| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
Transposition of SRY into the ancestral pseudoautosomal region creates a new pseudoautosomal boundary in a progenitor of simian primates
Introduction
Results
Isolation of lemur SRY and STS
STS maps in the X-Y pairing segment-distant from SRY-in lemurs
The ancestral eutherian PAR is not larger than the modern human PAR
Discussion
STS maps within the PAR in prosimian lemurs
SRY maps distant from the PAR in prosimian lemurs
Phylogenetic timing of major events leading to the present-day human PAR
SRY transposition induces reorganization of the X-specific Xp22 segment in simian primates
Materials And Methods
Screening of a prosimian genomic library
DNA sequencing
Chromosome preparation
FISH
Fluorescence microscopy and imaging
Acknowledgements
References
Transposition of SRY into the ancestral pseudoautosomal region creates a new pseudoautosomal boundary in a progenitor of simian primates
Received June 3, 1999; Revised and Accepted August 3, 1999
We have isolated the prosimian lemur homologues for STS and SRY. FISH unambiguously co-localized STS with SHOX, IL3RA, ANT3 and PRK into the meiotic X-Y pairing region (PAR) of lemurs. In contrast to the close proximity of SRY to the pseudoautosomal boundary (PAB) on the Y chromosome in simian primates, SRY maps distant from the PAR in lemurs. Most interestingly, we were able to determine a DNA sequence divergence of 12.5% between the human and lemur SRY HMG box. This divergence directs to a 52 million year period of separate evolution of human and lemur SRY genes. Phylogenetically, this time period falls in between the times that prosimians and New World monkeys branched from the human lineage. Thus, we conclude that ~52 million years ago a transposition of SRY into the ancestral eutherian PAR distal to STS and PRK defined a new PAB in a simian progenitor. By this event, STS and PRK, amongst other genes, were excluded from the X-Y crossover process and thus became susceptible to rearrangements and/or deterioration on the Y chromosome in simian primates.
INTRODUCTION
In eutherian (placental) mammals the pseudoautosomal region (PAR) is a small region of sequence identity between the X and Y chromosomes, necessary for pairing and chiasma formation and subsequent normal segregation during male meiosis. In principle, it thus behaves like an autosomal pair (1-4). In mouse, the gene for steroid sulfatase (Sts), is part of the PAR on the distal long arms of the X and Y chromosomes, whereas Sry maps to the short arm, opposite to the PAR on the Y chromosome. In contrast, the human STS gene is located some 4 Mb proximal to the pseudoautosomal boundary (PAB) on the X chromosome (PABX), and has degenerated to a pseudogene on the human Y long arm, whereas SRY maps in close proximity to the PAB on the distal Y short arm (PABY). The idea that STS was formerly a pseudoautosomal gene is further supported by the observation that the human STS gene is only partially X-inactivated, thus giving the impression that STS is on its way to being integrated into the sex chromosome system (5). Assuming the murine Y to be closer to the ancestral Y chromosome structure of eutherian mammals, a model was postulated interpreting the STS and SRY gene locations in human as being the result of a pericentric inversion on the Y chromosome, having occurred between the times that prosimians and simians diverged (6-8). Meanwhile, substantial evolutionary molecular data for the KAL gene seem to support this model, according to which these Xp22 genes were originally part of an extended ancestral PAR. A single pericentric inversion moved the proximal portion of this ancestral PAR from Yp to Yq redefining a new PAB on X and Y chromosomes (9-11).
Comparative FISH-mapping of further Xp22 genes and their Y homologues revealed that the genes residing proximal to the PABX have a highly conserved order on the simian X chromosomes but show rearrangements on the Y chromosomes (12-16). These data are, nevertheless, at variance with the hypothetical single pericentric inversion that is proposed to have disrupted the PAR during primate evolution. In chimpanzee, orang-utan and gibbon, the Y homologues of the Xp22 genes map close to the PAR, although separated from the pseudoautosomal genes at least by the SRY and ZFY genes (14). It can furthermore be shown that homologues of the human pseudoautosomal genes ANT3 and CSF2RA, as well as homologues of the proximal Xp22 genes PRK and STS, map to the meiotic pairing regions of dog and sheep (17). Indeed, this indicates that ANT3, CSF2RA, PRK and STS could well be part of an extended ancestral PAR in non-primate eutherian mammals. Moreover, the close proximity of SRY to the PABY in all simians investigated (15,16), and the clearly visible chromosomal distance between SRY and the PABY in dog (18) and sheep (19), lends support to the view that, in an ancestral primate PAR, it was the transposition of SRY distal to STS and PRK that excluded these loci from the region of X-Y crossing-over and gave rise to the human PABY. The timing of this SRY transposition event during early primate lineage remains to be determined.
So far only in one study have human Xp22 genes been comparatively mapped on chromosomes of prosimian lemurs suggesting an autosomal location of STS and ANT3 homologues in two prosimian lemurs (20). In analogy to the translocations to autosomes of the mouse Csf2ra and Il3ra genes (21,22), these autosomal locations of STS and ANT3 were then interpreted as partial loss of the PAR in prosimians (23). However, these autosomal hybridizations of STS and ANT3 have to be interpreted with caution, as only human-derived gene sequences have been hybridized to chromosomes of such distantly related lemur species. Moreover, and most importantly, there were no data for the location of the SRY gene on prosimian Y chromosomes.
We therefore decided to isolate genomic clones for the SRY and STS genes of the prosimian crowned lemur (Eulemur coronatus) in order to simultaneously and unambiguously map SRY and STS to their relative positions on the chromosomes of prosimian lemurs, thereby also clarifying the relative mapping position of STS and ANT3.
RESULTS
Isolation of lemur SRY and STS
Screening of a genomic library of a male crowned lemur resulted in the isolation of two lemur phages each for SRY and STS. The identity of these lemur clones was verified by cross-hybridization with the human 227 bp PCR fragment SRY-high mobility group (HMG) only and the human cDNA STS3[prime], respectively.
Sequencing of one subclone of a lemur phage clone SRY2 resulted in a 517 bp sequence including the total HMG box region of the lemur SRY gene.
Using the BLAST program blastn version 2.0.8 (24) the comparison of this 517 bp sequence with known sequences in the database results in significant homologies to the SRY gene of a large number of eutherian mammalian species including the human, orang-utan, gorilla and papio. Alignment of SRY sequences of crowned lemur, human, orang-utan, gorilla and papio indicates that over this 517 bp region, including the HMG box of the SRY genes, the average sequence identity between human and crowned lemur is 69%. Within the 240 bp HMG box of the SRY gene sequence identity amounts to 87.5%.
STS maps in the X-Y pairing segment-distant from SRY-in lemurs
Chromosomal mapping of lemur-specific gene probes for STS and SRY by FISH unambiguously located STS into the distal long arm segments of the X and Y chromosomes of the ring-tailed lemur as well as of the crowned lemur. The signals for SRY appear in a clearly visible distance proximal to STS on the small acrocentric Y chromosomes of both lemur species (Fig. 1). Taking into account that a medium sized chromosomal band corresponds to ~5-10 Mb, the physical distance between STS and SRY signals can be estimated to amount to at least 5 Mb on both lemur Y chromosomes. Two-colour FISH with human-derived cosmid probes for SHOX and IL3RA as well as for SHOX and PRK on metaphase spreads of male ring-tailed and crowned lemurs resulted in a distinct co-hybridization of all these gene probes in the distal long arm segment of the X and Y chromosomes (Fig. 2a-d). In addition, in a further experiment ANT3 and PRK could also be mapped into this distal long arm segments of the X chromosomes of a female ring-tailed lemur (Fig. 2e and f). It should be pointed out that distinct FISH signals for human-derived probes could only be achieved under optimal hybridization conditions (see Materials and Methods) and, most importantly, plasma-free metaphase spreads of the lemurs. Even under such optimal conditions no specific hybridization came up with a human-derived STS probe. A synopsis of our comparative mapping data on the X and Y chromosomes in both lemur species and in the human is shown in Figure 3. Unequivocally, our FISH results show that the human-derived pseudoautosomal gene probes for SHOX, IL3RA and ANT3 as well as for PRK, located proximal to the human PAR, co-hybridize with the lemur homologue of STS on the telomeric long arms of the lemur X and Y chromosomes. Interestingly, these X and Y long arm hybridizations coincide with the meiotic X-Y pairing region of the ring-tailed lemur (25). Furthermore, it is obvious that SRY maps distant from this X-Y pairing segment on the Y chromosomes of both lemur species. Instead, on the human Y chromosome SRY is located directly adjacent to the PAR genes while PRKY and an STS pseudogene are located Y-specifically distant from the PAR.
Figure 1. Two-colour FISH of lemur-specific DNA probes for STS and SRY to metaphase chromosomes of (a) the ring-tailed lemur (L.catta) and (b) the crowned lemur (E.coronatus). The colours of the inserted gene names correspond to those of the fluorescence signals (green, biotin-FITC; red, digoxigenin-TRITC) on the DAPI-counterstained plates. Note that STS maps at the distal long arm segments of X and Y, and SRY maps in a distinct and clearly visible distance proximal to STS on the Y chromosomes of both lemur species. X and Y centromeres are marked by small bars.
Figure 2. FISH of human gene probes for SHOX, IL3RA, ANT3 and PRK to metaphase chromosomes of the ring-tailed lemur (L.catta) (a, c, e and f) and the crowned lemur (E.coronatus) (b and d). The colours of the inserted gene names correspond to those of the fluorescence signals (green, biotin-FITC; red, digoxigenin-TRITC) on the DAPI-counterstained plates. Note that all gene probes map into the distal long arm segments of X and Y chromosomes. X and Y centromeres are marked by small bars.
Figure 3. Schematic comparison of the FISH mapping data of genes on R-banded idiogrammatic layouts of the X and Y chromosomes of human, ring-tailed lemur and crowned lemur. Brackets that connect the genes within the yellow coloured meiotic X-Y pairing segment (PAR) indicate that a discrimination of these loci was not possible by FISH, thus the relative order is unknown in lemurs. Note that PRK and STS are X- and Y- specific in the human, but map within the PAR in lemurs, and that SRY maps close to the PAR in human but distant from the PAR in lemurs.
The ancestral eutherian PAR is not larger than the modern human PAR
A comparison of physical distances and arrangement of genes within the human Xp22 segment with those of the corresponding X-chromosomal segments in lemurs and dog is schematically outlined in Figure 4. At first glance a much larger ancestral eutherian PAR might be deduced from the physical distances of Xp22 genes, such as STS and PRKX, from the PAR on the human X chromosome. Our FISH-mapping data, however, clearly show that PRK and STS on the chromosomal level are not at all physically separated but show co-localization with several human pseudoautosomal genes, such as SHOX, IL3RA and ANT3, within a rather small telomeric segment on the X and Y chromosomes of the two prosimian lemur species and the dog. Interestingly, only in simian primates is the banding appearance as well as the physical gene arrangement in the Xp22 segment highly conserved as documented for the human X chromosome (26,27,14).
Figure 4. Schematic comparison of FISH mapping data of genes within the R-banded human Xp22 segment with those of corresponding X-chromosomal segments in lemurs and dog. Brackets that connect the genes within the yellow coloured meiotic X-Y pairing segment (PAR) indicate that a discrimination of these loci was not possible by FISH, thus the relative order is unknown in lemurs and dog. Note that pseudoautosomal genes including STS and PRK in lemurs and dog show co-localization within a rather small telomeric R-band on the X chromosomes in the two lemur species and the dog.
DISCUSSION
We have isolated the lemur homologues of the genes for STS and SRY. Sequencing of a subclone of the crowned lemur SRY and alignment of this SRY sequence to those of the human, gorilla, orang-utan and papio resulted in an average sequence identity of 69% between lemur and higher primate SRY. Interestingly, for the HMG box of the SRY gene this value of sequence identity amounts to 87.5%. Thus, our results confirm the data from Whitfield et al. (28) that sequence conservation of SRY is largely confined to the HMG box while showing that the flanking regions are poorly conserved in simian primates.
STS maps within the PAR in prosimian lemurs
Chromosomal mapping of the lemur-specific STS probe by FISH unequivocally located STS into the early replicating telomeric long arm segments of the X and Y chromosomes in the crowned lemur (E.coronatus) and the ring-tailed lemur (Lemur catta). Moreover, co-localization of the human pseudoautosomal genes SHOX, IL3RA and ANT3 as well as of the proximal Xp22-linked gene PRK, was demonstrated within these distal Xq and Yq regions of both lemur species. Altogether, these locations fall within the meiotic X-Y pairing region where a synaptonemal complex forms and crossing-over occurs during the pachytene stage of spermatogenesis in the ring-tailed lemur (25). Likewise, these locations are in accordance with our former mapping data for the human-derived pseudoautosomal STIR sequences on the telomeric long arm segments of lemur X and Y chromosomes (27). Thus, we conclude that STS and PRK, together with SHOX, IL3RA and ANT3, are still pseudoautosomal in both lemur species, and therefore are part of the ancestral PAR of eutherian mammals.
SRY maps distant from the PAR in prosimian lemurs
Lemur-specific SRY maps at a distinct and clearly visible distance from the PAR on Y chromosomes of the crowned lemur and the ring-tailed lemur. From our two-colour FISH experiments the physical distance between the SRY and the PAR can roughly be estimated to be at least 5 Mb on the Y chromosomes. As summarized in Table 1, in dog (18) and sheep (19) SRY also maps distant from the PABY. Furthermore, as in lemurs, homologues of STS, PRK and ANT3 map to the PAR of the dog, and homologues of STS and CSF2RA to the PAR of the sheep (17). In contrast to dog, sheep and prosimian lemurs, for the human and all other simian primates investigated, a close proximity of the SRY gene to the PABY can be demonstrated. Moreover, neither STS nor PRK homologues are pseudoautosomal but, rather, map within X- and Y-specific regions of these simian primates (15,16).
Table 1. Comparative mapping position of human X/Y homologous loci and SRY in a variety of eutherian mammalian species
| Gene locus | Humana | Lemur | Dog | Sheep | Mouse |
| SHOX | PAR | PAR | No hybridization | ||
| CSF2RA | PAR | PAR | Autosome; no. 19 | ||
| IL3RA | PAR | PAR | Autosome; no. 14 | ||
| ANT3 | PAR | PAR | PAR | No hybridization | |
| XG | Spans PABX Deleted in PABY |
No hybridization | |||
| ARSE | Xp22.33 (Yq11.21) |
No hybridization | |||
| PRK | Xp22.33 (Yp11.2) |
PAR | PAR | X-specific Near centromere |
|
| STS | Xp22.31 (Yq11.21) |
PAR | PAR | PAR | PAR |
| KAL | Xp22.31 (Yq11.21) |
No hybridization | |||
| FXY | X-specific Xp22.31 |
Spans PABX Deleted in PABY |
|||
| AMEL | Xp22.2 Yp11.2 |
X-specific Proximal PABX |
|||
| SRY | Yp11.32 Close PAB |
Yq proximal Distant PABY |
Y centromere Distant PABY |
Yq Distant PABY |
Yp Distant PABY |
Interestingly, sequence divergence of the HMG box of the SRY gene between the crowned lemur and the human can be estimated to be 12.5%. Taking into account a rate of sequence divergence of 0.24% per million years for two genetically isolated loci (29), DNA sequence divergence of the HMG box of the SRY genes of the human and the prosimian lemur goes back ~52 million years. Phylogenetically, this time period falls between the presumed branching of the prosimian lineages and the New World monkey lineage from the human lineage (30).
Therefore, we conclude that a Y chromosomal transposition of SRY into the ancestral eutherian PAR in a simian progenitor some 52 million years ago has defined a new PABY. By this transposition, STS and PRK, amongst other genes, were moved out of the PAR making them Y specific and thus susceptible to rearrangements or deterioration on the Y chromosomes in simian primates including the human.
Phylogenetic timing of major events leading to the present-day human PAR
In a broader evolutionary context it is believed that the mammalian X and Y chromosomes have evolved from an autosomal pair (31). The proto X retained and the proto Y chromosome gradually lost most ancestral genes only after the proto Y chromosome acquired a strict sex-determining function in the form of the SRY gene. Moreover, substantial experimental data suggest that the ancestral sex chromosomes of eutherian (placental) mammals resulted only after fusion with other autosomal segments comprising the ancestral eutherian PAR (32).
The experimental findings that all human pseudoautosomal genes known at present are either located autosomally or cannot be detected in the mouse genome (33,34) makes it very unlikely that the mouse PAR reflects this ancestral eutherian situation (Table 1).
As outlined in a phylogenetic tree in Figure 5, we prefer to suggest that the ancestral eutherian PAR is represented by the dog (carnivores) and the sheep (artiodactyls), and the gene content of this ancestral eutherian PAR is still conserved in the prosimian lemur and loris lineage. Although not yet proven, Southern blot data make it very likely, too, that STS is still pseudoautosomal in prosimian tarsiers (7). Our molecular and FISH mapping data strongly indicate that only after the branching of the prosimian lineages did the Y-chromosomal transposition of SRY into this ancestral eutherian PAR occur in a common ancestor of simian primates creating a new PABY just within the XG gene (38). By means of that transposition event the close proximity of SRY to the PABY in simian resulted. At the same time, several formerly pseudoautosomal genes including STS and PRK as well as KAL and ARSE were excluded from recombination and therefore became X and Y specific. On the Y chromosome these genes are now subject to further species-specific rearrangements, and/or to mutational degeneration in simian primates including the human (14). In all species of New World monkeys investigated so far, STS and KAL genes are not detectable on their Y while retained on their X chromosomes (7,10,11), leading to the assumption that this deletion must have occurred shortly after the branching of the New World monkey lineage.
Figure 5. Phylogenetic tree of the order primates modified after Martin (30); phylogenetic branching times of sheep (order artiodactyls) and dog (order carnivores), that were chosen as an outgroup, are according to Novacek (36). Major events of evolutionary modelling of the present-day human PAB are numbered. 1, ancestral eutherian PAR including STS and PRK in addition to human pseudoautosomal genes; SRY maps distant from PABY; 2, transposition of SRY into the ancestral PAR distal to STS and PRK has defined a new PAB in a simian progenitor; by this transposition STS and PRK, amongst other genes, were excluded from the X-Y crossing-over process, and SRY got in close proximity to PABY; 3, deletion of STS and KAL from the Y chromosome in New World monkeys (7,10); 4, degeneration of STS, KAL and ARSE to pseudogenes on the Y chromosomes; 5, insertion of an Alu repeat element into the proximal PAR on the Y chromosome, redefining the PAB at a position 220 bp more distal (38); Myr, million years before present.
An average sequence divergence of 12% with no significant differences between intronic and exonic regions of STS and its Y-linked pseudogene homologue STSP has been reported (7). These data strongly suggest that the Y-linked homologue lost its function soon after it started to diverge from the STS gene some 50 million years ago in a common ancestor of Old World monkeys, great apes and the human. In fact, the rates of the average sequence divergence between X and Y copies reported for the human KAL (10,11) and ARSE (13) genes differ from the STS rate and point to independent mutational events leading to deterioration and pseudogene formation of these genes on the Y chromosomes, respectively.
The present-day PABY in human is defined by an Alu repeat element that is inserted, on the Y chromosome only, in a common ancestor of great apes and human (36-38).
SRY transposition induces reorganization of the X-specific Xp22 segment in simian primates
The SRY transposition into the ancestral eutherian PAR moves several formerly pseudoautosomal genes out of the ancestral PAR making them Y specific and subject to rearrangements and deterioration on the Y chromosomes in simian primates including the human. Likewise, on the X chromosome these formerly pseudoautosomal genes like STS, KAL, ARSE and PRK were shuffled into the X-specific part of the Xp22 segment in simian primates. As shown by our comparative FISH mapping data, the physical distances and arrangements of these Xp22 genes on the X chromosomes of extant simian primates do by no means mirror their physical distances and arrangements within the PAR in prosimian lemurs, and non-primate eutherians like dog and sheep. Rather, only after the SRY transposition event did these formerly pseudoautosomal Xp22 genes become physically rearranged on a progenitor X chromosome of the simian lineage. By recom- bination in female meiosis this X-chromosomal arrangement of Xp22 genes proximal to the PAR remained highly conserved in all extant simian primates including the human.
MATERIALS AND METHODS
Screening of a prosimian genomic library
To isolate lemur genomic clones, a genomic lambda library of a male crowned lemur (E.coronatus) (Stratagene, La Jolla, CA) was screened with the cDNA probe, STS3[prime], from the human STS gene (39), and furthermore with a 227 bp PCR fragment, SRY-HMG only, containing only sequences from the HMG box region of the human SRY gene. To amplify this 227 bp fragment from human male genomic DNA by PCR, primers 5[prime]-GTGAAGCGACCCATGAACGCATTC-3[prime] (positions 274-297 in the DNA sequence SRYA; GenBank accession no. L10101), and 5[prime]-GCCTTCCGACGAGGTCGATACTTA-3[prime] (positions 477-500 in SRYA) were used. Two primary positives for each of SRY and STS were cored and subsequently rescreened at lower titres, resulting in two lemur phages for each of the SRY (SRY2 and SRY3) and STS (STS16 and STS18). Phage plating, filter lifts and clone purification were according to standard procedures.
DNA sequencing
To sequence part of lemur SRY, the isolated phage clone SRY2 was pstI digested. The restriction fragments were subcloned into Bluescript plasmid and one of the subclones was sequenced by cycle-sequencing in the ABI 310 Sequencer (Perkin Elmer, Weiterstadt, Germany).
Chromosome preparation
Chromosome spreads were prepared from phytohaemagglutinin-stimulated peripheral blood lymphocytes taken from male and female crowned lemur (E.coronatus) and ring-tailed lemur (L.catta). For all chromosome preparations standard methods were applied including hypotonic treatment with 0.56% KCl-fetal calf serum (1:1) and fixation with ethanol-acetic acid (3:1) freshly prepared for each step. The cell suspension was dropped on clean slides and air-dried at room temperature. Some of the slide preparations were stained with acridine orange (50 µg/ml) and checked for a well spreading and plasma-free preparation of metaphase plates. Only slides from such batches that were judged to present optimal metaphase preparations were considered for FISH, and stored at -80°C until use.
FISH
Prior to FISH, the slides were treated with RNase followed by pepsin digestion as described by Ried et al. (40). FISH using the human-derived cosmid probes for the pseudoautosomal genes SHOX (cos SHOX34F5) (41), IL3RA (K. Schiebel, unpublished data) and ANT3 (cos KS3) (42), as well as the Xp22 gene PRKX (cos ICRFc104I154) (12), followed essentially the methods as described (43). The amount of probe DNA used was increased to a total of 600-800 ng/hybridization, and hybridization time was increased to at least 3 days. Performing FISH with the genomic lambda clones for SRY and STS from the crowned lemur (E.coronatus) to chromosome spreads of the crowned lemur (E.coronatus) and the ring-tailed lemur (L.catta) instead of human Cot-1 DNA whole genomic DNA of a male crowned lemur (E.coronatus) sonicated to an average size between 200 and 600 bp was used. Otherwise standard conditions were applied.
Fluorescence microscopy and imaging
Preparations were evaluated using a Zeiss Axiophot epi- fluorescence microscope equipped with single-bandpass filters for excitation of red, green and blue (Chroma Technologies, Brattleboro, VT). During exposures, only excitation filters were changed allowing for pixelshift-free image recording. Images of high magnification and resolution were obtained using a black and white CCD camera (Photometrix Kodak KAF 1400; Kodak, Tucson, AZ) connected to the Axiophot. Camera control and digital image acquisition involved the use of an Apple Macintosh Quadra 950 computer.
ACKNOWLEDGEMENTS
We thank Ann Chandley and Michael Leipoldt for critical reading of the manuscript, Walter Just and Dietmar Pfeifer for valuable technical discussions, and Sylvia Richter for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Sche 214/6-3/4).
REFERENCES
+To whom correspondence should be addressed. Tel: +49 761 270 7062; Fax: +49 761 270 7041; Email: schemppw{at}ukl.uni-freiburg.de
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