Description of a Synteny on the Chicken Chromosome Zp23-22

GENETICS

C. Y. Wang and F. C. Leung1

Department of Zoology, The University of Hong Kong, Hong Kong, China

ABSTRACT Comparative genomics offers a powerful found among these species, indicating that intrachromo- opportunity to identify the considerable synteny and somal inversions had occurred more frequently than in- thereby gain an understanding of how the genome has terchromosomal translocations since the divergence of been remodeled during evolution. Using the chicken pro- birds and mammals. Although zebraﬁsh PRLR and GHR Downloaded from https://academic.oup.com/ps/article-abstract/86/3/453/1569750 by guest on 08 December 2018 lactin receptor (cPRLR) and growth hormone receptor were localized on 2 distinct linkage groups (LG21 and (cGHR) genes as seed orthologs, 13 genes were mapped LG8), 2 syntenies on LG21 and LG5 were consistently on the chicken chromosome Z and the synteny compared with those in other vertebrates including human, chim- observed in all species examined. The current result sug- panzee, rat, mouse, and zebraﬁsh. Strikingly, highly con- gested that the 2 syntenies were extremely conserved served syntenies were noticed among the 4 mammalian during vertebrate genome evolution, and most large gene species and chicken. However, changes in arrangement syntenies including the PRLR-GHR region were formed and orientation of genes within the conserved region were after teleosts. Key words: synteny, prolactin receptor, growth hormone receptor, chicken, chromosome Z 2007 Poultry Science 86:453–459

INTRODUCTION arrangements in detail, thus providing an opportunity for a detailed synteny characterization. Studying these Synteny refers to the linkage of 2 or more genes on the molecular rearrangements is one of the approaches to same chromosome of more than 1 species. It provides a understand biological evolution at the chromosome level. concept for many conventional and convenient ap- Using high-resolution human and mouse genomes, many proaches useful in comparative genomics studies. Many conservative syntenic regions were later found to be inter- conserved syntenic regions had been identified between rupted by insertions, inversions, transpositions, deletions, birds and mammals (Burt et al., 1995, 1999; Groenen et translocations, and other sorts of rearrangements (Carver al., 1999, 2000; Nanda et al., 2002). Detecting these synten- and Stubbs, 1997; Pevzner and Tesler, 2003). ies in model organisms is a threshold to reunifying the Prolactin receptor (PRLR) and growth hormone recep- ancestral synteny before the species diverged. For the tor (GHR) belong to the growth hormone-prolactin cyto- chicken chromosome Z, previous studies demonstrated kine receptor superfamily. Chicken PRLR and GHR genes were mapped onto the chicken chromosome Zp23-22 (Ta- that major conserved syntenies were located on human naka et al., 1992; Cheng et al., 1995). The linkage of PRLR chromosomes 9 and 5, and minor syntenies on human and GHR genes was also found in human chromosome chromosomes 18 and 8 (Nanda et al., 1999, 2000, 2002; 5p14-13 (Barton et al., 1989; Arden et al., 1990), mouse Schmid et al., 2000), implying the occurrence of strong chromosome 15 (Barton et al., 1989; Nanda et al., 1999), interchromosomal rearrangements after the separation and rat chromosome 2 (Barker et al., 1992). In the current between birds and mammals. In local chromosomal re- study, a conserved syntenic region was described that gions, studies on synteny, in particular the gene order includes up to 13 genes in the human and chicken ge- inside, will facilitate the understanding of intrachromoso- nomes. These genes are located on the human chromo- mal shuffling. However, due to low resolution of genomic some 5p14-q13 (HSA5) and chicken chromosome Z maps in previously published reports, subtle internal re- (GGAZ). A comparative analysis was done in their ho- arrangements within the conserved syntenic regions have mologous chromosomes in the mouse, rat, and chimpan- not been described. The current high-resolution genomic zee. In addition, the comparison was extended to zebra- maps with confirmatively correct annotations provide a fish to test whether the GHR-PRLR syntenic region in base to demonstrate the inter- and intrachromosomal re- chicken and mammals was formed before the evolutionary divergence between teleosts and tetrapods about 450 million yr ago (Kumar and Hedges, 1998).

©2007 Poultry Science Association Inc. MATERIALS AND METHODS Received March 15, 2006. Accepted September 21, 2006. In a current study, the PRLR and GHR genes were used 1Corresponding author: [email protected] as key seed orthologs to deﬁne the gene synteny in this

453 454 WANG AND LEUNG genomic region because of their similar and unique loca- 12, chimpanzee chromosome 5, mouse chromosomes 15 tions in homologous chicken and human chromosomes and 13, and 4 zebrafish linkage groups (LG5, LG8, LG10, (Nanda et al., 2000). The identification of syntenic genes and LG21). Tables 1 and 2 briefly summarize the results of among different species is generally based on sequence chicken orthologs loci in human, chimpanzee, rat, mouse, similarity. In addition, the identification of syntenic genes and zebrafish with their corresponding NCBI or Ensembl depends heavily on the completeness and quality of gene gene accession numbers examined in the current study. annotations. The human, mouse, and rat genomes in the National Center for Biotechnology Information (NCBI) Comparative Mapping of the PRLR-GHR and chicken, chimpanzee, and zebrafish genomes in En- Syntenic Region of GGAZ sembl (www.ensembl.org), as well as their associated an- on the Mammalian Chromosomes notation, were used, to demonstrate the method of or- tholog detection. The putative genes and transcripts were With the limitation of the expressed sequence tag data- Downloaded from https://academic.oup.com/ps/article-abstract/86/3/453/1569750 by guest on 08 December 2018 then individually reviewed. To implement this method, base and genome sequence collections, chicken PRLR- based on the chicken release sequence data from Ensembl GHR syntenic regions holding more or less orthologous (Release 28, Feb. 2005), chicken candidate genes located genes were found in the mouse, rat, and chimpanzee around the PRLR and GHR regions were first identified genomes. The KIAA0303 gene was not found in the as seed orthologous genes if they satisfied the following mouse; the Ndufs4 and CENPH genes were not detected 3 criteria: 1) they have human counterparts; 2) they have in rat; and 12 orthologous genes were identified in the single locus sites on the chicken chromosome Zp23-22; chimpanzee chromosome 5. Figure 1 is a graphical repre- and 3) they have consistent order in the chicken and sentation of the conserved syntenic regions of the human human genomes. Orthologous genes were generated by HSA5p14-q13, rat genomic region 2q16-12, chimpanzee the following processes. First, the sequences of chicken chromosome 5, mouse chromosomes 15 (4.6 cM) and 13 candidate genes were used to run basic local alignment (51.0 to 64.0 cM), and chicken GGAZ. The syntenic regions search tool (BLAST) for identifying the chromosomal po- were further divided into 3 subunits in terms of internal sition on the reference genome (chicken) in Ensembl. The reversed gene order. The KIAA0303, CENPH, and THBS4 BLAST results were evaluated by the E-value threshold. genes were in subunit 1; and GHR, NNT, FGF10, ISL1, This initial step of matches was filtered to eliminate repeat ITGA1, Ndufs4, and FST genes in subunit 2; and the PRLR, sequences. By comparing E-values, the match between GDNF, and LIFR genes in subunit 3. The gene order was query and subject sequences, of at least 50 bp and sharing consistent in 3 subunits between chicken and the other at least 80% identity, was retained. Second, the retained 4 species. chicken genes acted as the seed to locate the orthologous A comparative map of the human HSA5q14-p13 and genes in the human genome. The orthologous human the chicken GGAZp showed, within the 3 subunits, the genes were selected if they satisfied the 3 criteria de- orthologs gene order was conserved, in spite of com- scribed previously in the seed orthologous genes. Or- pletely reverse gene order found in the human chromo- thologous genes were sorted by their chromosome posi- some region (Figure 2). On the chicken-mouse compara- tions to identify the syntenic regions in chicken and hu- tive map (Figure 3), 12 chicken orthologous genes (exclud- man genomes. Using chicken and human cDNA ing the KIAA0303 gene) were mapped on 2 mouse sequences as query, the rat and mouse orthologous genes chromosomes 13 and 15, respectively. Subunit 1 was well were identified from NCBI and chimpanzee and zebrafish preserved but in the reversed direction. Subunit 2 (exclud- orthologous genes from Ensembl through the same pro- ing the GHR gene) was inversely located on mouse chro- cesses described in chicken and human. mosome 13. Interestingly, the NNT, FGF10, ISI1, ITGA1, FST, and Ndufs4 loci of subunit 2 on mouse chromosome RESULTS 13 were in the same order as in the chicken. The GHR gene in the chicken was split from subunit 2 and moved A total of 13 orthologous chicken genes were identified; to the mouse chromosome 15 along with PRLR, GDNF, KIAA0303 protein (KIAA0303), centromere protein H and LIFR genes. (CENPH), Thrombospondin (THBS4), nicotinamide nu- cleiotide transhydorgenase (NNT), fibroblast growth factor 10 (FGF10), ISL1 transcription factor (ISL1), alpha Comparative Mapping of the GHR-PRLR integrin (ITGA1), Follistatin (FST), NADH dehydroge- Syntenic Region of GGAZ on Zebrafish nase Fe-S protein (Ndufs4), glial cell line-derived neuro- Chromosomes trophic factor (GDNF), and leukemia inhibitory factor receptor (LIFR) were identified and mapped. All of these To investigate whether the conserved syntenic region genes were linked together in the chicken GGAZ, and was also conserved in fish, zebrafish genome was studied their order in the chicken GGAZ served as a reference as an out-group for tracing the ancestral genome structure for the other species. Such a large gene synteny was iden- of avian and mammalian genomes. Figure 4 shows that 10 tified for the first time in the chicken, and its correspond- chicken orthologous genes were identified in 4 zebrafish ing syntenic regions were also characterized in the human linkage groups (LG). Although the GHR and PRLR were genomic region HSA5p14-q13, rat genomic region 2q16- located on distinct zebrafish linkage groups (LG8 and SYNTENY ON CHICKEN CHROMOSOME 455

Table 1. The summary of orthologous loci in the chicken, human, chimpanzee, rat, mouse, and zebraﬁsh genomes

Gene1 Chicken Human2 Mouse Rat3 Chimpanzee Zebraﬁsh

KIAA0303 Z 4.51 5q12.3 — 2q12 — — CENPH Z 5.14 5q12.3 13 D1 — 5 43.3Mb — THBS4 Z 5.25 5q13 13 C3 2q12 5 35.7Mb LG21, 5 GHR Z 6.50 5p13-12 15 4.6cM 2q16 5 73.7Mb LG8 (M) NNT Z 6.82 5p13.1-5 13 D2 2q16 5 72.7Mb LG21 (M) FGF10 Z 7.01 5p13-12 13 75cM 2q15 5 71.1Mb LG21 ISL1 Z 8.10 5q11.2 13 D2.3 2q15 5 65.5Mb LG5 ITGA1 Z 8.66 5q11.2 13 65cM 2q16-21 5 63.9Mb — FST Z 8.93 5q11.2 13 D2.2 2q16 5 63.4Mb LG5 Ndufs4 Z 8.95 5q11.1 13 D2.2 — 5 63.2Mb LG5 PRLR Z 9.80 5p14-13 15 4.6cM 2q16 5 81.56Mb LG21 GDNF Z 10.7 5p13.1-12 15 A1 2q16 5 78.8Mb LG10

LIFR Z 11.0 5p13-12 15 4.6cM 2q16 5 78.12Mb LG5 Downloaded from https://academic.oup.com/ps/article-abstract/86/3/453/1569750 by guest on 08 December 2018

1The loci of genes were taken from the Ensembl (www.ensembl.org). Zebraﬁsh THBS4, GHR, and NNT were not single copy genes. THBS4 was found in LG21 and LG5, whereas the sequences of GHR and NNT genes were localized on the 2 locations on respective zebraﬁsh chromosomes, based on the sequences data recently released (Ensembl release 40, Aug. 2006). 2The physical map location of human chromosome 5 was 34 to 79 Mbp. 3The physical map location of rat chromosome 2 was 22 to 59 Mbp.

LG21), 2 syntenies (THBS4-FST-ISL1-Ndufs4-LIFR and that the homologous region between chicken GGAZ and THBS4-FGF10-NNT-PRLR) were identified on zebrafish human HSA9 was mapped into 7 different mouse chro- LG5 and LG21, respectively. Only 2 genes, GHR and mosomes, providing another example for the special na- GDNF, were located on the LG8 and LG10. In addition, ture of gene syntenies in the mouse genome. Therefore, THBS4, GHR, and NNT were not single copy genes. These conserved syntenies are more frequently disrupted by genes were located on more than 1 position of the zebra- interchromosomal rearrangements than by intrachromo- fish linkage groups. Zebrafish LG5 and LG21 are thus somal rearrangements in mice. In contrast to human ge- probably syntenic to chicken GGAZ. nome, the mouse genome is highly derived (Burt et al., 1999), probably because of generation time (Laird et al., DISCUSSION 1969; Li et al., 1996) or body size (Martin and Palumbi, 1993; Bromham, 2002). Although the conserved syntenic A large conserved synteny of 13 chicken orthologous region was interrupted, the gene order was intact within genes has been identified in the chicken chromosome Z the 2 small syntenic regions. In view of the nearly identical and 5 other species. Although 13 chicken orthologous synteny in human, chimpanzee, and rat, the interchromo- genes were mapped in the PRLR-GHR syntenic region of somal rearrangements in the mouse are inferred to be human chromosome 5, and more or less orthologous recent events. As to the difference between the human genes in the other 4 species PRLR-GHR syntenic region, and chimpanzee, what drives the completely reversed the gene order within 3 subunits was conserved in the gene arrangement order remains a question. In summary, species examined (excluding zebrafish). In the mouse, the extensive orthologous chromosomal regions were probably because of interchromosomal rearrangements, generally disrupted by intrachromosomal re- the conserved syntenic region was split and 2 chromo- arrangements, such as inversions and translocations. somal regions were found. Nanda et al. (2000) revealed Hopefully, the rearrangement history of the chromo-

Table 2. Gene accession numbers in GenBank and Ensembl

Gene Chicken Human Mouse Rat Chimpanzee Zebraﬁsh KIAA0303 XM_424758 AB002301 — XM_001063274 — — CENPH NM_204611 NM_022909 NM_021886 ENSRNOG000000186151 DQ054165 XM_690652 THBS4 L27263 NM_003248 NM_011582 X89963 AY369846 NM_173226 GHR NM_001001293 NM_000163 NM_010284 NM_017094 XM_56938 XM_683592 NNT XM_424784 BC110544 NM_008710 BC091271 XM_517777 NM_214756 FGF10 NM_204696 NM_004465 NM_008002 NM_012951 XM_526931 NM_182870 ISL1 NM_205414 NM_002202 NM_021459 NM_017339 ENSPTRG00000168581 NM_130962 ITGA1 NM_205069 NM_181501 NM_001033228 NM_030994 ENSPTRG000000168591 XM_694435 FST NM_205200 M19480 J03771 NM_008046 NM_012561 XM_517768 NM_131037 Ndufs4 AF461018 NM_002495 NM_010887 NM_001025146 ENSPTRG000000168641 ENSDARG000000528251 PRLR NM_204854 NM_000949 NM_011169 M19304 XM_517810 AY375318 GDNF AF176017 AF053748 NM_010275 NM_019139 XM_526944 NM_131732 LIFR NM_204575 NM_002310 NM_013584 NM_031048 ENSPTRG000000168091 XM_688401 1No National Center for Biotechnology Information GenBank number is available, and Ensembl (www.ensembl.org) gene number is used as reference instead. 456 WANG AND LEUNG Downloaded from https://academic.oup.com/ps/article-abstract/86/3/453/1569750 by guest on 08 December 2018

Figure 1. A graphical representation of the conserved syntenic regions of human HSA5p14-q13, chimpanzee chromosome 5, rat chromosome 2q16-12, mouse chromosomes 13 (51.0 to 64.0 cm) and 15 (4.6 cm), and chicken GGAZ. Dotted lines indicate that the conserved syntenic region is divided into 3 subunits in terms of internal reversed gene order. somes can be discerned after sufﬁciently detailed ge- of chromosomal rearrangements between chicken and nomes for model organisms become available. human is lower, implying that the organization and struc- No matter as a branch-end or intermediate species, the ture of the chicken genome is closer to the human (Burt chicken is a model to determine an ancestral synteny for et al., 1999). Furthermore, Bourque et al. (2005) revealed mammals. Burt et al. (1999) demonstrated that the number that the number of interchromosomal rearrangements

Figure 2. Comparative map of chicken GGAZ aligned with the homologous human chromosome 5 (HSA5). Thirteen human orthologous genes were mapped on the chicken GGAZ, including CENPH, GHR, FST, and PRLR previously reported (Nanda et al., 2000). Gene order within every subunit was conserved, with the exception of gene order within the PRLR-GHR syntenic region, which was not preserved between the chicken GGAZ and human HSA5. SYNTENY ON CHICKEN CHROMOSOME 457 Downloaded from https://academic.oup.com/ps/article-abstract/86/3/453/1569750 by guest on 08 December 2018

Figure 3. Chicken GGAZ – mouse genes synteny comparative map. Twelve chicken orthologous genes (excluding KIAA0303 gene) were mapped on the mouse chromosomes 13 and 15, respectively. Subunit 1 was well conserved in spite of the reversed direction. Subunit 2 (excluding GHR) was inversely located on mouse chromosome 13, subunit 1. The GHR in chicken was shown to be split off from subunit 2, along with PRLR, GDNF, and LIFR, and moved to the mouse chromosome 15.

Figure 4. Conserved synteny with chicken GGAZ and the homologous zebrafish linkage groups (LG). The orthologous chicken genes are scattered into 4 zebrafish linkage groups; LG5, LG8, LG10, and LG21. One synteny THBS4-FGF10-NNT-PRLR was localized on the LG21. Another synteny FST-Ndufs4-ISL1-LIFR was mapped on the LG5. Genes GHR and GNDF were identified on the LG 8 and LG 10, respectively. 458 WANG AND LEUNG that occurred on the evolutionary path from human to intrachromosomal rearrangements. Here, the present chicken is slightly higher than that of interchromosomal studies of the PRLR-GHR regional syntenies among 6 rearrangements on the path from human to mouse and species revealed that 2 members of growth hormone- rat, implying that the chicken underwent an extremely prolacin cytokine receptor superfamily, PRLR and GHR, low rate of interchromosomal rearrangements during the and unrelated genes were linked together after teleosts. evolutionary path (Bourque et al., 2005). So the chicken, In local chromosome regions, variance in gene orders in as a model, provides an available opportunity to recon- syntenies are intriguing and worth further investigation. struct the architecture of the ancestral mammalian synteny. A comparative map of human HSA5p14-q13 and ACKNOWLEDGMENTS chicken GGAZp showed a translocation within a synteny that can be divided into several subunit syntenic regions. The current study was partly funded and supported by Recently, several analyses revealed a slower re- Research Grant Council of the Hong Kong Government, arrangement rate in the chicken lineage (Hillier et al., HKU7345/03M, Faculty of Science Research Develop- Downloaded from https://academic.oup.com/ps/article-abstract/86/3/453/1569750 by guest on 08 December 2018 2004), suggesting that gene order of chicken syntenies is ment Fund, and The University of Hong Kong Research closer to ancestral status than that of mammalian synten- Development Fund for Strategic Research Theme on Ge- ies. Thus, the present results indicated that at least 3 nomics, Proteomics and Bio-informatics 10206152-11222- intrachromosomal rearrangements occurred in mammals 21700-302-01. The authors are grateful to P. Y. Wang for during evolution, 2 translocations between subunit 1 and revising the manuscript and giving helpful comments. subunit 3, and an orientation inversion within subunit 3. 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