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Determining QTL allele frequency in the dam population

Although two possible methods for estimating QTL allele frequency were proposed, Weller et al., (2002) presented an attractive method based on a modification of the granddaughter design (MGDD). In the MGDD, the maternal granddaughters of a QTL-heterozygous sire are genotyped, and the average trait value of three daughter genotype groups obtained:
- Group 1 that did not receive either of their MGS chromosomes for the region containing the QTL. These represent mean population value according to population allele frequencies at the QTL;
- Group 2 that received the positive QTL region from their MGS. These represent a group with higher frequency of the positive QTL allele than Group 1;
- Group 3 that received the negative QTL region from their MGS. These represent a group with higher frequency of the negative QTL allele than Group 1.

QTL allele frequencies are obtained by comparing mean trait values of the groups. A program was written in Fortran to trace haplotypes from the MGS to his granddaughters. Two data sets, from RP1 and RP4 were analysed. In addition, an extension of the MGDD design which included information on MGS that were homozygous at the QTL was developed and evaluated by simulation.

The haplotype tracing program. Methods: The program is a modification of Weller et al., 2002 [ 4], allowing for haplotypes of two or three markers. The haplotype transmitted to the granddaughter from the sire of the daughter is first determined, and from this the haplotype transmitted from the dam. In the next step, and differently from Weller et al. (2002), a probabilistic algorithm is used to define the probability that the granddaughter inherited either of the QTL alleles of the grandsire, or the haplotype transmitted from the granddam. If it is not possible to state with high probability either of those options, the granddaughter is considered non-informative and is not included in the overall analysis. Results: The program was able to determine the inherited MGS QTL allele for 45% of granddaughters in RP1, and 63% of the granddaughters RP4. QTL allele frequency estimation. Materials and Methods.

Two sires denoted C and S1, heterozygous at a QTL affecting PP on BTA20 were chosen for analysis. Genotypes were obtained for 431 grand daughters of sire S1 and 303 grand daughters of sire C; the program provided information on QTL transmission for 461 granddaughters across both MGS. Analyses were performed with proc GLM in SAS. QTL allele frequencies were estimated separately for each MGS, sires of daughters were fit as a fixed effect. The QTL allele frequency estimate of Q (positive allele) for RP4 based on one MGS was 0.43, contrary to expectation the second MGS appeared to be homozygous for the negative QTL allele. For RP1, genotypes at a QTL affecting PP on BTA13 were obtained for 156, 126, and 167 grandaughters for S1, S2 and S3, respectively, and the program provided information on 201 granddaughters (total) of the three sires. Sire 2 appeared to be homozygous for negative allele at the QTL; The QTL allele frequency estimate of Q from the other two sires was 0.79. An extension of the MGDD design. Weller et al. (2002) included only bulls heterozygous at the QTL in the analysis. The status of a bull (homozygous or heterozygous) had to be determined prior to inclusion in the design.

However, if a bull is homozygous for the QTL, the means of granddaughter groups receiving the two alternative marker haplotypes bracketing the QTL should both be either lower or higher than the mean of the granddaughter group having received none of the grandpaternal haplotypes, depending on whether the sire is homozygous for the positive or negative allele a t the QTL. Looking at several grandsires at the same time, if the means of offspring of one type of homozygous sire depart less from the means of offspring not having received a grandpaternal haplotype than the other type we may conclude that the population frequency of this QTL allele is higher.

A simulation study was performed extending Weller�s MGDD in this way, to allow for maternal grandsires (MGS) homozygous at the QTL on the assumption that zygosity state of the MGS would be determined from the granddaughter data. The proposed approach worked well when population allele frequencies of the QTL were moderate but was seriously biased when either of the QTL alleles was at high frequency. Future work will includes simulations based on prior knowledge on zygosity of the MGS, and may provide more reliable results.

Conclusions: Validation of the MGDD method of Weller et al. (2002) and the accompanying program for tracing MGS haplotypes to maternal granddaughters will be useful to breeding organizations in applying the MGDD for estimating allele frequency for QTL that are targets for MAS. Furthermore, MGDD is the only method now available to determine whether a sire is homozygous for positive or negative allele at a QTL, which is very important information for MAS.


Moshe SOLLER, (Head of Unit)
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