Optimal haplotype structure for linkage disequilibrium-based fine mapping of quantitative trait loci using identity by descent

Abstract

A linkage disequilibrium-based method for fine mapping quantitative trait loci (QTL) has been described that uses similarity between individuals' marker haplotypes to determine if QTL alleles are identical by descent (IBD) to model covariances among individuals' QTL alleles for a mixed linear model. Mapping accuracy with this method was found to be sensitive to the number of linked markers that was included in the haplotype when fitting the model at a putative position of the QTL. The objective of this study was to determine the optimal haplotype structure for this IBD-based method for fine mapping a QTL in a previously identified QTL region. Haplotypes consisting of 1, 2, 4, 6, or all 10 available markers were fit as a "sliding window" across the QTL region under ideal and nonideal simulated population conditions. It was found that using haplotypes of 4 or 6 markers as a sliding "window" resulted in the greatest mapping accuracy under nearly all conditions, although the true IBD state at a putative QTL position was most accurately predicted by IBD probabilities obtained using all markers. Using 4 or 6 markers resulted in greater discrimination of IBD probabilities between positions while maintaining sufficient accuracy of IBD probabilities to detect the QTL. Fitting IBD probabilities on the basis of a single marker resulted in the worst mapping accuracy under all conditions because it resulted in poor accuracy of IBD probabilities. In conclusion, for fine mapping using IBD methods, marker information must be used in a manner that results in sensitivity of IBD probabilities to the putative position of the QTL while maintaining sufficient accuracy of IBD probabilities to detect the QTL. Contrary to expectation, use of haplotypes of 4-6 markers to derive IBD probabilities, rather than all available markers, best fits these criteria. Thus for populations similar to those simulated here, optimal mapping accuracy for this IBD-based fine-mapping method is obtained with a haplotype structure including a subset of all available markers.

Figure 1.

The correlation between IBD probabilities for the true QTL position and all other putative QTL positions estimated using haplotypes of 1, 2, 4, or 10 markers. With a haplotype size of 1, the true QTL position was at position 5. Results are based on 1000 replicates of the default scenario with a marker spacing of 1 cM. (▴) IBD-1, (x) IBD-2, (⋄) IBD-4, (▪) IBD-10, (∇) QTL position.

Figure 2.

The log-likelihood for each putative QTL position averaged across 1000 replicates of the default scenario with marker spacing of 1 cM. (▴) IBD-1, (x) IBD-2, (⋄) IBD-4, (•) IBD-6, (□) IBD-10, (∇) QTL position.