Genetics. Published Articles Ahead of Print: December 1, 2005, Copyright © 2005
doi:10.1534/genetics.105.048686


A more recent version of this article appeared on March 1, 2006.

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

Laura Grapes 1, Mehmet Z. Firat 2, Jack C.M. Dekkers 1, Max F. Rothschild 1 and Rohan Luigi Fernando 1*

1 Iowa State University
2 Akdeniz University

* To whom correspondence should be addressed. E-mail: rohan{at}iastate.edu.

Submitted on July 22, 2005
Revised on September 14, 2005
Accepted on 2 November 2005


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) in order 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 one, two, four, six or all ten available markers were fit as a "sliding window" across the QTL region under ideal and non-ideal simulated population conditions. It was found that using haplotypes of four or six markers as a sliding "window" resulted in the greatest mapping accuracy in 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 four or six markers resulted in greater discrimination of IBD probabilities between positions while maintaining sufficient accuracy of IBD probabilities to detect the QTL. Fitting IBD probabilities based on a single marker resulted in the worst mapping accuracy in 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 four to six 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.

Key Words: QTL, fine mapping, linkage disequilibrium mapping




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