probabilistically for nonsegregation (through parental homozygosity or dual matings). We show analytically and through analysis of pedigree data simulated under a two-locus heterogeneity model that using a disease allele frequency of 0.05 in the dominant case and 0.25 in the recessive case is quite robust in producing positive multipoint lod scores with close flanking markers across a broad range of conditions including varying allele frequencies, epistasis, genetic heterogeneity and phenocopies.