title: Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus interspecies hybrids.
abstract: Development of spontaneous melanoma in Xiphophorus interspecies backcross hybrid progeny, (X. hellerii × [X. maculatus Jp 163 A × X. hellerii]) is due to Mendelian segregation of a oncogene (xmrk) and a molecularly uncharacterized locus, called R(Diff), on LG5. R(Diff) is thought to suppresses the activity of xmrk in healthy X. maculatus Jp 163 A parental species that rarely develop melanoma. To better understand the molecular genetics of R(Diff), we utilized RNA-Seq to study allele-specific gene expression of spontaneous melanoma tumors and corresponding normal skin samples derived from 15 first generation backcross (BC1) hybrids and 13 fifth generation (BC5) hybrids. Allele-specific expression was determined for all genes and assigned to parental allele inheritance for each backcross hybrid individual. Results showed that genes residing in a 5.81 Mbp region on LG5 were exclusively expressed from the X. hellerii alleles in tumor-bearing BC1hybrids. This observation indicates this region is consistently homozygous for X. hellerii alleles in tumor bearing animals, and therefore defines this region to be the R(Diff) locus. The R(Diff) locus harbors 164 gene models and includes the previously characterized R(Diff) candidate, cdkn2x. Twenty-one genes in the R(Diff) region show differential expression in the tumor samples compared to normal skin tissue. These results further characterize the R(Diff) locus and suggest tumor suppression may require a multigenic region rather than a single gene variant. Differences in gene expression between tumor and normal skin tissue in this region may indicate interactions among several genes are required for backcross hybrid melanoma development.
authors.affiliation: The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Yuan
authors.identifier: 0000-0002-2420-4804
authors.initials: Y
authors.lastname: Lu
authors.affiliation: The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Mikki
authors.initials: M
authors.lastname: Boswell
authors.affiliation: The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: William
authors.initials: W
authors.lastname: Boswell
authors.affiliation: Physiological Chemistry, Biozentrum, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University Clinic Würzburg, Würzburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.affiliation: Physiological Chemistry, Biozentrum, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University Clinic Würzburg, Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hausmann
authors.affiliation: Physiological Chemistry, Biozentrum, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University Clinic Würzburg, Würzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klotz
authors.affiliation: Physiological Chemistry, Biozentrum, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University Clinic Würzburg, Würzburg, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Regneri
authors.affiliation: The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Markita
authors.initials: M
authors.lastname: Savage
authors.affiliation: Institute of Neuroscience, University of Oregon, Eugene, Oregon.
authors.forename: Angel
authors.initials: A
authors.lastname: Amores
authors.affiliation: Institute of Neuroscience, University of Oregon, Eugene, Oregon.
authors.forename: John
authors.initials: J
authors.lastname: Postlethwait
authors.affiliation: The Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Wesley
authors.initials: W
authors.lastname: Warren
authors.affiliation: Physiological Chemistry, Biozentrum, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University Clinic Würzburg, Würzburg, Germany.|Texas A&M Institute for Advanced Studies and Department of Biology, Texas A&M University, College Station, Texas.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schartl
authors.affiliation: The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas.
authors.forename: Ronald
authors.initials: R
authors.lastname: Walter
mesh_terms: D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D003532:Cyprinodontiformes / Q000235:genetics*; D005260:Female; D029941:Fish Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006824:Hybridization, Genetic; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D029941:Fish Proteins; D020794:Receptor Protein-Tyrosine Kinases; C077101:Xmrk protein, Xiphophorus
keywords: Gordon-Kosswig model; allele specific gene expression; bioinformatics; genetic interaction; interspecies hybrids