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300 million years of conserved synteny between chicken Z and human chromosome 9
Author: I. Nanda
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"B irds diverged from mammals 300?350 million years ago 1 (Mya). In mam- mals, the male is the heterogametic sex (XY male and XX female) and ?maleness? is under the control of a testis-determin- ing factor, SRY, located on the Y chromo- some. In contrast, sex determination in birds operates through a ZZ/ZW system in which the female is the heterogametic sex. It is not clear, however, whether this system is controlled by a dominant factor on the W chromosome or by Z-chromosome dosage 2,3 . Comparative gene mapping is an effec- tive tool for the study of genome evolution in phylogenetically distant species that represent key stages in vertebrate evolu- tion. The presence of orthologous genes on interspecific homologous chromosome segments (conservation of synteny) reflects the common phylogenetic origin of species and probably also the ancestral genomic organization 4,5 . Using both physical and genetic methods 6,7 , we found that 11 of 18 genes of the chicken Gallus gallus, GGA Z chromosome have ortho- logues on human (HSA) chromosome 9, bands pter- q22 (Fig. 1). Although the overall homology between GGA Z and HSA 9 is extensive, the gene order has changed. For example, an inversion has moved GGTB2- ACO1 to the Z-long arm or to the HSA 9-short arm. Additional translocations or insertion events during vertebrate evolution have moved smaller segments from the avian Z to other chro- mosomes. The distal long arm of HSA 9q32- qter shows conserved synteny with the chicken linkage group E41W17, which corresponds to a microchromosome. In contrast with Ohno?s original prop- osition 8 , the avian and mammalian sex chromosomes have evolved indepen- dently. Chicken Z and W share two genes and appear to be remnants of an ancestral pair of chromosomes 9 . Our results show that this ancestral autosome gave rise to most of avian Z and HSA 9. The delin- eated homology represents thus far the largest region of chromosomal synteny that has been conserved since separation of the avian and mammalian lineages over 300 Mya. In mammals, sex is determined by the male-dominant factor on the Y chromo- some, SRY (ref. 10). Sex-reversal syn- dromes in humans, however, indicate the presence of other downstream sex-deter- mining genes. Monosomy for the distal short arm of HSA 9 has been associated with failure of testicular development and XY sex reversal, which is most likely due to haploinsufficiency of a dosage-sensitive gene 11,12 . Recently, the human DM- domain gene expressed in the testis, 300 million years of conserved synteny between chicken Z and human chromosome 9 correspondence 258 nature genetics ? volume 21 ? march 1999 in the highly conserved ?YXDD? motif (Fig. 1a). The existence of alleles with an intact YXDD-motif, and therefore a pre- sumably completely intact provirus, is not known. The HERV-K(HML-2.HOM)- encoded proteinase demonstrated self- cleavage and processing of the Gag protein 7 (Fig. 2). HERV-K10- encoded endonuclease has been reported to have enzymatic activity 8 . We have noted that the endonuclease ORF of HERV-K(HML- 2.HOM) is nearly identical to the HERV- K10 endonuclease (data not shown), suggesting that it is likely to be active 9 . The 3� portion of pol, the env gene and the 3� LTR sequence share sequence iden- tity with a described env mRNA (ref. 10), indicating that the formerly described env sequence originated from the HERV-K provirus and that the provirus retained transcriptional activity. Part of an Alu ele- ment (54 bp) was identified immediately downstream of the 3� LTR, and therefore it is possible that the provirus integrated into an Alu element, with the remaining Alu sequence upstream of the 5� LTR. FISH analysis using the env sequence of HERV- K(HML-2.HOM) localized the provirus to chromosome 7p22 (data not shown). Using primers specific to the env sequence of HERV-K(HML-2.HOM) (nt 8,406- 8,430) and 3� flanking Alu sequence, we amplified a product of expected size (1.2 kb) in 54 human DNA samples from vari- ous ethnic groups (European, African and Asian). This indicates that at least one human chromosome 7 in each of these individuals harbours the proviral sequence. HERV-K(HML-2.HOM) therefore seems to be frequent, if not ubiquitous, in the human population. In contrast, no such PCR product was amplified from a chim- panzee DNA sample (data not shown), indicating that the provirus integrated into the human genome after the evolutionary split from chimpanzee. HERV-K(HML-2.HOM) is the most intact human endogenous retrovirus yet identified. The explanation for why an intact HERV-K provirus, or any of its genes, should be preserved during evolu- tion remains unclear. HERV-K(HML- 2.HOM) may have arisen from retrotransposition, which in Hominoidea appears to have involved only the HERV- K(HML-2.HOM) proviruses harbouring a partially deleted gag gene 11 . The findings described here and in another study 12 sug- gest that the HERV-K(HML-2) provirus retained retrotranspositional activity until a relatively recent period in evolutionary time. Retrotransportation, however, would require a second, almost intact provirus, raising the question of the origin of the this latter provirus. This may have involved the germ cell integration of an exogenous HERV-K(HML-2) variant. Acknowledgements We thank N. Kienzle for providing African, Asian and Oceanian DNA samples and B. Glass for critical reading of the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Mu 452/4-1 and SFB 399?Molekularpathologie der Proliferation A1/B2) and the Commission of the European Union (Gene-CT 93-0019). Jens Mayer 1,2 , Marlies Sauter 2 , Alexander R�cz 1 , Daniela Scherer 1 , Nikolaus Mueller-Lantzsch 2 & Eckart Meese 1 1 Institut f�r Humangenetik, Haus 60; 2 Institut f�r Medizinische Mikrobiologie und Hygiene, Abteilung Virologie, Haus 47; Universit�tskliniken des Saarlandes, 66421 Homburg/Saar, Germany. Correspondence should be addressed to E.M. (e-mail: hgemee@med-rz.uni-sb.de). 1. Ono, M., Yasunaga, T., Miyata, T. & Ushikubo, H. J. Virol. 60, 589?598 (1986). 2. Lower, R., Lower, J. & Kurth, R. Proc. Natl Acad. Sci. USA 93, 5177?5184 (1996). 3. Mayer, J., Meese, E. & Mueller-Lantzsch, N. Cytogenet. Cell Genet. 78, 1?5 (1997). 4. Mayer, J., Meese, E. & Mueller-Lantzsch, N. Cytogenet. Cell Genet. 79, 157?161 (1997). 5. Dangel, A.W., Baker, B.J., Mendoza, A.R. & Yu, C.Y. Immunogenetics 42, 41?52 (1995). 6. Lavrentieva, I. et al. Hum. Genet. 102, 107?116 (1998). 7. Mueller-Lantzsch, N. et al. AIDS Res. Hum. Retroviruses 9, 343?350 (1993). 8. Kitamura, Y., Ayukawa, T., Ishikawa, T., Kanda, T. & Yoshiike, K. J. Virol. 70, 3302?3306 (1996). 9. Kulkosky, J., Jones, K.S., Katz, R.A., Mack, J.P. & Skalka, A.M. Mol. Cell. Biol. 12, 2331?2338 (1992). 10. Lower, R., Tonjes, R.R., Korbmacher, C., Kurth, R. & Lower, J. J. Virol. 69, 141?149 (1995). 11. Mayer, J., Meese, E. & Mueller-Lantzsch, N. J. Virol. 72, 1870?1875 (1998). 12. Medstrand, P. & Mager, D.L. J. Virol. 72, 9782?9787 (1998). 13. Rao, J.K., Erickson, J.W. & Wlodawer, A. Biochemistry 30, 4663?4671 (1991). 14. Repaske, R., Hartley, J.W., Kavlick, M.F., O?Neill, R.R. & Austin, J.B. J. Virol. 63, 1460?1464 (1989). � 1999 Nature America Inc. ? http://genetics.nature.com � 1999 Nature America Inc. ? http://genetics.nature.com correspondence nature genetics ? volume 21 ? march 1999 259 DMRT1, which shares significant struc- tural homology with male sexual regula- tory genes from Caenorhabditis elegans (mab-3) and Drosophila melanogaster (dsx), has been identified in the critical region 13 . We reasoned that an orthologous gene on GGA Z might be involved in avian testis development. A human DMRT1 EST (AA412330) was used to isolate a 1.5-kb chicken cDNA (TUPSp573J1773Q3, RZPD library 573). This cDNA was used as a probe to isolate a cosmid (MPMGc125B0641Q5, RZPD library 125) that was then FISH mapped to GGA Zp21 (Fig. 2). The amino acid trans- lation of the cDNA sequence (GenBank accession number AF123456) revealed a DM domain showing 86% similarity to human DMRT1, indicating that it is a true homologue of DMRT1. Hybridization of chicken genomic and cosmid DNA with DMRT1 cDNA under low stringency con- ditions indicated the presence of a single DM-domain gene in chicken. As SRY is not sex-specific in birds and reptiles, it cannot be considered an ances- tral vertebrate sex-determining gene. Because of its chromosomal location and the fact that its male regulatory function is highly conserved across evolution, DMRT1 is, so far, the only candidate testis-deter- mining gene in birds. Two other Z-linked genes, ZOV3 and VLDLR, have been impli- cated in the function of the chicken ovary 14,15 . It may be that two copies of DMRT1 are required for testis formation, whereas a single copy along with the W chromosome leads to female sexual differ- entiation. This is consistent with the view that, although sex determination has undergone considerable evolutionary changes, regulatory genes such as DMRT1 are highly conserved in their function 3 . Acknowledgements We thank W.J. Schneider, V.M. Fowler, G. Dechant and G. Goodwin for providing chicken DNA probes; H.H. Arnold, B. Andree and T. Brand for the chick cDNA library; and C. M�ller for help with the preparation of the manuscript. Supported by grants from the Commission of the European Communities (FAIR PL97-3796, BIO4 98-0288) and the German Research Foundation (Ha 1374/5-1). Genome research at the Roslin Institute is supported by the Ministry of Agriculture, Fisheries and Food, the Biotechnology Sciences Research Council and the Commission of the European Communities. Indrajit Nanda 1 , Zhihong Shan 2 , Manfred Schartl 3 , Dave W. Burt 4 , Michael Koehler 1 , Hans- Gerd Nothwang 2 , Frank Gr�tzner 2 , Ian R. Paton 4 , Dawn Windsor 4 , Ian Dunn 4 , Wolfgang Engel 5 , Peter Staeheli 6 , Shigeki Mizuno 7 , Thomas Haaf 2 & Michael Schmid 1 1 Department of Human Genetics, Biocenter, University of W�rzburg, D-97074 W�rzburg, Germany. 2 Max-Planck-Institute of Molecular Genetics, D-14195 Berlin, Germany. 3 Department of Physiological Chemistry I, Biocenter, University of W�rzburg, Germany. 4 Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS, Scotland, UK. 5 Department of Human Genetics, University of G�ttingen, Germany. 6 Department of Virology, University of Freiburg, D-79008 Freiburg, Germany. 7 Department of Applied Biological Chemistry, Tohoku University, Sendai 981, Japan. 1. Kumar, S. & Hedges, S.B. Nature 392, 917?920 (1998). 2. Bull, J.J. Evolution of Sex Determining Mechanisms (Benjamin Cummings, Menlo Park, California, 1983). 3. Marin, I. & Baker B.S. Science 281, 1990?1994 (1998). 4. Andersson, L. et al. Mamm. Genome 7, 717?734 (1996). 5. O?Brien, S.J. et al. Nature Genet. 3, 103?112 (1993). 6. Nanda, I. et al. Chromosoma 107, 204?210 (1998). 7. Burt, D.W., Bumstead, N., Bitgood, J.J., Ponce de Leon, F.A. & Crittenden, L.B. Trends Genet. 11, 190?194 (1995). 8. Ohno, S. Sex Chromosomes and Sex-linked Genes (Springer-Verlag, New York, 1967). 9. Fridolfsson, A.-K. et al. Proc. Natl Acad. Sci. USA 95, 8147?8152 (1998). 10. Goodfellow, P.N. & Lovell-Badge, R. Annu. Rev. Genet. 27, 71?92 (1993). 11. Flejter, W.L., Fergestad, J., Gorski, J., Varvill, T. & Chandrasekharappa, S. Am. J. Hum. Genet. 63, 794?802 (1998). 12. Guioli, S. et al. Am. J. Hum. Genet. 63, 905?908 (1998). 13. Raymond, C.S. et al. Nature 391, 691?695 (1998). 14. Kunita, R., Nakabayashi, O., Kikuchi, T. & Mizuno, S. Differentiation 62, 63?70 (1997). 15. Bujo, H. et al. Proc. Natl Acad. Sci. USA 92, 9905?9909 (1995). Chick Z Chick microchromosome (linkage group E41W17) IFN1/IFNA1 IFN2/IFNB1 DMRT1 VLDLR NTRK2 GGTB2/B4GALT1 ACO1 TMOD ALDOB PTCH AMBP ABL1 AK1 RPL7A CD39L1 BRM/SMARCA2 Human 9 Fig. 1 Comparative loca- tion of orthologous genes on chicken Z and human chromosome 9. The G-banded idiogram of chicken (GGA) Z chro- mosome (left) opposite an idiogram of G- banded human (HSA) chromosome 9 (right). Comparatively mapped genes are indicated between the idiograms. The distal long arm of HSA 9q32- qter appears to be homologous to chicken linkage group E41W17 on a microchro- mosome. Human map- ping information was obtained from OMIM. Fig. 2 FISH mapping of DMRT1 on chicken Z chromosome. a, Hybrid- ization of DMRT1 cos- mid to a female chicken metaphase spread. The biotinylated DNA probe is detected by FITC- avidin (green fluores- cence). Chromosomes are counterstained with DAPI. b, DAPI banding of the same metaphase spread, converted by Oncor Image software into G-like bands. c, G- banded karyotype of chicken macrochromo- somes hybridized with DMRT1 (green spot on Z chromosome). a c b � 1999 Nature America Inc. ? http://genetics.nature.com � 1999 Nature America Inc. ? http://genetics.nature.com "
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