Detection of novel quantitative trait loci for cutaneous melanoma by genome-wide scan in the MeLiM swine model.
Human cutaneous melanoma is a complex trait inherited in about 10% of cases. Although 2 high-risk genes, CDKN2A and CDK4, and 1 low risk gene, MC1R, have been identified, susceptibility genes remain to be discovered. Here, we attempted to determine new genomic regions linked to melanoma using the pig MeLiM strain, which develops hereditary cutaneous melanomas. We applied quantitative trait loci (QTL) mapping method to a significant genome-wide scan performed on 331 backcross pigs derived from this strain. QTLs were detected at chromosome-wide level for a melanoma synthetic trait corresponding to the development of melanoma. The peak positions on Sus scrofa chromosomes (SSC) were at 49.4 and 88.0 cM (SSC1), 56.0 cM (SSC13), 86.5 cM (SSC15) and 39.8 cM (SSC17), and, on SSC2, at 16.9 cM, in families derived from F1 males only (p < 0.05, except for SSC13, p < 0.01). Analysis of 7 precise specific traits revealed highly significant QTLs on SSC10 (ulceration), on SSC12 (presence of melanoma at birth), on SSC13 (lesion type), and on SSC16 and SSC17 (number of aggressive melanomas) at the respective positions 42.0, 95.6, 81.0, 45.3 and 44.8 cM (p < 0.001 and p < 0.05 respectively at the chromosome- and genome-wide levels). We also showed that MeLiM MC1R*2 allele, which determines black coat colour in pigs, predisposes significantly to melanoma. Interactions were observed between MC1R and markers located on SSC1 (p < 0.05). Taken together, these results indicate that MeLiM swine is a model for human multigenic diseases. Comparative mapping revealed human regions of interest to search for new melanoma susceptibility candidates.
Du
Zhi-Qiang
ZQ
CEA, DSV, DRR, Laboratoire de Radiobiologie et d'Etude du Génome, INRA Jouy-en-Josas, F-78352 France.
Vincent-Naulleau
Silvia
S
Gilbert
Hélène
H
Vignoles
Florence
F
Créchet
Françoise
F
Shimogiri
Takeshi
T
Yasue
Hiroshi
H
Leplat
Jean-Jacques
JJ
Bouet
Stephan
S
Gruand
Joseph
J
Horak
Vratislav
V
Milan
Denis
D
Le Roy
Pascale
P
Geffrotin
Claudine
C
D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D010802:Phylogeny; D040641:Quantitative Trait Loci; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D013552:Swine / Q000145:classification / Q000235:genetics*; D013556:Swine, Miniature / Q000145:classification / Q000235:genetics*
D044102:Receptor, Melanocortin, Type 1