Abstract
In recent years, several F2 crosses between outbred lines of livestock have been developed to identify quantitative trait loci (QTL). These populations are valuable for further genetic analysis, including positional candidate gene loci (CGL). Analysis of CGL in F2 populations is, however, hindered by extensive between-breed linkage disequilibrium (LD). The objectives here were to develop and evaluate three tests for CGL in simulated F2 breed-cross populations. 1) A standard association test, based on the fixed effect of CGL genotype. This test was significant for CGL at considerable distances from the QTL. 2) A marker-assisted association test, based on a test at the CGL of the fixed effect of CGL genotype in a breed-cross QTL interval mapping model. This removed the impact of between-breed LD, but was not powerful in detecting CGL closely linked to the QTL, unless the CGL was the QTL. 3) An F-drop test, comparing F ratios for a QTL at the CGL with and without the CGL included as fixed effect. It had low power to distinguish close from distant CGL. Power to distinguish two CGL within 10 cM from the QTL was limited and little improved by including QTL effects associated with markers to remove between-breed LD, although the power was greater when one of the CGL was the causative mutation. Therefore, while we conclude that candidate gene tests in QTL mapping populations must be interpreted with caution, we now have a clearer picture of the value of candidate gene tests in these populations.
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Acknowledgements
This work was supported by CSREES IFAFS # 00-52100-9610. The authors thank Dan Nettleton for statistical advice and Radu Totir, Hauke Thomsen, Massoud Malek, Petek Settar, David Casey, Jing Wang, Joseph McElroy, and Napapan Chaiwong for helpful discussion and suggestions.
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Appendix
Appendix
The between- and within-breed LD in the simulated F2 populations is derived. Following Lo et al. (1993), the expected between-breed LD between the QTL and a candidate gene locus (CGL) in the F2 is ¼(1 − 2r)(P SireQ − P DamQ )(P SireC − P DamC ), where r is the recombination rate between the QTL and the CGL, and P Sirek and P Damk are the frequencies of allele k in the F0 sires and dams, respectively. Because alleles Q and C were simulated with the same frequencies in the F−20, their frequencies in the F0 are expected to be the same, that is, P SireQ = P SireC = ½ (P AQ +P BQ ) and P DamQ = P DamC = ½ (P CQ +P DQ ), where P ik is the frequency of allele k in ancestral breed i in the F−20. Therefore, between-breed LD in the F2 was calculated as:
The LD that existed in the F−18 (Fig. 2) from the cross A × B in the F−20 is ¼(1 − 2r)(P AQ −P BQ )(P AC − P BC ) (Lo et al. 1993), which equals ¼(1 − 2r)(P AQ − P BQ )2 since frequencies of alleles Q and C were equal in the F−20. This LD decayed each generation by a factor (1 − r). Therefore, the LD that existed in the F0 sires is (1 − r)18[¼(1 − 2r)(P AQ -P BQ )2].
Similarly, the LD that existed in the F0 dams is (1 − r)18[¼(1 − 2r)(P CQ − P DQ )2], which equals (1 − r)18[¼(1 − 2r)(P AQ − P BQ )2] because P AQ − P BQ = P DQ − P CQ (Table 1). From the F0 to the F2, this LD was further reduced by (1−r)2, therefore, the expected within-breed LD between the QTL and a CGL in the F2 is:
Setting r = 0 in Eq [1], the expected between-breed LD within the QTL in the F2 is:
The within-breed LD for the QTL with itself in the F2 originated not only from the cross of ancestral breeds in the F−20, but also from the LD that existed in ancestral breed i, which is equal to P iQ (1 − P iQ ). Setting r = 0 in Eq [2] and adding the average LD within breeds A and B in the F−20, the expected within-breed LD for the QTL in the F2 is:
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Zhao, H., Rothschild, M.F., Fernando, R.L. et al. Tests of candidate genes in breed cross populations for QTL mapping in livestock . Mamm Genome 14, 472–482 (2003). https://doi.org/10.1007/s00335-002-2215-y
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DOI: https://doi.org/10.1007/s00335-002-2215-y