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X/Y Translocations Resulting from Recombination Between Homologous Sequences on Xp and Yq PAULINE H

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X/Y Translocations Resulting from Recombination Between Homologous Sequences on Xp and Yq PAULINE H Proc. Natl. Acad. Sci. USA Vol. 88, pp. 8944-8948, October 1991 Genetics X/Y translocations resulting from recombination between homologous sequences on Xp and Yq PAULINE H. YEN*t, SIAO-PING TSAI*t, SHARON L. WENGERf, MARK W. STEELEt, THULUVANCHERI K. MOHANDASt, AND LARRY J. SHAPIRO*t§ *Howard Hughes Medical Institute, and Departments of tPediatrics and §Biological Chemistry, University of California, Los Angeles, School of Medicine, Harbor-University of California, Los Angeles, Medical Center, Torrance, CA 90509; and tDivision of Medical Genetics, Children's Hospital of Pittsburgh, PA 15213 Communicated by Elizabeth F. Neufeld, July 17, 1991 ABSTRACT Several regions of sequence homology be- tric inversion of the Y chromosome during primate evolution tween the human X and Y chromosomes have been identified. (11). These segments are thought to represent areas of these chro- X/Y translocations occur rarely in the human population mosomes that have engaged in ineiotic recombination in rela- and some 50 cases have been reported (16-21). The majority tively recent evolutionary times. Normally, the X and Y of these-translocations have breakpoints at Xp22 and Yq11 chromosomes pair during mdosis and exchange DNA only when analyzed cytogenetically. The reciprocal products of within the pseudoautosomal region at the distal short arms of the translocations have never been recovered. Some ofthese both chromosomes. However, it has been suggested that aber- translocations are sporadic events, whereas others are inher- rant recombination involving other segments ofhigh homology ited. All females with Xp22;Yqll translocations have been could be responsible for the production of X/Y translocations. phenotypically normal except for short stature. All males We have studied four X/Y translocation patients using mo- carrying such translocations have an additional intact Y lecular probes detecting homologous sequences on X and Y chromosome. Although some of these males appear to have chromosomes. In one translocation the breakpoints have been a normal phenotype, others have various abnormalities. They isolated and sequenced. The mapping data are consistent with are usually short and, depending on the breakpoints on the X the hypothesis that X/Y translocations arise by homologous chromosome, some have mental retardation, ichthyosis, and recombination. The sequencing data from one translocation other phenotypic anomalies. Because of extensive sequence demonstrate this directly. similarities between Xp22 and Yq1l, homologous recombi- nation between these sequences has been suggested as the The mammalian sex chromosomes are thought to have etiology ofX/Y translocations (19). In this report we present evolved from an ancestral homologous chromosome pair (1). our studies on four X/Y translocations using probes from Although sequences have been deleted, inserted, or rear- Xp22.3 that detect homologous sequences on Yql1. In one ranged on the sex chromosomes over time to accommodate translocation the translocation junction was isolated and their now specialized functions, significant sequence simi- sequenced,¶ and the data showed that this X/Y translocation larities remain between the present-day X and Y chromo- was the result of a precise homologous recombination be- somes. Sequences in the pseudoautosomal region at the tween the X and the Y sequences. terminal portions of the short arms of the sex chromosomes are identical and, during male meiosis, there is a single and MATERIALS AND METHODS obligatory X-Y crossover within this region (2). Occasionally the X-Y interchange occurs outside the pseudoautosomal Patient RP and Cell Lines. Patient RP has a 46,Y,t(X;Y) region and the testis-determining factor (TDF) gene is trans- (p22.3;q11.2) karyotype. He inherited the translocation chro- ferred to the X chromosome resulting in an XX male phe- mosome from his mother. Both RP and his mother are Xga notype (3, 4). Outside the pseudoautosomal region, homol- negative whereas both maternal grandparents are Xga posi- ogous sequences have been found on the long arm of the X tive and have normal karyotypes, suggesting that the X/Y chromosome and the short arm or the proximal long arm of translocation occurred in the maternal grandfather. At birth, the Y chromosome. These regions share >95% similarity as RP had a depressed nasal bridge, anteverted nares, and detected by probes DXYS1, DXYS61, and others (5-10). bilateral simian creases. At 13 months of age, he had severe Because some of these sequences are found only on the X developmental delay, seizures, and ichthyosis. A lympho- chromosome of great apes, they are thought to have been blastoid cell line was established from RP. CF94 (22), CF108 generated by transposition of sequences from the X chromo- (23), and CF109 (24) contain three previously reported X/Y some to the Y chromosome after the divergence of humans translocation chromosomes in which the breakpoints are from great apes; however, recent loss of the Y homologs in cytogenetically indistinguishable from that in RP. These great apes is also a possible explanation. In addition, several translocated chromosomes have been segregated from the loci in the Xpter-Xp22 region were found to share 85-95% normal Y chromosome in somatic cell hybrids by fusion of similarity with sequences in Yqll or the pericentric region of the patients' fibroblasts with HPRT- A9 cells. Our previous the Y chromosome. These include the genes for steroid studies have shown that CF108 retains the functional STS sulfatase (STS; refs. 11 and 12), the tooth enamel protein locus on the X chromosome, whereas CF94, CF109, and RP amelogenin (AMG; ref. 13), and several loci defined by have deleted the X chromosome-linked STS gene (25-27). anonymous DNA fragments (14, 15). The homology shared DNA Probes. Probes used to define the breakpoints in these by the short arm of the X chromosome and the long arm of X/Y translocations come from the distal short arm of the the Y chromosome has been cited as evidence for a pericen- human X chromosome. M1A (15), CS17D, CS21B, and CS19AB (27) are from the DXS31, S232A, S232B, and S232C The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" IThe sequences reported in this paper have been deposited in the in accordance with 18 U.S.C. §1734 solely to indicate this fact. GenBank data base (accession nos. M76716 and M76717). 8944 Downloaded by guest on September 27, 2021 Genetics: Yen et al. Proc. Natl. Acad. Sci. USA 88 (1991) 8945 loci on the X chromosome, respectively. CS12C is from the X 't GOa QO S232E locus on the Y chromosome (27). Probe pSTS118A is X x >- L LL L co x xx m o m from the seventh intron ofthe STS gene (11). All ofthe above probes detect homologous sequences on the X and the Y chromosomes. Probe dic56 from the DXS143 locus is X In a mouse chromosome-specific (28). addition, AMG cDNA STS clone pGEM17-2 (29) was used that detects the AMG locus in the Xp22.1-p22.3 region and the AMGL locus in the pericentric region of the Y chromosome (13). General Procedures. Isolation of genomic DNA from cul- tured cells, restriction endonuclease digestion, Southern blot X - _ analysis, and isolation of phage and plasmid DNA were carried out according to standard procedures (30). DNA 12C-X sequences were determined using the dideoxynucleotide chain-termination method (31). Cloning the Translocation Breakpoint in Patient RP. Probe CS19AB (S232C) detects an altered 13-kilobase (kb) EcoRI S232sY2x- AMO& w genomic fragment containing the translocation breakpoint in VW RP. DNA from the lymphoblastoid cell line derived from RP k,- was digested with EcoRI and size-fractionated by sucrose- Y--20 gradient centrifugation. Fractions containing 13- to 20-kb S232C 3 fragments were pooled and were ligated to the arms of X- .- -1 EMBL4, packaged in vitro, and used to transfect Escherichia coli. The library constructed was screened with labeled FIG. 1. Southern blot analysis of the breakpoints in the X/Y CS19AB using standard procedures (30). translocation chromosomes. Genomic DNA was isolated from fibro- blasts of a female with four X chromosomes (XXXX), a normal RESULTS female (XX), a normal male (XY), a lymphoblastoid cell line of patient RP with X/Y translocation, mouse-human hybrid cell lines Molecular Studies of the Breakpoints in X/Y Transloca- containing unrelated X/Y translocation chromosomes (CF94, tions. We have studied translocation breakpoints on the X CF109, and CF108), and mouse cell line B82. The DNA was digested and Y chromosomes in four X/Y translocations. Three ofthe with EcoRI and analyzed on Southern blots with probes detecting translocation chromosomes have been isolated in mouse- homologous sequences on the X and the Y chromosomes as indi- human hybrids CF94, CF108, and CF109 (25). The fourth one cated. A probe from the S232C locus detects an altered fragment in RP. was initially studied in a lymphoblastoid cell line established from a male patient, RP. This translocation chromosome was X/Y translocation from RP. The results are summarized in subsequently separated from the normal Y chromosome in a Table 1. In addition to mouse-human hybrid clone CF158. Cytogenetically, all these the previously mapped translocation translocations have breakpoints at and These breakpoints on the X chromosome in CF94 and RP, the X Xp22.3 Yqll.2. chromosome in CF108 and are now breakpoints were further studied using probes that detect breakpoints CF109 homologous sequences on the distal short arm of the X mapped to the interval between DXS31 and S232A and chromosome and the proximal long arm of the Y chromo- between S232C and DXS143, respectively. The order ofthese some. Long-range restriction mapping of the area immedi- loci on the Y chromosome has not been previously deter- ately proximal to the pseudoautosomal region on the X mined.
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