Linkage analysis in the presence of errors II: marker-locus genotyping errors modeled with hypercomplex recombination fractions.
It is well known that genotyping errors lead to loss of power in gene-mapping studies and underestimation of the strength of correlations between trait- and marker-locus genotypes. In two-point linkage analysis, these errors can be absorbed in an inflated recombination-fraction estimate, leaving the test statistic quite robust. In multipoint analysis, however, genotyping errors can easily result in false exclusion of the true location of a disease-predisposing gene. In a companion article, we described a "complex-valued" extension of the recombination fraction to accommodate errors in the assignment of trait-locus genotypes, leading to a multipoint LOD score with the same robustness to errors in trait-locus genotypes that is seen with the conventional two-point LOD score. Here, a further extension of this model to "hypercomplex-valued" recombination fractions (hereafter referred to as "hypercomplex recombination fractions") is presented, to handle random and systematic sources of marker-locus genotyping errors. This leads to a multipoint method (either "model-based" or "model-free") with the same robustness to marker-locus genotyping errors that is seen with conventional two-point analysis but with the advantage that multiple marker loci can be used jointly to increase meiotic informativeness. The cost of this increased robustness is a decrease in fine-scale resolution of the estimated map location of the trait locus, in comparison with traditional multipoint analysis. This probability model further leads to algorithms for the estimation of the lower bounds for the error rates for genomewide and locus-specific genotyping, based on the null-hypothesis distribution of the LOD-score statistic in the presence of such errors. It is argued that those genome scans in which the LOD score is 0 for >50% of the genome are likely to be characterized by high rates of genotyping errors in general.
Göring
H H
HH
Department of Genetics and Development, Columbia University, New York, NY, USA.
Terwilliger
J D
JD
D000465:Algorithms; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008126:Lod Score; D008540:Meiosis / Q000235:genetics; D008957:Models, Genetic; D011995:Recombination, Genetic / Q000235:genetics*; D015203:Reproducibility of Results; D012107:Research Design
D005819:Genetic Markers