Fine mapping of quantitative trait loci (QTL) using linkage and linkage disequilibrium analysis in half-sib designs

The main aim of this study was to investigate and develop linkage map and linkage disequilibrium mapping methods to detect and localize the positions of QTL in outbred livestock populations. The objective of the first study was to investigate the variance component approach (REML) to QTL linkage mapping in half-sib designs and to compare it with the simple regression method. Specifically, the power of QTL detection using the variance component approach and the simple regression method were compared. The empirical power using the regression method was 0.800, 0.918 and 0.978 for 5, 10, and 20 sires, respectively, versus 0.876, 0.978 and 0.992 using REML. The power was 0.740, 0.800, 0.928, and 0.950 using regression versus 0.768, 0.876, 0.942, and 0.974 using REML for QTL variance ratios (lambda) of 0.05, 0.1, 0.2, and 0.3, respectively. The variance component approach showed slightly more potential than the regression method in QTL mapping and is certainly feasible using modern computers for real data sets, even with extensive permutation testing to determine significance levels. The objective of the second study was to investigate the performance of several transmission disequilibrium tests (TDT) for detection of QTL in data structures typical of outbred livestock populations. The empirical power for Q-TDT (quantitative trait loci TDT), 1-TDT (one parent genotype TDT) and S-TDT (sibling based association test) were 0.966, 0.602 and 0.974, respectively, in a large population, versus 0.700, 0.414 and 0.654, respectively, in a small population. The empirical power of these tests were 0.709, 0.287 and 0.634 for a small QTL and a small population. The empirical power for Q-TDT and 1-TDT with a linear model was 0.978 and 0.995, respectively. The results show that the TDT is detecting the QTL when the marker is closely linked to the QTL. The objective of the third study was to develop the linear haplotype sharing transmission disequilibrium test (LHS-TDT) to estimate the precision of the QTL position in half-sib designs and compare it with combined linkage and linkage disequilibrium analysis using the simple regression method and the LHS-TDT. The means of absolute differences (A) of each method were considered in six different scenarios consisting of combinations of a variety of number of markers and the most frequent haplotypes. The mean of A, using the simple regression method, was 4.38 centiMorgan (cM). For these simulation data, the means of A using the LHS-TDT method were less than the simple regression method in all scenarios and equaled 2.48, 1.86, 3.05, 3.02, 3.81 and 3.56 cM for scenarios one to six, respectively. The means of A, using the combined method, equaled 2.91, 2.32, 3.71, 3.75, 4.36 and 4.14 cM for scenarios one to six, respectively. Therefore, for populations similar to the population simulated in this study, the LHS-TDT method was better than either the simple regression method or the combined method for finding the position of QTL.