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Intragenic Sex-Chromosomal Crossovers of Xmrk Oncogene Alleles Affect Pigment Pattern Formation and the Severity of Melanoma in Xiphophorus

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Intragenic Sex-Chromosomal Crossovers of Xmrk Oncogene Alleles Affect Pigment Pattern Formation and the Severity of Melanoma in Xiphophorus Copyright 1999 by the Genetics Society of America Intragenic Sex-Chromosomal Crossovers of Xmrk Oncogene Alleles Affect Pigment Pattern Formation and the Severity of Melanoma in Xiphophorus Heidrun Gutbrod and Manfred Schartl Physiological Chemistry I, Biocenter, University of WuÈrzburg, D-97074 WuÈrzburg, Germany Manuscript received July 23, 1998 Accepted for publication October 21, 1998 ABSTRACT The X and Y chromosomes of the platy®sh (Xiphophorus maculatus) contain a region that encodes several important traits, including the determination of sex, pigment pattern formation, and predisposition to develop malignant melanoma. Several sex-chromosomal crossovers were identi®ed in this region. As the melanoma-inducing oncogene Xmrk is the only molecularly identi®ed constituent, its genomic organization on both sex chromosomes was analyzed in detail. Using X and Y allele-speci®c sequence differences a high proportion of the crossovers was found to be intragenic in the oncogene Xmrk, concentrating in the extracellular domain-encoding region. The genetic and molecular data allowed establishment of an order of loci over z0.6 cM. It further revealed a sequence located within several kilobases of the extracellular domain-encoding region of Xmrk that regulates overexpression of the oncogene. N the platy®sh Xiphophorus maculatus, three sex chro- Two pigment pattern loci of X. maculatus also locate to I mosomes coexist. They have been characterized as the SD and P-containing region. The red-yellow pattern X, Y, and W. Over a large geographic range the individ- (RY) locus [this locus has been referred to by other ual populations are polymorphic for these three chro- research groups as XANT (see Morizot et al. 1993), or mosomes. A balanced genetic system gives rise to WX, Ptr (see Anders 1992)] is responsible for different red, WY, and XX females as well as XY and YY males (Orzack brown, orange, and yellow patterns (Kallman 1975) et al. 1980; Kallman 1984). that are due to local high concentrations of pigment The X and Y appear to be very similar. Meiotic recom- cells of the xanthophore/erythrophore lineage in the bination has been observed over the entire linkage iris, on the body, and the ®ns. This locus appears to group, suggesting that the pseudo-autosomal region is consist of a series of closely linked genes (Kallman still very large (Kallman 1975, 1984; Morizot et al. 1975). The macromelanophore-determining locus, Mdl, 1991). Both X and Y carry a set of genetically well- contains the genetic information for a speci®c type of characterized, closely linked loci. melanin-containing pigment cells, which are much The locus that de®nes the identity of the gonosome larger than the normal melanophores, the micromela- is the sex-determining locus, SD (in Xiphophorus earlier nophores. Macromelanophores compose certain bold also referred to as SEX; see Morizot 1990). Nothing is black markings. known about the biological nature of SD and how it is The macromelanophore locus has attracted special related to the mammalian testes-determining factor, attention, because it has been shown for some of these SRY. The genetic analysis of sex determination in the patterns that upon certain crossings their expression is platy®sh led to the hypothesis that a male-determining enhanced in the hybrids, giving rise to severe melanosis gene (M) is present on X, W, and Y, but only the Y-chro- and even malignant melanoma (Kallman 1975; Anders mosomal allele is active due to suppression of MX and 1991; Schartl 1995). The capacity to develop mela- MW by autosomal repressors. The W is thought to contain noma is contributed by a dominant oncogene, ONC- another suppressor speci®c for MY (Kallman 1984). Xmrk, which is very closely linked to Mdl (Weis and The second gene in this region is the so-called pituitary Schartl 1998). ONC-Xmrk codes for a growth factor (P) gene that determines the onset of sexual matura- receptor from the epidermal growth factor receptor tion. At present, nine alleles of P have been found. subclass of receptor tyrosine kinases (RTKs; Wittbrodt Again, the platy®sh populations are polymorphic for P et al. 1989). Its oncogenic action is suppressed in the alleles, leading to a wide variety of phenotypes that wild platy®sh by an autosomal tumor suppressor locus, range from very early to very late maturing animals R. Hybridization experiments set up so that the R-con- (Kallman 1989; Schreibman et al. 1994). taining autosomes are substituted through introgressive breeding by R-free chromosomes from Xiphophorus ®sh from other populations or species release ONC- Corresponding author: Manfred Schartl, Physiological Chemistry I, Biocenter, University of WuÈrzburg, Am Hubland, D-97074 WuÈrzburg, Xmrk from its control, and neoplastic growth of macro- Germany. E-mail: [email protected] melanophores occurs. Genetics 151: 773±783 (February 1999) 774 H. Gutbrod and M. Schartl The unit of ONC-Xmrk and certain alleles of Mdl is MATERIALS AND METHODS equivalent to the earlier de®ned Tu-locus sensu Anders Fish: All ®sh used in this study (see Table 1) were bred (Anders 1991; see Weis and Schartl 1998). Many of and maintained in the aquarium facilities of the Biozentrum these Mdl-ONC-Xmrk combinations exist and each gives (WuÈrzburg, Germany) under standard conditions. F1 hybrids a peculiar phenotype of the pigment pattern and the of X. maculatus with X. helleri were produced by arti®cial insemi- melanoma with respect to the onset, compartment, in- nation. The melanoma phenotype was analyzed in F1 and backcross hybrids with X. helleri (strain 17), while for RFLP tensity, and the extension of the pattern on the one linkage analysis F1 and backcross hybrids with X. gordoni and hand and the onset, location, and severity of the cancer- X. couchianus (strains 13 and 14, respectively) were used. For ous disease on the other hand (Schartl and Well- mapping INV-Xmrk, backcross hybrids of X. variatus with X. brock 1998). It is unknown whether these features helleri were used. The mutant and recombinant sex chromo- attribute either to Mdl or to the region controlling somes arose either spontaneously or following X-ray mutagen- esis (Anders et al. 1973) and were maintained in the genetic transcription of ONC-Xmrk, or to structural differences background of the original population from which the wild- in the transcribed part that alter the biochemical prop- type chromosome originated. All were generously made avail- erties of the oncogenic growth factor receptor. able by A. and F. Anders (Gieûen, Germany), except for the The platy®sh populations are highly polymorphic Sr crossover 3084B (strain 10) and the wild platy®sh strain 4, for the multiple alleles of Mdl-ONC-Xmrk, which are which were kindly supplied by K. D. Kallman, and platy®sh grouped in ®ve classes: the spotted dorsal (Sd), the strain 3, which was obtained from the Xiphophorus Genetic Stock Center (San Marcos, TX). striped (Sr), spotted (Sp), nigra (Ni), and spotted belly DNA extraction and PCR ampli®cations: Genomic DNA (Sb) patterns (Gordon 1948). The percentage of mac- from pooled organs of individual ®sh was extracted as pre- romelanophore-pattern-carrying ®sh can range from viously described (Schartl et al. 1995). From X. maculatus ,1% to more than half of the individuals of a popula- (Rio Jamapa, ONC2, strain 3), genomic DNA for PCR was tion (Gordon and Gordon 1957). ONC-Xmrk has so prepared from ®n clips according to the protocol of Altsch- mied et al. (1997). As template for ampli®cation of the introns far been found only in conjunction with Mdl. However, of Xmrk, either phage Sac1-3-1 isolated from a subgenomic it should be noted that in other Xiphophorus species library of X. maculatus (Rio Jamapa, Sd, strain 1; see Table 1; Mdl alleles that are unlinked to ONC-Xmrk exist. These Adam et al. 1991), which contains exon 2 to 22 of ONC-Xmrk, are not melanomagenic (Weis and Schartl 1998). or genomic DNA of female X. maculatus (strain 1) was used. ONC-Xmrk has arisen through a gene duplication PCR ampli®cations were performed for 35 cycles with a dena- turing step at 948 for 30 sec, annealing at 28 below Tm of the event from its corresponding proto-oncogene, INV- respective primer for 30 sec, and an extension at 728 for 30 Xmrk (Adam et al. 1993). This gene is also located in to 330 sec according to the size of the expected product. In the same region where ONC-Xmrk, Mdl, RY, P, and SD the ®rst cycle, denaturation was for 180 sec and in the last are residing (Schartl 1990). Although some sugges- cycle extension time was 180 sec. Allele-speci®c primers for tions about a gene order have been made (Anders et the X and Y copies of ONC-Xmrk had the following sequences: 9 9 9 al. 1973; Kallman 1975; Schartl 1990; Sohn 1991), Xfor 5 -CTTACGTTGAAAGCACGTGA-3 , Xrev 5 -AAAGGA GGCTTCATGGAGGG-39, Yfor 59-TTTGGTGTCTTACTTCT so far a ®ne mapping has been impossible to achieve GTG-39, and Yrev 59-TTCCTCCTACTTGGCTAAAC-39 (Cough- due to the extremely low frequency of recombination lan et al. 1998). Primers ¯anking a 1.4-kb deletion in the car- between these loci. This information, however, is boxyterminal domain of the X allele are Ins4 (59-GCCTC needed for positional cloning approaches employing CTGGGAGGACAGCGAC-39) and Ins5 (59-AGCGAGCCCTGC chromosome walking out of the single cloned sites from ATCCCGCCG-39). Products of different size for the X- and Y-ONC-Xmrk allele (X, 5.3 kb; Y, 3.4 kb) from the ®rst intron this region, the Xmrk genes. were generated with primers Hg93 (59-CTGCAGTCGTCAT The W chromosome is very different, despite being GGAAACC-39) and Hg96 (59-CCTCCTGCCGAATCGTTCAG- involved in sex determination.
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