A complete DNA sequence map of the ovine Major Histocompatibility Complex

  • Jianfeng Gao1, 2Email author,

    Affiliated with

    • Ka Liu2, 4Email author,

      Affiliated with

      • Haibo Liu2, 4,

        Affiliated with

        • Hugh T Blair3,

          Affiliated with

          • Gang Li1, 2,

            Affiliated with

            • Chuangfu Chen1,

              Affiliated with

              • Pingping Tan2 and

                Affiliated with

                • Runlin Z Ma2, 4Email author

                  Affiliated with

                  BMC Genomics201011:466

                  DOI: 10.1186/1471-2164-11-466

                  Received: 10 May 2010

                  Accepted: 10 August 2010

                  Published: 10 August 2010

                  Abstract

                  Background

                  The ovine Major Histocompatibility Complex (MHC) harbors clusters of genes involved in overall resistance/susceptibility of an animal to infectious pathogens. However, only a limited number of ovine MHC genes have been identified and no adequate sequence information is available, as compared to those of swine and bovine. We previously constructed a BAC clone-based physical map that covers entire class I, class II and class III region of ovine MHC. Here we describe the assembling of a complete DNA sequence map for the ovine MHC by shotgun sequencing of 26 overlapping BAC clones.

                  Results

                  DNA shotgun sequencing generated approximately 8-fold genome equivalent data that were successfully assembled into a finished sequence map of the ovine MHC. The sequence map spans approximately 2,434,000 nucleotides in length, covering almost all of the MHC loci currently known in the sheep and cattle. Gene annotation resulted in the identification of 177 protein-coding genes/ORFs, among which 145 were not previously reported in the sheep, and 10 were ovine species specific, absent in cattle or other mammals. A comparative sequence analyses among human, sheep and cattle revealed a high conservation in the MHC structure and loci order except for the class II, which were divided into IIa and IIb subregions in the sheep and cattle, separated by a large piece of non-MHC autosome of approximately 18.5 Mb. In addition, a total of 18 non-protein-coding microRNAs were predicted in the ovine MHC region for the first time.

                  Conclusion

                  An ovine MHC DNA sequence map was successfully assembled by shotgun sequencing of 26 overlapping BAC clone. This makes the sheep the second ruminant species for which the complete MHC sequence information is available for evolution and functional studies, following that of the bovine. The results of the comparative analysis support a hypothesis that an inversion of the ancestral chromosome containing the MHC has shaped the MHC structures of ruminants, as we currently observed in the sheep and cattle. Identification of relative large numbers of microRNAs in the ovine MHC region helps to provide evidence that microRNAs are actively involved in the regulation of MHC gene expression and function.

                  Background

                  The sheep is one of the major domestic animal species for human meat protein, milk, and its wool is a source of industrial fiber. The Major Histocompatibility Complex (MHC) of the sheep, also designated as ovine Lymphocyte Antigen (OLA), harbors clusters of immunological genes involved in overall resistance/susceptibility of the animal to infectious diseases [13]. A number of agriculturally important traits, especially those related to disease resistance to various pathogenic viruses, bacteria and parasites, are closely linked to genes in the MHC [46]. Furthermore, genetic loci in the MHC are organized to form distinct functional clusters as class I, class II, and class III, which show a considerable level of conservation among mammal species [719]. The importance of sheep MHC molecules in disease resistance [6, 2023] and the associated structure features in artiodactyls have led to increased studies on the sheep MHC [5, 21, 2426]. However, the detailed sequence information for ovine MHC is not sufficiently adequate, and only a small number of ovine MHC genes have been identified as compared to those in sheep and cattle.

                  Studies of the ovine MHC also help to provide valuable information on comparative genome evolution in mammals. The extreme high level of polymorphism observed for MHC loci may be a result of the evolutionary consequences of intensive interactions between infectious pathogens and the host defensive system [7]. Haplotype difference among different breeds adds another level of complexity. Previous studies on the OLA have largely been focused on the gene content and polymorphisms of the class region [2732]. Based on the genetic linkage studies, the ovine MHC seems to have a special feature in that the class II has been divided into two sub-regions, similar to that of bovine [3337]. However, with the limited sequence information available for the sheep, such structural features can not be adequately assessed by comparison with that of the cattle.

                  We previously constructed a BAC-clone-based physical map of the ovine MHC for Chinese merino fine-wood sheep [26], a valued sheep breed predominant in Northwest China especially in the Xinjiang Uygur autonomous region. The DNA used for BAC library construction was obtained from a heterozygous Chinese merino male, this animal being a merino ram that shares less than 1/32 of the blood from a local Chinese sheep breed. The BAC clone source we established facilitates the physical map construction for sheep MHC and for whole sheep genome, which serve as a reference frame work for subsequent sequencing. To facilitate the DNA sequencing, a BAC clone gap which previously existed between locus Notch4 and Btnl2 was successfully closed by addition of two more overlapping BAC clones [38].

                  Here we describe our work on sequencing of the entire ovine MHC by shotgun sequencing of the 26 BAC clones, assembling of the sequence data into a finished DNA sequence map as guided by the physical map, and the sequence analysis that resulted in identification and annotation of 177 genes and 18 microRNAs in ovine MHC region.

                  Results and Discussion

                  DNA shotgun sequencing was successfully performed for 26 overlapping BAC clones, generating approximately 8-fold coverage of the genome equivalent data. The fully-assembled sequences for all of the BAC clones were deposited into GenBank with accession numbers FJ986852 - FJ985877 (Table 1). The quality of the sequence determined was adequate, with an estimated error rate less than 0.025% for most of the BAC clones. An average of 1.3 gaps existed per BAC clone, mostly due to highly repetitive sequence. A gap here refers to a stretch of DNA for which the exact nucleotide base identity (A, G, T, or C) remain ambiguous after resequencing, represented by a tandem number of "N" between the determined sequences.
                  Table 1

                  Assembly of 26 BAC-clone based DNA sequences covering entire Ovine MHC region

                  BAC clone ID

                  GenBank Accession Number

                  Insert length (bp)

                  Average coveragea

                  Single-base error probabilityb

                  Reads numberc

                  High repeat sequence

                  Scaffoldsd

                  No. of Gaps insidee

                  No. of Gaps outside

                  271H22

                  FJ985865

                  159959

                  7.93491

                  1.118 × 10-4

                  2974

                  No

                  1

                  0

                  0

                  304C7

                  FJ985867

                  134586

                  8.0733

                  2.127 × 10-4

                  2509

                  Yes

                  1

                  1

                  0

                  142M19

                  FJ985860

                  134479

                  8.11391

                  4.257 × 10-4

                  2715

                  Yes

                  1

                  2

                  0

                  373D13

                  FJ985872

                  172485

                  8.15691

                  5.308 × 10-4

                  3311

                  No

                  1

                  3

                  0

                  283N15

                  FJ985866

                  155021

                  7.165

                  0.268 × 10-4

                  2472

                  No

                  1

                  0

                  0

                  222G18

                  FJ985862

                  167309

                  7.78757

                  0.790 × 10-4

                  2783

                  No

                  1

                  0

                  0

                  55L9

                  FJ985854

                  145292

                  8.22565

                  0.195 × 10-4

                  2941

                  No

                  1

                  0

                  0

                  197N2

                  FJ985876

                  90102

                  6.50404

                  0.488 × 10-4

                  1438

                  No

                  1

                  2

                  0

                  429P24

                  FJ985873

                  198404

                  9.02502

                  3.497 × 10-4

                  4009

                  No

                  1

                  2

                  0

                  225J15

                  FJ985863

                  139059

                  7.9057

                  68.30 × 10-4

                  2335

                  Yes

                  1

                  1

                  0

                  453O11

                  FJ985874

                  143310

                  8.05201

                  0.802 × 10-4

                  2473

                  No

                  1

                  2

                  0

                  63M17

                  FJ985856

                  129209

                  8.52801

                  37.780 × 10-4

                  2394

                  No

                  1

                  1

                  0

                  163P3

                  FJ985861

                  165447

                  7.55517

                  1.049 × 10-4

                  2833

                  No

                  1

                  0

                  0

                  119K1

                  FJ985858

                  156603

                  7.75008

                  0.309 × 10-4

                  2665

                  No

                  1

                  2

                  0

                  349I12

                  FJ985871

                  149708

                  8.4984

                  7.600 × 10-4

                  2994

                  No

                  1

                  2

                  0

                  345B17

                  FJ985869

                  134643

                  7.69046

                  10.58 × 10-4

                  2736

                  No

                  2

                  0

                  1

                  68G10

                  FJ985857

                  165531

                  8.14164

                  6.535 × 10-4

                  3681

                  Yes

                  1

                  1

                  0

                  346G21

                  FJ985870

                  138311

                  8.67944

                  9.059 × 10-4

                  2807

                  No

                  1

                  1

                  0

                  44I10

                  FJ985853

                  134434

                  8.32584

                  16.47 × 10-4

                  2705

                  No

                  1

                  2

                  0

                  282P19

                  FJ985875

                  174317

                  7.27217

                  0.490 × 10-4

                  2989

                  No

                  2

                  1

                  1

                  239C1

                  FJ985864

                  142287

                  7.9438

                  0.736 × 10-4

                  2940

                  No

                  1

                  2

                  0

                  141C4

                  FJ985859

                  160633

                  7.65743

                  0.624 × 10-4

                  2992

                  No

                  1

                  1

                  0

                  374N21

                  FJ985877

                  83460

                  9.112

                  3.860 × 10-4

                  3648

                  No

                  2

                  1

                  1

                  21H3

                  FJ985852

                  119055

                  8.13723

                  0.380 × 10-4

                  2157

                  No

                  1

                  1

                  0

                  304D17

                  FJ985868

                  140735

                  8.14013

                  4.291 × 10-4

                  2599

                  No

                  1

                  1

                  0

                  58G13

                  FJ985855

                  135958

                  8.827674

                  2.187 × 10-4

                  3845

                  No

                  2

                  4

                  0

                  a Defined as a ratio between total number of base pairs sequenced and total number of base pairs of the inserts in a given BAC clone.

                  b Error probability of a particular base call, corresponding to a quality value as determined by the equation:

                  Q = -10log10(Pe), where Pe is the error probability.

                  c The total number of shotgun DNA sequencing reactions performed for a given BAC clone.

                  d In genomic mapping, a series of contigs that are in the right order but not necessarily connected in one continuous stretch of sequence.

                  e The number of regions where the exact nucleotide base (G, A, T, or C) could not determined, represented by a strips of "N" in a given BAC clone.

                  A complete DNA sequence map of the ovine MHC was successfully assembled as guided by the BAC clone physical map (Figure 1). The map spans approximately 2,434,000 nucleotide bases in length, covering almost all MHC loci currently known for both ovine and bovine species. The finished sequence map was discontinuous, as expected from the physical map. The major sequence segment spans approximately 2,071,000 nucleotide bases, harboring class I, class III, and class IIa of the ovine MHC. The shorter sequence segment spans approximately 363,000 nucleotide bases, harboring loci in the class IIb region and extending into the non-MHC region.
                  http://static-content.springer.com/image/art%3A10.1186%2F1471-2164-11-466/MediaObjects/12864_2010_Article_3060_Fig1_HTML.jpg
                  Figure 1

                  A feature map of Ovine MHC sequence. The map spans 2,434,000 nucleotide bases in length, containing 177 protein-coding genes/ORFs and 18 miRNA coding genes. Each locus is represented by an arrow or arrow head, and annotated according to type, orientation, and location within the MHC. The tiling path of the sequenced BACs and the MHC structure are shown on the top. Micro RNA (18 shown): Identified gene that has high sequence homology with conserved gene encoding the functional mircoRNA in other species, noted following the given name of that species. Predicted (36 shown): Gene that either has high sequence similarity to that of the predicted gene in other species, or has a predicted ORF but no high sequence homologies with ESTs of Ovine or other species. Novel (10 shown): Ovine-specific gene identified with a defined open reading frame (ORF) that has not been found in any other species to date. The novel genes are annotated with OaN1 to OaN8 (Oa for Ovis aries; N for novel; another two with no cloning data, no annotation), from left to the right of the map. Known (131 in total): The functional genes previously annotated in Bovine, Ovine or other species.

                  Sequence analysis resulted in the identification and annotation of 177 protein-coding genes/ORFs in the ovine MHC (Figure 1, Additional table 1). Of the 177 ovine genes identified, 131 were homologous to previously annotated genes in cattle, sheep or other mammal species, 36 matched to the predicted but not yet annotated genes in the cattle, and 10 were ovine species specific, having not been found in human, mouse, cattle or other mammal sequences. The location, transcriptional orientation, and relative size of the identified genes were determined (Figure 1). Among the genes identified, a total of 145 identified ovine genes were reported for the first time by this study. The ovine-specific genes were temporally nominated as "OaN " followed by a numeric number, where "Oa" is abbreviation for Ovis aries, and "N" for novel (Additional file1). Preliminary experiments confirmed the mRNA transcripts for 4 of the predicted ovine-specific genes (data not shown). The distribution of these novel genes seems to be random throughout the ovine MHC region. It is interesting to notice that a multiple DQ loci (DQ cluster) were identified, each with different orientation of transcription, when compared with those of other sheep breeds [39, 40]. Such difference may be due either to breed or haplotype differences, as a subsequence of differential gene duplication [41].

                  An additional 18 genes encoding micro RNAs were identified by software prediction in an effort to search for non-protein-coding genes/components using the Rfam database analysis tools (Table 2). The orientation and distribution of these micro RNAs showed a randomized pattern throughout MHC region. This is the first time that a relatively large number of microRNAs have been identified in ovine MHC region. Given the functional importance of microRNAs for regulating gene expression by mRNA cleavage or repression, this preliminary finding help to provide evidence that microRNAs may be actively involved in the MHC response to pathogens in general.
                  Table 2

                  List of non-protein-codning microRNA genes identified in MHC by Rfam analysis

                  Gene Name

                  Rfam Accession No.

                  Start coordinate

                  End coordinate

                  Orientation

                  Scorea

                  let-7

                  RF00027

                  35

                  51

                  +

                  34.2

                  miR-160

                  RF00247

                  173327

                  173343

                  +

                  34.2

                  miR-156

                  RF00073

                  180706

                  180722

                  -

                  34.2

                  miR-17

                  RF00051

                  243137

                  243153

                  -

                  34.2

                  miR-166

                  RF00075

                  465267

                  465295

                  +

                  34.2

                  miR-166

                  RF00075

                  1062114

                  1062131

                  -

                  36.2

                  miR-2

                  RF00047

                  1243062

                  1243078

                  +

                  34.2

                  lin-4

                  RF00052

                  1608564

                  1608580

                  +

                  34.2

                  miR-10

                  RF00104

                  1978042

                  1978059

                  +

                  36.2

                  miR-101

                  RF00253

                  2046800

                  2046816

                  +

                  34.2

                  miR-395

                  RF00451

                  2082358

                  2082373

                  -

                  32.2

                  miR-156

                  RF00073

                  2084006

                  2084023

                  -

                  36.2

                  miR-219

                  RF00251

                  2098884

                  2098955

                  -

                  127

                  miR-219

                  RF00251

                  2098930

                  2098950

                  -

                  42.1

                  miR-156

                  RF00073

                  2131290

                  2131307

                  -

                  36.2

                  miR-156

                  RF00073

                  2339014

                  2339030

                  +

                  34.2

                  miR-166

                  RF00075

                  2348202

                  2348217

                  -

                  32.2

                  miR-399

                  RF00445

                  2354071

                  2354086

                  +

                  32.2

                  a The scores are bits (logs-odds) scores which represent the log of the probability of the query given the model over the probility of random sequence given the model.

                  Sequence alignments among the human, sheep, and cattle MHC showed an overall conservation, with the level of homology reaching over 85% for the MHC class I, class III, and part of class II regions. The major difference in the MHC structures was found in the class II region. In human it was a continuous segment with no interruption, while in the sheep and cattle it was divided into IIa and IIb subregions by a large piece of non-MHC autonomic insertion. In addition, the gene order of class IIb in both ovine and bovine regions showed an opposite orientation relative to that of human (Figure 2).
                  http://static-content.springer.com/image/art%3A10.1186%2F1471-2164-11-466/MediaObjects/12864_2010_Article_3060_Fig2_HTML.jpg
                  Figure 2

                  Gene order comparisons for the selected class II loci from HLA, OLA, and BoLA. Genetic loci in class II region were compared by aligning HLA, OLA and BoLA at telemere→centromere orientation. The orthologous loci were linked by solid lines. Solid and open box represent the selected class II loci and non-MHC loci, respectively. Shaded carmine boxes indicate regions of conservation among species. Red ellipses indicate the potential breaking points. Tel : Telomere, Cen : Centromere.

                  Analysis of the sequence homology between ovine and bovine MHC regions demonstrated a remarkable conservation, with the overall homology reaching 86%. The actual level of homology could be higher because a number of gaps (over 10-40 kb) in the available bovine sequence contributed negatively to the homology score. For virtually any locus currently identified in bovine MHC, a homologous match could be identified in the ovine MHC, including those in the class IIb region (Figure 2). It is noteworthy that the ovine and bovine MHC class IIa and IIb regions exhibited exactly the same gene order and structural layout. In addition, the piece of non-MHC autonomic insertion between IIa and IIb was estimated to be of the same length (approximately 18.5 Mb) for both species. Furthermore, the order of bovine and ovine genetic loci within the inserted autonomic region was essentially the same as tested by over 120 SS-PCRs (data not shown). Taken together, these results support the hypothesis that cattle and sheep shared an ancestral chromosome containing the MHC before their divergence by evolution.

                  The hypothesis that cattle and sheep shared an ancestral chromosome was previously proposed in the studies of cattle [4244]. Detailed mapping of BTA23 by radiation hybrid analysis [43, 45] suggested that the ancestral MHC was likely disrupted by a large inversion that produced the bovine MHC class IIa and IIb regions. With the availability of detailed sequence information from the two ruminant species (bovine and ovine), the hypothesis has now gained additional support from the experimental data.

                  Our sequence analysis also identified a butyrophilin-like (Btnl) cluster at the boundary between the ovine class IIa and III (Figure 3). Banal is critical for milk secretion and production [46]. Comparison of Btnl loci duplication showed that sheep has a moderate number of Btnl copies, more than that seen in platypus but less than those shown by mouse, rat or swine that have a larger litter sizes (Figure 3). Btnl is absent in non-mammal species like amphioxus, frog, and chicken, appears (Btnl2) in platypus, and is duplicated extensively in mammals that have more litter sizes. This might be an indication that milk production was closely associated with the function of MHC in mammals, due to the apparent need for mammals to protect their offspring from microbial infections via milk ingestion. Taken together, we propose a hypothesis that, formation of the Btnl loci is associated not only with the gene duplication of immunological loci, but also with the emergence of mammals in evolutionary history.
                  http://static-content.springer.com/image/art%3A10.1186%2F1471-2164-11-466/MediaObjects/12864_2010_Article_3060_Fig3_HTML.jpg
                  Figure 3

                  A comparative alignment ofBtnlloci among known MHC/loci of different species. Solid and open box represent the known coding gene and predicted gene, respectively, with an arrow head of box indicating the orientation of gene transcription. A numeric number in a solid box indicates the gene family number of Btnl families. MHC of swine was interrupted by the Centromere as shown

                  Conclusion

                  A complete ovine MHC sequence map was assembled by successful shotgun sequencing of 26 overlapping BAC clones. This makes the sheep the second ruminant species for which the MHC sequence is available for evolutionary and functional studies. Gene annotation resulted in the identification of 177 genes, among which 145 were identified for the first time, and 10 were ovine-species specific. In addition, a total of 18 microRNAs coding sequences were predicted in the ovine MHC for the first time. Comparative analysis revealed a remarkable conservation of MHC sequence between sheep and cattle, supporting the hypothesis that the two species shared an ancestral chromosome that shaped the ruminant MHC as currently observed. Identification of a relatively large number of micro RNAs in the ovine MHC region helps to provide evidence that micro RNAs are actively involved in the regulation of MHC gene expression and function.

                  Methods

                  DNA shotgun sequencing

                  Shotgun sequencing libraries were constructed individually for each of the 26 BAC clones following the modified protocols described by Celera Genomics Group [47]. Briefly, E. coli stock containing the target BAC clones were used to prepare the BAC clone DNA, which were solicited to form randomized small DNA fragments between 0.5 - 2.0 kb. After cloning of the small fragments into the plasmids, random DNA sequencing was performed with an ABI 3730 automated DNA sequencers (Applied Biosystems, USA) to generate the randomized short DNA sequence reads.

                  Assembling of BAC clone sequences

                  The short random DNA sequences generated by the sequencing were assembled into full-length sequence utilizing the Prep program (U.W., Seattle, WA, USA) for each of the BAC clones. Resequencing was performed when necessary for gaps detected during the sequence assembly, including sequencing by primer walking of the PCR-amplified fragments for regions showing low level of accuracy. Blast alignments [48] of the repeat-masked, assembled sequence against NCBI EST and non-redundant nucleotide databases were performed to identify expressed sequences and other highly conserved regions likely to contain functional genes.

                  Sequence analysis

                  The assembled ovine MHC sequence was analyzed using an automatic Ensemble pipeline [49] with modifications to aid the manual duration process. Simple and interspersed repeats were detected using Tandem Repeats Finder [50] and Repeat Masker, respectively, using the mammalian library along with cow-specific repeats submitted to EMBL/NCBI/DDBJ. The combination of simple and interspersed repeats was used as a filter to mask the sequence during analysis. Novel genes or CDS loci were identified by having an open reading frame (ORF), plus certain similarity to the known genes or proteins. A predicted gene was defined by having high sequence homology to the predicted gene or ORF in other species. Pseudo genes were identified by sequence homology to known Pseudo genes (not shown). Comparative sequence alignments were performed using the waviest pipeline http://​genome.​lbl.​gov/​cgi-bin/​WGVistaInput.

                  Declarations

                  Acknowledgements

                  We thank Professor Jun Wang for assistance in the sequence analysis and gene annotation, and anonymous reviewers of BMC-Genomics for their critical review comments that helped to improve the quality of the manuscript. This work was funded by research grants from National Natural Science Foundation of China (30125024; 30771148), Ministry of Science and Technology of China (2006DFA33750), and China Ministry of Agriculture (2008ZX08008-005B). Professor Hugh Blair is funded by the National Research Centre for Growth and Development.

                  Authors’ Affiliations

                  (1)
                  School of Life Sciences, Shihezi University
                  (2)
                  Institute of Genetics and Developmental Biology, Chinese Academy of Science
                  (3)
                  Institute of Veterinary Animal and Biomedical Sciences, Massey University
                  (4)
                  Graduate School of Chinese Academy of Sciences, Beijing

                  References

                  1. Danchin E, Vitiello V, Vienne A, Richard O, Gouret P, McDermott MF, Pontarotti P: The major histocompatibility complex origin. Immunological reviews 2004, 198: 216–232.PubMedView Article
                  2. Flajnik MF, Kasahara M: Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 2001, 15 (3) : 351–362.PubMedView Article
                  3. Kaufman J: The origins of the adaptive immune system: whatever next? Nature immunology 2002, 3 (12) : 1124–1125.PubMedView Article
                  4. Escayg AP, Hickford JG, Bullock DW: Association between alleles of the ovine major histocompatibility complex and resistance to footrot. Research in veterinary science 1997, 63 (3) : 283–287.PubMedView Article
                  5. Buitkamp J, Filmether P, Stear MJ, Epplen JT: Class I and class II major histocompatibility complex alleles are associated with faecal egg counts following natural, predominantly Ostertagia circumcincta infection. Parasitology research 1996, 82 (8) : 693–696.PubMedView Article
                  6. Konnai S, Takeshima SN, Tajima S, Yin SA, Okada K, Onuma M, Aida Y: The influence of ovine MHC class II DRB1 alleles on immune response in bovine leukemia virus infection. Microbiology and immunology 2003, 47 (3) : 223–232.PubMed
                  7. The MHC Sequencing Consortium: Complete sequence and gene map of a human major histocompatibility complex. Nature 1999, 401 (6756) : 921–923.View Article
                  8. Takada T, Kumanovics A, Amadou C, Yoshino M, Jones EP, Athanasiou M, Evans GA, Fischer Lindahl K: Species-specific class I gene expansions formed the telomeric 1 mb of the mouse major histocompatibility complex. Genome research 2003, 13 (4) : 589–600.PubMedView Article
                  9. Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L: Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. Genome research 2003, 13 (12) : 2621–2636.PubMedView Article
                  10. Hurt P, Walter L, Sudbrak R, Klages S, Muller I, Shiina T, Inoko H, Lehrach H, Gunther E, Reinhardt R, Himmelbauer H: The genomic sequence and comparative analysis of the rat major histocompatibility complex. Genome research 2004, 14 (4) : 631–639.PubMedView Article
                  11. Debenham SL, Hart EA, Ashurst JL, Howe KL, Quail MA, Ollier WE, Binns MM: Genomic sequence of the class II region of the canine MHC: comparison with the MHC of other mammalian species. Genomics 2005, 85 (1) : 48–59.PubMedView Article
                  12. Yuhki N, Beck T, Stephens RM, Nishigaki Y, Newmann K, O'Brien SJ: Comparative genome organization of human, murine, and feline MHC class II region. Genome research 2003, 13 (6A) : 1169–1179.PubMedView Article
                  13. Renard C, Hart E, Sehra H, Beasley H, Coggill P, Howe K, Harrow J, Gilbert J, Sims S, Rogers J, Ando A, Shigenari A, Shiina T, Inoko H, Chardon P, Beck S: The genomic sequence and analysis of the swine major histocompatibility complex. Genomics 2006, 88 (1) : 96–110.PubMedView Article
                  14. Belov K, Deakin JE, Papenfuss AT, Baker ML, Melman SD, Siddle HV, Gouin N, Goode DL, Sargeant TJ, Robinson MD, Wakefield MJ, Mahony S, Cross JG, Benos PV, Samollow PB, Speed TP, Graves JA, Miller RD: Reconstructing an ancestral mammalian immune supercomplex from a marsupial major histocompatibility complex. PLoS Biology 2006, 4 (3) : e46.PubMedView Article
                  15. Matsuo MY, Asakawa S, Shimizu N, Kimura H, Nonaka M: Nucleotide sequence of the MHC class I genomic region of a teleost, the medaka (Oryzias latipes). Immunogenetics 2002, 53 (10–11) : 930–940.PubMedView Article
                  16. Ohta Y, Okamura K, McKinney EC, Bartl S, Hashimoto K, Flajnik MF: Primitive synteny of vertebrate major histocompatibility complex class I and class II genes. Proceedings of the National Academy of Sciences of the United States of America 2000, 97 (9) : 4712–4717.PubMedView Article
                  17. Terado T, Okamura K, Ohta Y, Shin DH, Smith SL, Hashimoto K, Takemoto T, Nonaka MI, Kimura H, Flajnik MF, Nonaka M: Molecular cloning of C4 gene and identification of the class III complement region in the shark MHC. J Immunol 2003, 171 (5) : 2461–2466.PubMed
                  18. Shiina T, Shimizu S, Hosomichi K, Kohara S, Watanabe S, Hanzawa K, Beck S, Kulski JK, Inoko H: Comparative genomic analysis of two avian (quail and chicken) MHC regions. J Immunol 2004, 172 (11) : 6751–6763.PubMed
                  19. Elsik CG, Tellam RL, Worley KC, Gibbs RA, Muzny DM, Weinstock GM, Adelson DL, Eichler EE, Elnitski L, Guigo R, Hamernik DL, Kappes SM, Lewin HA, Lynn DJ, Nicholas FW, Reymond A, Rijnkels M, Skow LC, Zdobnov EM, Schook L, Womack J, Alioto T, Antonarakis SE, Astashyn A, Chapple CE, Chen HC, Chrast J, Camara F, Ermolaeva O, Henrichsen CN, et al.: The genome sequence of taurine cattle: a window to ruminant biology and evolution. Science (New York, NY) 2009, 324 (5926) : 522–528.View Article
                  20. Bonneaud C, Richard M, Faivre B, Westerdahl H, Sorci G: An Mhc class I allele associated to the expression of T-dependent immune response in the house sparrow. Immunogenetics 2005, 57 (10) : 782–789.PubMedView Article
                  21. Dukkipati VS, Blair HT, Garrick DJ, Murray A: 'Ovar-Mhc' - ovine major histocompatibility complex: structure and gene polymorphisms. Genet Mol Res 2006, 5 (4) : 581–608.PubMed
                  22. Galindo RC, Ayoubi P, Garcia-Perez AL, Naranjo V, Kocan KM, Gortazar C, de la Fuente J: Differential expression of inflammatory and immune response genes in sheep infected with Anaplasma phagocytophilum. Veterinary immunology and immunopathology 2008, 126 (1–2) : 27–34.PubMedView Article
                  23. Mena A, Nichani AK, Popowych Y, Godson DL, Dent D, Townsend HG, Mutwiri GK, Hecker R, Babiuk LA, Griebel P: Innate immune responses induced by CpG oligodeoxyribonucleotide stimulation of ovine blood mononuclear cells. Immunology 2003, 110 (2) : 250–257.PubMedView Article
                  24. Gruszczynska J, Brokowska K, Charon KM, Swiderek WP: Restriction fragment length polymorphism of exon 2 Ovar-DRB1 gene in Polish Heath Sheep and Polish Lowland Sheep. Journal of applied genetics 2005, 46 (3) : 311–314.PubMed
                  25. Miltiadou D, Ballingall KT, Ellis SA, Russell GC, McKeever DJ: Haplotype characterization of transcribed ovine major histocompatibility complex (MHC) class I genes. Immunogenetics 2005, 57 (7) : 499–509.PubMedView Article
                  26. Liu H, Liu K, Wang J, Ma RZ: A BAC clone-based physical map of ovine major histocompatibility complex. Genomics 2006, 88 (1) : 88–95.PubMedView Article
                  27. Deverson EV, Wright H, Watson S, Ballingall K, Huskisson N, Diamond AG, Howard JC: Class II major histocompatibility complex genes of the sheep. Animal genetics 1991, 22 (3) : 211–225.PubMedView Article
                  28. Ballingall KT, Fardoe K, McKeever DJ: Genomic organisation and allelic diversity within coding and non-coding regions of the Ovar-DRB1 locus. Immunogenetics 2008, 60 (2) : 95–103.PubMedView Article
                  29. Scott PC, Choi CL, Brandon MR: Genetic organization of the ovine MHC class II region. Immunogenetics 1987, 25 (2) : 116–122.PubMedView Article
                  30. Escayg AP, Hickford JG, Montgomery GW, Dodds KG, Bullock DW: Polymorphism at the ovine major histocompatibility complex class II loci. Animal genetics 1996, 27 (5) : 305–312.PubMedView Article
                  31. Snibson KJ, Maddox JF, Fabb SA, Brandon MR: Allelic variation of ovine MHC class II DQA1 and DQA2 genes. Animal genetics 1998, 29 (5) : 356–362.PubMedView Article
                  32. van der Poel JJ, Groenen MA, Dijkhof RJ, Ruyter D, Giphart MJ: The nucleotide sequence of the bovine MHC class II alpha genes: DRA, DOA, and DYA. Immunogenetics 1990, 31 (1) : 29–36.PubMedView Article
                  33. McShane RD, Gallagher DS Jr, Newkirk H, Taylor JF, Burzlaff JD, Davis SK, Skow LC: Physical localization and order of genes in the class I region of the bovine MHC. Animal genetics 2001, 32 (5) : 235–239.PubMedView Article
                  34. Amills M, Ramiya V, Norimine J, Lewin HA: The major histocompatibility complex of ruminants. Revue scientifique et technique (International Office of Epizootics) 1998, 17 (1) : 108–120.
                  35. Everts-van der Wind A, Kata SR, Band MR, Rebeiz M, Larkin DM, Everts RE, Green CA, Liu L, Natarajan S, Goldammer T, Lee JH, McKay S, Womack JE, Lewin HA: A 1463 gene cattle-human comparative map with anchor points defined by human genome sequence coordinates. Genome research 2004, 14 (7) : 1424–1437.PubMedView Article
                  36. Childers CP, Newkirk HL, Honeycutt DA, Ramlachan N, Muzney DM, Sodergren E, Gibbs RA, Weinstock GM, Womack JE, Skow LC: Comparative analysis of the bovine MHC class IIb sequence identifies inversion breakpoints and three unexpected genes. Animal genetics 2006, 37 (2) : 121–129.PubMedView Article
                  37. Maddox JF, Davies KP, Crawford AM, Hulme DJ, Vaiman D, Cribiu EP, Freking BA, Beh KJ, Cockett NE, Kang N, Riffkin CD, Drinkwater R, Moore SS, Dodds KG, Lumsden JM, van Stijn TC, Phua SH, Adelson DL, Burkin HR, Broom JE, Buitkamp J, Cambridge L, Cushwa WT, Gerard E, Galloway SM, Harrison B, Hawken RJ, Hiendleder S, Henry HM, Medrano JF, et al.: An enhanced linkage map of the sheep genome comprising more than 1000 loci. Genome research 2001, 11 (7) : 1275–1289.PubMedView Article
                  38. Liu K, Zhang P, GaO J, Liu H, Li G, Qiu Z, Zhang Y, Ren J, Tan P, Ma RZ: Closing a gap in the physical map of the ovine major histocompatibility complex. Animmal Genetics, in press.
                  39. Qin J, Mamotte C, Cockett NE, Wetherall JD, Groth DM: A map of the class III region of the sheep major histocompatibilty complex. BMC genomics 2008, 9: 409.PubMedView Article
                  40. Herrmann-Hoesing LM, White SN, Kappmeyer LS, Herndon DR, Knowles DP: Genomic analysis of Ovis aries (Ovar) MHC class IIa loci. Immunogenetics 2008, 60 (3–4) : 167–176.PubMedView Article
                  41. Glass EJ, Oliver RA, Russell GC: Duplicated DQ haplotypes increase the complexity of restriction element usage in cattle. J Immunol 2000, 165 (1) : 134–138.PubMed
                  42. Skow LC, Snaples SN, Davis SK, Taylor JF, Huang B, Gallagher DH: Localization of bovine lymphocyte antigen (BoLA) DYA and class I loci to different regions of chromosome 23. Mamm Genome 1996, 7 (5) : 388–389.PubMedView Article
                  43. Band M, Larson JH, Womack JE, Lewin HA: A radiation hybrid map of BTA23: identification of a chromosomal rearrangement leading to separation of the cattle MHC class II subregions. Genomics 1998, 53 (3) : 269–275.PubMedView Article
                  44. Andersson L, Rask L: Characterization of the MHC class II region in cattle. The number of DQ genes varies between haplotypes. Immunogenetics 1988, 27 (2) : 110–120.PubMedView Article
                  45. Itoh T, Watanabe T, Ihara N, Mariani P, Beattie CW, Sugimoto Y, Takasuga A: A comprehensive radiation hybrid map of the bovine genome comprising 5593 loci. Genomics 2005, 85 (4) : 413–424.PubMedView Article
                  46. Ogg SL, Weldon AK, Dobbie L, Smith AJ, Mather IH: Expression of butyrophilin (Btn1a1) in lactating mammary gland is essential for the regulated secretion of milk-lipid droplets. Proceedings of the National Academy of Sciences of the United States of America 2004, 101 (27) : 10084–10089.PubMedView Article
                  47. Adams MD, Celniker SE, Holt RA, Evans CA, Gocayne JD, Amanatides PG, Scherer SE, Li PW, Hoskins RA, Galle RF, George RA, Lewis SE, Richards S, Ashburner M, Henderson SN, Sutton GG, Wortman JR, Yandell MD, Zhang Q, Chen LX, Brandon RC, Rogers YH, Blazej RG, Champe M, Pfeiffer BD, Wan KH, Doyle C, Baxter EG, Helt G, Nelson CR, et al.: The genome sequence of Drosophila melanogaster. Science (New York, NY) 2000, 287 (5461) : 2185–2195.View Article
                  48. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ: Basic local alignment search tool. Journal of molecular biology 1990, 215 (3) : 403–410.PubMed
                  49. Potter SC, Clarke L, Curwen V, Keenan S, Mongin E, Searle SM, Stabenau A, Storey R, Clamp M: The Ensembl analysis pipeline. Genome research 2004, 14 (5) : 934–941.PubMedView Article
                  50. Benson G: Tandem repeats finder: a program to analyze DNA sequences. Nucleic acids research 1999, 27 (2) : 573–580.PubMedView Article

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                  © Gao et al. 2010

                  This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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