Using haplotypes for the prediction of allelic identity to fine-map QTL: Characterization and properties

Abstract

Background: Numerous methods have been developed over the last decade to predict allelic identity at unobserved loci between pairs of chromosome segments along the genome. These loci are often unobserved positions tested for the presence of quantitative trait loci (QTL). The main objective of this study was to understand from a theoretical standpoint the relation between linkage disequilibrium (LD) and allelic identity prediction when using haplotypes for fine mapping of QTL. In addition, six allelic identity predictors (AIP) were also compared in this study to determine which one performed best in theory and application. Results: A criterion based on a simple measure of matrix distance was used to study the relation between LD and allelic identity prediction when using haplotypes. The consistency of this criterion with the accuracy of QTL localization, another criterion commonly used to compare AIP, was evaluated on a set of real chromosomes. For this set of chromosomes, the criterion was consistent with the mapping accuracy of a simulated QTL with either low or high effect. As measured by the matrix distance, the best AIP for QTL mapping were those that best captured LD between a tested position and a QTL. Moreover the matrix distance between a tested position and a QTL was shown to decrease for some AIP when LD increased. However, the matrix distance for AIP with continuous predictions in the [0,1] interval was algebraically proven to decrease less rapidly up to a lower bound with increasing LD in the simplest situations, than the discrete predictor based on identity by state between haplotypes (IBS hap), for which there was no lower bound. The expected LD between haplotypes at a tested position and alleles at a QTL is a quantity that increases naturally when the tested position gets closer to the QTL. This behavior was demonstrated with pig and unrelated human chromosomes. Conclusions: When the density of markers is high, and therefore LD between adjacent loci can be assumed to be high, the discrete predictor IBS hap is recommended since it predicts allele identity correctly when taking LD into account.