Differential expression pattern of XqPAR-linked genes SYBL1 and IL9R correlates with the structure and evolution of the region
Differential expression pattern of XqPAR-linked genes SYBL1 and IL9R correlates with the structure and evolution of the regionMaurizio D'Esposito1,+, Maria Rosaria Matarazzo1,+, Alfredo Ciccodicola1, Maria Strazzullo1, Richard Mazzarella2, Nandita A. Quaderi3, Hiroyuki Fujiwara4, Minoru S. H. Ko4, Lucy B. Rowe5, Angela Ricco6, Nicoletta Archidiacono6, Mariano Rocchi6, David Schlessinger2 and Michele D'Urso1,*
1International Institute of Genetics and Biophysics, CNR, 80125 Naples, Italy, 2Department of Molecular Microbiology, Washington University Medical School, St. Louis, MO 63110, USA, 3Telethon Institute of Genetics and Medicine, DIBIT, Via Olgettina 58, 20132 Milan, Italy, 4Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 5047 Gullen Mall, Detroit, MI 48202, USA, 5The Jackson Laboratory, Bar Harbor, ME 04609, USA and 6Istituto di Genetica, Università di Bari, Via Amendola 165/A 70126 Bari, Italy
Received June 2, 1997;Revised and Accepted July 25, 1997
The recently discovered second pseudoautosomal region (XqPAR) contains at least two genes, IL9R and SYBL1. Recent findings show that, like XpPAR genes, IL9R escapes X inactivation and its Y allele is also expressed, but SYBL1 seems to act like an X-linked gene, expressed from the active X chromosome but not from the inactive X or Y. Here we show that differences are also seen in the evolution of the sex chromosome locations of IL9R and SYBL1. IL9R is known to be autosomal in mice, and is X-linked only in primates. SYBL1, however, has been found to be on the X chromosome in all mammals tested, from marsupials to humans. Both genes were duplicated on the Y homologue of the terminal portion of the X chromosome during the evolution of Homo sapiens from other higher primates. The inactivation pattern of SYBL1 may be correlated with its longer history of X linkage, and at a more centromeric chromosomal position during evolution; the more recent X linkage and more telomeric position of the IL9R gene may explain its autosomal, `uninactivated' transcriptional status.
Sex chromosomes are thought to derive from a homomorphic pair of sex chromosomes,with gradual reduction of the Y chromosome in a complex multistep process recently called the `addition-attrition hypothesis' (1 ). Homologous regions on both the long and short arms of the X and Y chromosomes attest to their common origin (2 ,3 ). Various lines of evidence (4 ,5 ) revealthat a special class of homology occurs in a region, the XpPAR, 2.6 Mb in length, that recombines between X and Y, ensuring correct segregation at male meiosis (6 ).
In the pseudoautosomal region (PAR), the requirement for dosage compensation, which underlies Ohno's law (7 ) of the conservation of genes on the X chromosome, is relaxed. As a result, addition-attrition could lead to variation in PARs among different species; in fact, the mouse homologues of two genes in thehuman XpPAR, CSFR2A and IL3RA (8 ,9 ) have been mapped to autosomes.
A second, 320 kb PAR at the Xq end of the chromosome recently has been characterized (10 -12 ). Its evolutionary history is only partially known. Anonymous probes like DXYS61 (3 ) showed X linkage in higher primates and presence on both human X and Y; but the inclusion of those probes in a PAR was only clear when DNA from the whole region was cloned (13 ). The sequence at the PAR boundary on the X and Y chromosomes indicates that the XqPAR may have arisen by transposition via illegitimate recombination between LINE sequences (12 ).
A more detailed analysis of the molecular history of the XqPAR has become possible with the isolation of two genes encoded in the region (14 ,15 ). In spite of their close linkage in the XqPAR, their transcriptional status is quite different: like XpPAR genes, IL9R escapes X inactivation and its Y alleleis also expressed. In contrast, SYBL1 seems to act like an X-linked gene; it is expressed on the active X chromosome but not from the inactive X or the Y.
IL9R was shown recently (16 ) to be autosomal in the mouse while it is X-linked in apes and X/Y-linked only in the human lineage. It thus represents a fourth case of a gene eluding conservation of X linkage in eutherian mammals.
In contrast, we show that, using the XqPAR synaptobrevin-like gene SYBL1 (15 ) as an evolutionary marker, at least one XqPAR-linked gene shows conservation of X linkage among eutherian species.This coincides with previous observations in marsupials and monotremes for otherXq genes (17 ). In order to explore the evolutionary history of the locus, we identified SYBL1 homologues in marsupials, mice and higher primates, and we show that this gene is X-linked in each species studied. A further step in Homo sapiens progenitors added the corresponding segment to the Y to create the modern human XqPAR.
A bipartite structure and evolution of this region can thus be suggested that correlates with the striking differences in transcriptional behaviour of the two genes so far studied.
Previous reports localized two genes, in the human XqPAR, IL9R and SYBL1 (14 ,15 ), the former in a more telomeric position withrespect to the latter (Fig. 1 A).Using the human SYBL1 cDNA sequence as a query, the BLAST (18 ) algorithm indicated a high degree of conservation for the SYBL1 gene, with strong similarity to a plant synaptobrevin and weaker similarity to a cohort of other eukaryotic synaptobrevins (15 ), a class of proteins that provides specificity in targeting pathways within cells, including those of the nervous system. In experiments using the human cDNA as a probe, Southern blot hybridization with DNAs from a number of species showed comparably strong signals from Arabidopsis, chicken, rat, mouse, primates and humans, and fainter bands from yeast and Drosophila (not shown). Figure 1 B shows the high level of conservation between the human and the newly isolated (Materials and Methods) mouse homologue. Both species have a 220 amino acid open reading frame (ORF) with identical start and stop codons. The 1583 bp mouse sequence is 82.1% identical at the nucleotide level with its human counterpart; and base substitutions are clustered mainly in the 5' and 3' untranslated regions (UTRs). A comparison of the mouse and human SYBL1 putative proteins reveals six amino acid substitutions between the two species, three of which are conservative. This comparison defines the region of the probable transmembrane segment as comprising amino acids 189-206, since the human protein contains a proline at amino acid 207 that would disrupt the [alpha]-helix beyond that point. Since members of the synaptobrevin family are thought to insert post-translationally into the endoplasmic reticulum (ER) via their C-terminus and are then transported to their site of function, this topology places amino acids 1-188 in the cytoplasm and amino acids 207-220 in the lumen of the ER. The absolute conservation of four cytoplasmic cysteines and two luminal cysteines raises the possibility that they are involved in intramolecular and intermolecular disulphide bonding, respectively.
For most genes, the X chromosome of all eutherian mammalsfollows the predictions of Ohno's law (7 ) regarding the evolutionary conservation of genes on the X. Ohno suggested that the complement of genes on the X chromosome tends to stabilize over evolutionary time to avoid disrupting dosage compensation and sex determination. This suggestion has also been supported in marsupials and monotremes for a subset of eutherian X-linked genes, those located on the long arm of the human X (17 ). The isolation of the XqPAR gene, SYBL1 (15 ), permitted us to extend the examination of this prediction, and to assess some features of the functional conservation of the X chromosome.
Using the human cosmid c8.2, which contains part of the human SYBL1 gene (12 ,15 ), fluorescence in situ hybridization (FISH) on metaphase spreads from a kidney cell line derived from an adult female rat-kangaroo (Potorous tridactylis apicalis) showed signals at the distal end of the Xq (Fig. 2 ); note that the X chromosome is similar in length and centromere position to some autosomes, but is characterized by a large secondary constriction near the centromere in the long arm (19 ).
Primers designed from the 3'UTR of the murine Sybl1 cDNA were used to amplify DNAs from two related mouse species by PCR. Mus spretus genomic DNA produced a single amplification product of the expected size (see Materials and Methods). However, amplification of C57BL/6J genomic DNA produced a tight doublet of bands, the smaller of which co-migrated with the M.spretus amplification product. The unique C57BL/6J band wasmappedin both reciprocal backcrosses from The Jackson Laboratory.Analysis of the haplotype data revealed that thisSybl1 locusmapped in the most proximal position on the mouse X chromosome (Fig. 3 A). The combined BSS and BSB data (only hemizygous males could be scored from the BSB) show 2/137 recombination events between Sybl1 and DXMit26/DXBir1, placing Sybl1 1.46cM +- 1.02cM proximal to DXMit26/DXBir1 (Fig. 3 B).
A probe derived from the cosmid c8.2 was hybridized in situ, as already described (20 ), to metaphase spreads of lymphoblastoid cell lines derived from chimpanzee (Pan troglodytes, PTR), gibbon (Hylobates lar, HLA), gorilla (Gorilla gorilla, GGO) and macaque (Macaque fascicularis, MFA). Signals are seen only in the Xq28 region in all cases (Fig. 4 B). (Note that the signal on the GGO X is subtelomeric, displaced by a distal heterochromatic region in Xq28.)
Recent studies on monotreme and marsupial chromosomes reveal that genes mapped on the long arm of the human X chromosome retain this linkage in these distantly related genomes (17 ). Those studies postulated the presence of an XCR (X conserved region) including all of Xq, beginning before or at the time of divergence between Prototheria, Methateria and Eutheria, or ~170 million years ago (17 ). This can be taken as a confirmation and refinement of Ohno's law, though exceptions have also been noted (8 ,9 ).
Previous calculations (3 ,12 ), based on sequence divergence of the LINE element at the humanXqPAR boundary compared with homologues, indicate that the chromosome translocation and subsequent X/Y inheritance for sequence elements in this region occurred 15-20 million years ago. On the other hand, divergences between human, chimpanzee and gorilla lineages seem to have occurred more recently in evolution. The details are uncertain because expert opinion varies on the `star-like' branching and timing of the process, but one estimate suggests a critical period 6-8 million years ago (21 ).
Earlier evidence for X-Y homologous DNA near the Xq/Yq termini in humanswas found by Bickmore and Cooke (3 ), who showed that an anonymous probe DXYS61 (formerly called 2:13) in the region was X-linked in great apes but was found on both X and Y in humans. Because the DXYS61 sequence is limited to higher primates and is not expressed, this analysis was necessarily limited, and only hinted at the possibility of more extensive homologies.
The use of the human SYBL1 gene as a probe has permitted us to detect the mouse and marsupial homologues and determine some features of the molecular and functionalevolution of the XqPAR. Apparently the conservation of syntenic equivalence in Xq extends to the humanSYBL1 gene, but not to the somewhat more telomeric gene, IL9R [16 ; the genes are ~ 40 kb apart (A.Ciccodicola et al., in preparation)]. The simplest evolutionary pathway for the human XqPARwould start from a time at which the SYBL1 gene was already at a subtelomeric position on the X. An IL9R gene copy would then have been interpolated from its earlier autosomal location (mouse chromosome 11 or its evolutionary equivalent) between the SYBL1 locus and the telomere, before the divergence of humanfrom the great apes (16 ). Then the region was duplicated on a Y chromosome homologue as well, possibly involving an illegitimate LINE-mediated recombination between X and Y chromosomes (12 ). Other additions in the XqPAR included the introduction of the proterminal repeat TelBam3.4 (16 ).
A PAR is defined by two criteria: a copy of the sequences is foundon both the X and the Y chromosomes, andthe region shows meiotic pairing and recombinationbetween the X and the Y. Genetic exchange between the X and Y homologues of the XqPAR has been demonstrated by the use of polymorphic markers in the region (11 ,22 ).Ongoing sequencing efforts have revealed that three markers (see Fig. 1 A) that have been used to detect polymorphism and recombinationare respectively within the SYBL1 gene (LH1, GDB name: DXYS225, between exons 5 and 6), closely linked to SYBL1 (sDF1, GDB name: DXYS154), and very near to IL9R (LH2, GDB name: DXYS227). In addition, sequencing results show thatthe X and Y copies of the coding sequences of SYBL1 areidentical at the nucleotide level, consistent with the active homogenization of the content of this part ofthe X and Y via recombination (A.Ciccodicola et al., in preparation). In their currently extant forms, the XpPAR and XqPAR both show relatively high recombination rates though, unlike the XpPAR (5 ), the XqPAR does not show an obligate cross-over in every meiosis.
Our more detailed understanding from the mapping data of the physical evolution of the XqPAR can be used to address questions about the function of genes in this region. The most striking difference between the two genes so far studied in the XqPARremains their modes of regulation of expression, that are reported elsewhere (15 ,16 ). IL9R expressionseems to be typically pseudoautosomal, occurring from both X and Ycopies; this may reflect its more recent introduction from an autosometo the X chromosome at this distal position. A sequence barrier may protect some X-linked genes, including genes inthe XpPAR (23 ), from the passage of a wave of inactivation. If so, such a barrier could exist between the SYBL1 and IL9R loci, since the X-linked copy ofSYBL1 is subject to X-inactivationand IL9R is not. The exact nature of such barriers is not yet known, but might include epigenetic changes, such as methylation of CpG islands, replication timing or absence of acetylated histone H4 (24 -26 ), or other structural changes in chromatin.
In addition to the X inactivation, the unusual inactivation of the SYBL1 copy on the Y chromosome suggests the presence of other mechanisms, that differfrom thosethat inactivate X chromosome genes, since there is no known inactivation centre on the Y. The effect is to render the function of the SYBL1 gene typical of normal X linkage, andto makethe Y homologue a reservoir of alleles that can be recruited back to active form by recombinational exchange.
In conclusion, our analysis suggests that the XqPAR includes a highly conserved, older, more centromeric part of the X which has been extended by punctate evolution in the more distal portion. We have demonstrated that theXqPAR is a region newly added to the human Y and not a remnant of an ancient X-Y homology region, and we postulate thatdifferences in expression of SYBL1 and IL9R can be explained by differences in the time of transfer of these segments to the X and Y chromosomes, and the proximity of each to the telomere. The mechanisms of regulation of these genes remain to be analysed.
A 17 days embryonic mouse (Swiss Webster/NIH pooled embryos) cDNA library in [lambda]gt10 (Clontech) was screened with a coding portion of the cDNA for the human SYBL1 gene (15 ). Three recombinant phages were isolated, and only the largest clone, 1.6 kb in length was subcloned and sequenced completely.
Mouse Sybl1 cDNA was subcloned into pGEM-4Z vector (Promega Biotech) and analysed by cycle sequencing on an Applied Biosystems 373A automated sequencer. The cDNA sequence has been submitted to EMBL, accession No. X96737.
PCR mapping. The primers sybl1F (5'-TCCCATTGCAGTTGATTTGA-3') and sybl2R (5'-ATAGCTCATAAGACTAGCGGCG-3') from the 3'UTR of the murine Sybl1 cDNA were used to PCR amplify SPRET/Ei and C57BL/6J parental and the BSS and BSB backcross progeny genomic DNAs (27 ). Twenty five ng of template DNA was used in 35 cycles of 94oC, 20 s; 57oC, 40 s; and 72oC, 40 s, and the amplification products were then resolved through 3% SeaPlaque agarose gels (FMC).Southern mapping. To map the second locus suggested by the doublet from the PCR of C57BL/6J DNA, a 0.5 kb probe from the 3'UTR of the murine Sybl1 cDNA was obtained by digestion with EcoRI and StyI. After digestion with EcoRI, 5 [mu]g ofmouse genomic DNA from each backcross animal in the Jackson BSS and BSB panels was electrophoresed on a0.9% agarose gel overnight. The DNAs were blotted onto HybondN nylon membrane (Amersham) by standard capillary transfer. Then, 25 ng of the fragment of Sybl1 cDNA was labelled with [[alpha]-32P]dCTP by RediPrime kit (Amersham). Hybridization was performed by standard methods (28 ). Stringent washing conditions were 20 min at 65oC in 0.1* SSC, 0.1% SDS solution.
Human metaphase spreads were obtained from phytohaemagglutinin (PHA)-stimulated peripheral blood lymphocytes from a normal human donor. Metaphase spreads from primates were obtained from lymphoblastoid cell lines of chimpanzee (Pan troglodytes, PTR), gibbon (Hylobates lar, HLA), gorilla (Gorilla gorilla, GGO) and macaque (Macaca fascicularis, MFA). Metaphase spreads from a female rat-kangaroo (Potorous tridactylis apicalis) were obtained from PtK1 kidney cell line (ATCC number: CCL-35).
Mouse metaphases were obtained from the mouse cell line WP-G5194, kindly donated by Dr H. Hameister. This cell line (Mus musculus domesticus) contains a specific Robertsonian translocation, allowing easier identification of mouse chromosomes [the X chromosome and the small chromosome 19 are the only acrocentric chromosomes (29 )]. Chromosome preparations were hybridized in situ with probes labelled with biotin by nick translation, essentially as described in (20 ), with minor modifications.
Briefly, 200 ng of labelled probe were used for each experiment; hybridization was performed at 37oC in 2* SSC, 50% (v/v) formamide, 10% (w/v) dextran sulphate, 5 mg of COT-1 DNA (Boehringer Mannheim) and 3 mg of sonicated salmon sperm DNA, in a volume of 10 ml. Post-hybridization washing was at 42oC in 2* SSC-50% formamide (*3) followed by three washes in 0.1* SSC at 60oC. Biotin-labelled DNA was detected with Cy3-conjugated avidin (Amersham). Chromosome identification was obtained by simultaneous 4',6'-diamidino-2-phenylindole (DAPI) staining, which produces a Q-banding pattern.
Digital images were obtained using a Leica DMRXA epifluorescence microscope equipped with a cooled CCD camera (Princeton Instruments, NJ). Cy3 and DAPI fluorescence, detected using specific filters, were recorded separately as grey scale images. The filter set used allows capturing of fluorescence signals without any image shifting. Pseudocolouring and merging of images were performed using the Adobe Photoshop software.
The authors gratefully acknowledge Professor R. Dulbecco for critical reading of the manuscript, Drs G. Persico, M. Di Giulio and S. Mumm for helpful comments, Drs T. Featherstone, F. Gianfrancesco, T. Esposito and M. Chiurazzi for help in the initial part of the work, Mrs M. and Mr A. Terracciano for their technical assistance and C. Bouchcinsky for her secretarial assistance. Also to the memory of G. Blasi for his continuing assistance and to whom this manuscript is dedicated. This work is supported by grants from Telethon-Italy (E.526) and EC contract BMH4-CT96-1134 to M.D'U. and by grants from the Italian Association for Cancer Research (AIRC) and from Telethon-Italy to M.R. N.A.Q. is funded by a TMR post-doctoral fellowship (ERBFMBICT960649) from the EU. L.B.R. and The Jackson Laboratory interspecific backcross mapping resource are supported by a grant from the NCHGR (HG00941). This work was also supported in part by a NIH (USA) grant (HD32243) to M.S.H.K and HG00247 to D.S.
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*To whom correspondence should be addressed. Tel/Fax: +39 81 7257247; Email: durso@iigbna.iigb.na.cnr +These authors contributed equally to this work
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