TY - JOUR

T1 - Linkage analysis in the presence of errors I

T2 - Complex-valued recombination fractions and complex phenotypes

AU - Göring, Harald H.H.

AU - Terwilliger, Joseph D.

N1 - Funding Information:
A Hitchings-Elion Fellowship from the Burroughs-Wellcome Fund (to J.D.T.) is gratefully acknowledged, as is grant HG00008 from the National Institute of Health to Jürg Ott (thesis advisor of H.H.H.G.).

PY - 2000

Y1 - 2000

N2 - Linkage is a phenomenon that correlates the genotypes of loci, rather than the phenotypes of one locus to the genotypes of another. It is therefore necessary to convert the observed trait phenotypes into trait-locus genotypes, which can then be analyzed for coinheritance with marker-locus genotypes. However, if the mode of inheritance of the trait is not known accurately, this conversion can often result in errors in the inferred trait- locus genotypes, which, in turn, can lead to the misclassification of the recombination status of meioses. As a result, the recombination fraction can be overestimated in two-point analysis, and false exclusions of the true trait locus can occur in multipoint analysis. We propose a method that increases the robustness of multipoint analysis to errors in the mode of inheritance assumptions of the trait, by explicitly allowing for misclassification of trait-locus genotypes. To this end, the definition of the recombination fraction is extended to the complex plane, as Θ = θ + εi; θ is the recombination fraction between actual ('real') genotypes of marker and trait loci, and ε is the probability of apparent but false ('imaginary') recombinations between the actual and inferred trait-locus genotypes. 'Complex' multipoint LOD scores are proven to be stochastically equivalent to conventional two-point LOD scores. The greater robustness to modeling errors normally associated with two-point analysis can thus be extended to multiple two-point analysis and multipoint analysis. The use of complex-valued recombination fractions also allows the stochastic equivalence of 'model-based' and 'model-free' methods to be extended to multipoint analysis.

AB - Linkage is a phenomenon that correlates the genotypes of loci, rather than the phenotypes of one locus to the genotypes of another. It is therefore necessary to convert the observed trait phenotypes into trait-locus genotypes, which can then be analyzed for coinheritance with marker-locus genotypes. However, if the mode of inheritance of the trait is not known accurately, this conversion can often result in errors in the inferred trait- locus genotypes, which, in turn, can lead to the misclassification of the recombination status of meioses. As a result, the recombination fraction can be overestimated in two-point analysis, and false exclusions of the true trait locus can occur in multipoint analysis. We propose a method that increases the robustness of multipoint analysis to errors in the mode of inheritance assumptions of the trait, by explicitly allowing for misclassification of trait-locus genotypes. To this end, the definition of the recombination fraction is extended to the complex plane, as Θ = θ + εi; θ is the recombination fraction between actual ('real') genotypes of marker and trait loci, and ε is the probability of apparent but false ('imaginary') recombinations between the actual and inferred trait-locus genotypes. 'Complex' multipoint LOD scores are proven to be stochastically equivalent to conventional two-point LOD scores. The greater robustness to modeling errors normally associated with two-point analysis can thus be extended to multiple two-point analysis and multipoint analysis. The use of complex-valued recombination fractions also allows the stochastic equivalence of 'model-based' and 'model-free' methods to be extended to multipoint analysis.

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U2 - 10.1086/302797

DO - 10.1086/302797

M3 - Article

C2 - 10712220

AN - SCOPUS:0033942602

VL - 66

SP - 1095

EP - 1106

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -