Modeling inheritance of malignant melanoma with DNA markers in Sinclair swine

Abstract

Cutaneous malignant melanoma in Sinclair swine is a hereditary disease that develops in utero or during the first 6 weeks of life. In many cases, the tumors regress and piglets survive the disease. Two different sets of gene(s) might be involved in the disease: tumor initiator (suppressor) locus or loci and loci affecting the aggressiveness of the disease (number and stage of tumors). We develop maximum-likelihood methods for interval mapping for both types of loci. The experimental design consisted of a boar mated to tumor-bearing sows with recording of tumor status and number of tumors in the 6 weeks of life of the offspring. The model to search for the tumor initiator locus (with alleles T and t) was tested by computer simulation. Estimates of penetrances (Psi(TT) and Psi(Tt) for genotypes TT and Tt, respectively) were accurate even for small family sizes. Statistical power was >99% for a family size of 70 with Psi(TT) = 1 and Psi(Tt) = 0. The models to test for number of tumors incorporated genotype information for the tumor initiator locus. All models were tested with data from a single boar family of 72 piglets over swine chromosomes 6 and 8 (SSC6 and SSC8). No tumor evidence for initiator loci was found associated with these chromosomes. However, association of a QTL affecting number of tumors at birth near microsatellite SW1953 on SSC8 was chromosomewise significant (P<0.0124).

Figure 1.—

Sinclair piglet with a malignant melanoma tumor in his right leg.

Figure 2.—

Marker genotype configuration in the boar for interval mapping.

Figure 3.—

Interval mapping searching for tumor initiator locus on SSC6 assuming a frequency of allele T of 0.9 and 0.6 in the gametes from the dams. Genetic distances are in morgans (M).

Figure 4.—

Interval mapping for tumor initiator locus on SSC8 assuming a frequency of allele T of 0.9 and 0.6 in the gametes from the dams. Genetic distances are in morgans (M).

Figure 5.—

Logarithm of odds comparing the maximum likelihood for a full model (allowing homozygotes to survive and to develop melanoma) vs. a model based on Blangero et al.'s (1996) hypothesis for SSC6.

Figure 6.—

Interval mapping for TBIRTH, T6WK, TB–6WK, and TMAX on SSC6 (A) not using information on the tumor initiator locus on SSC8 and (B) using information on the tumor initiator locus on SSC8.

Figure 7.—

Interval mapping for TBIRTH, T6WK, TB–6WK, and TMAX on SSC8 (A) not using information on the tumor initiator locus on SSC6 and (B) using information on the tumor initiator locus on SSC6.

Figure 7.—

Interval mapping for TBIRTH, T6WK, TB–6WK, and TMAX on SSC8 (A) not using information on the tumor initiator locus on SSC6 and (B) using information on the tumor initiator locus on SSC6.