Comp Genomic Sructure HLA DLA FLA

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Comparative Genomic Structure of

Human, Dog, and Cat MHC: HLA,

DLA, and FLANAOYA YUHKI, THOMAS BECK, ROBERT STEPHENS, BEENA NEELAM, AND STEPHEN J. OBRIEN

From the Laboratory of Genomic Diversity, National Cancer Institute at Frederick, Frederick, MD 21702-1201 (Yuhki,

OBrien); SAIC-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702-1201 (Beck); the Advanced

Biomedical Computing Center, National Cancer Institute at Frederick, Frederick, MD 21702-1201 (Stephens, Neelam).

Address correspondence to Dr. Naoya Yuhki at the address above, or e-mail: [email protected].

Abstract

Comparisons of the genomic structure of 3 mammalian major histocompatibility complexes (MHCs), human HLA, canineDLA, and feline FLA revealed remarkable structural differences between HLA and the other 2 MHCs. The 4.6-Mb HLAsequence was compared with the 3.9-Mb DLA sequence from 2 supercontigs generated by 7x whole-genome shotgun as-sembly and 3.3-Mb FLA draft sequence. For FLA, we confirm that 1) feline FLA was split into 2 pieces within the TRIM(member of the tripartite motif) gene family found in human HLA, 2) class II, III, and I regions were placed in the peri-centromeric region of the long arm of chromosome B2, and 3) the remaining FLA was located in subtelomeric region of theshort arm of chromosome B2. The exact same chromosome break was found in canine DLA structure, where class II, III, andI regions were placed in a pericentromeric region of chromosome 12 whereas the remaining region was located in a subtelo-meric region of chromosome 35, suggesting that this chromosome break occurred once before the split of felid and canidmore than 55 million years ago. However, significant differences were found in the content of genes in both pericentromericand subtelomeric regions in DLA and FLA, the gene number, and amplicon structure of class I genes plus 2 other class Igenes found on 2 additional chromosomes; canine chromosomes 7 and 18 suggest the dynamic nature in the evolution ofMHC class I genes.

The major histocompatibility complex (MHC) plays key rolesin controlling both adaptive and innate immune systems(Klein 1986). In the adaptive immune system, both MHCclass I and class II antigens recognize, bind, and present pep-tides to cytotoxic and helper T-cells, respectively (Bjorkmanet al. 1987a 1987b; Brown et al. 1988) and initiate cell-to-cellcommunication between antigen-presenting cells and T-cellsby forming immunological synapses and activating T-cells for

cellular and humoral immune systems (Grakoui et al. 1999).In addition, a number of gene clusters in this complex encodeproteins that play important roles for antigen processing(proteosome subunits, LMP2 and 7, antigen transporters;TAP1 and 2(Beck et al. 1992; Monaco 1992), antigen loadingfor the class I antigen, TAPASIN (Ortman et al. 1997),antigen loading for the class II antigens, DM (Fling et al.1994; Morris et al. 1994) and DO (Alfonso et al. 1999) mol-ecules). In the innate immune system, both classical (HLA-A, -B,-C in humans) and nonclassical (HLA-E, -G ) class I(Le Bouteiller et al. 1999; Voles-Gomez et al. 2000) antigensplus class Irelated molecules (MIC-A, -B) interact with the

natural killer (NK) receptors KIR (Parham 2005) and NKG2antigens and Ly49 and NKG2 (Takei et al. 2001) antigens inhuman and mouse, respectively, and inhibit and activateNK-cell functions.

In addition to the immunological importance, the MHCprovides important tools to study molecular evolution. Ex-tremely polymorphic features of both class I and class II anti-gens identified in most vertebrates provide large numbers of

peptide-binding grooves for both antigens in order to adaptto various pathogens. Natural and balancing selections playpivotal roles to generate and maintain these polymorphisms(Yuhki and OBrien 1990; Klein et al. 1993).

A large-scale sequencing project for the HLA (3.6 Mb)yielded findings of 224 tightly linked genes, including 128expressed genes and 96 pseudogenes ( MHC SequencingConsortium 1999). In addition, 2 complete MHC haplotypesequences spanning 4.6 Mb were published (Stewart et al.2004).

In contrast of this large complex structure of the HLA,the chicken MHC B-locus shows a minimal essential MHC

Journal of Hereditydoi:10.1093/jhered/esm056

The American Genetic Association. 2007. All rights reserved.For permissions, please email: [email protected].

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extending 92 kb and including 19 functional genes, raisingquestions about the structure of the other MHC systems(Kaufman et al. 1999). We have analyzed 2 additional MHCs,one from a canine generated by the 7x whole-genome shot-gun (WGS) assembly (Lindblad-Toh et al. 2005) and thesecond from a feline generated by Bacterial Artificial chro-mosome (BAC) sequencing (OBrien and Yuhki 1999; Yuhkiet al. 2003; Beck et al. 2005; Pontius J, et al. 2007).

Materials and Methods

Sequence

The human HLA sequence was downloaded from the SangerWeb site. The canine DLA, 2 supercontigs, were obtainedfrom Broad Institute (supercontigs 38195 and 40588). FelineMHC draft sequence was generated by shotgun sequencingwith an ABI3730XL analyzer and Phred base calling Phrap(Ewing and Green 1998; Ewing et al. 1998) assembly andConsed (Gordon et al. 1998, 2001) from selected BAC clonesbased on feline MHC BAC maps (Beck et al. 2005).

Sequence Comparisons

Sequence comparisons were performed by the PIPMAKERprogram (Schwartz et al. 2000). Gene identification and an-notation was done by GENSCAN (Burge and Karlin 1997)and BLAST program against the human Refseq database(Altschul et al. 1990).

Fluorescent In Situ Hybridization

Fluorescent in situ hybridization (FISH) was done usinga standard condition with fluorescein isothiocyanate(FITC-) and digoxigenin-labeled BAC clone DNA (Modi

et al. 1987).

Results

Two-Color FISH

Feline BAC clones 329i22 and 46j10 encode TRIM39,MHCI-Rp, and MHCI-S genes and TRIM26, TRIM15, andTRIM10 genes, respectively. These BAC clones were labeled with digoxigenin (329i22) and FITC (46j10) (329i22: pinkcolor, 46j10: green color) and hybridized with domesticcat chromosomal DNA. The results indicated that digoxige-nin and FITC showed signals on a centromere of the longarm and the telomere of the short arm of feline chromosomeB2, respectively (Figure 1A, 1B).

Annotation of MHC Class I Region in the Domestic Cat

Analysis of an approximately 1.8-Mbp sequence of the felineMHC class I region (2006 August freeze) revealed 72 codinggenes (FLAI-A through OLFR3) (Table 1).

Based on this analysis, we assigned 3 subregions asfollows:

1. Proximal class I subregion (Figure 1C): Proximal class Isubregion was defined as a region adjacent to the

BAT1 gene through OCT3 gene. Thirty class I genes/genefragments were found in this subregion. Of these genes,17 class I genes were confirmed by the GENSCAN,BLASTP, and BLASTN programs. In addition, 4 MHCclass Irelated (MIC) genes were found. This region spansapproximately 600 kbp adjacent to the class III region.

2. Central class I subregion: The central class I subregion wasdefined as a region from OCT3 gene through the pericen-tromeric region of the long arm of feline chromosome B2,spanning approximately 800 kbp (Figure 1C). Twenty-seven framework human genes, which have no class Ior class IIrelated function and conserved in humanHLA and murine H2 homologues, were found and scat-tered in this region. Two class I gene/gene fragments werelocated near the end of this region. One class I gene (I-Rp)appears to be a gene fragment based on dotplot analysisusing a full-length MHC class I cDNA sequence (data notshown), whereas another class I gene (I-S) appears to bea full-length MHC class I gene. This I-S class I gene wasconfirmed by the GENSCAN program as well. Those 2class I gene/gene fragments were located on the centro-meric side from the TRIM39 gene.

3. Distal class I subregion: Distal class I subregion was de-fined as a region between the subtelomeric region anda chromosomal break point, near the TRIM26 genethrough the third olfactory receptor gene OLFR homo-logue. This region spans approximately 300 kbp andencodes 10 framework genes; however, no class I genesor gene fragments were identified.

Alpha Satellite and Telomere Repeats

Two dotter dotplot analyses of the BAC sequence were per-

formed in order to obtain data that can show evidence of thepericentromeric and subtelomeric localizations of the centraland distal class I subregions (Figure 2A,B). One BAC clone329i22, which encodes TRIM39, and 2 class I gene/gene frag-ments were analyzed by self-to-self dotplot program in orderto detect repeat sequence structures. This analysis detected 3clusters of alpha satellite repeats, which were found near thecentromeric and telomeric regions in the domestic cat chro-mosomes (Modi et al. 1988), suggesting that this 329i22 BACclone has subheterochromatin-like features (Figure 2A).Similar dotplot analysis indicated that BAC clone 46j10has both alpha satellite and 47 units of telomeric repeats, sug-gesting that the 46j10 sequence has characteristics of the

subtelomeric region (Figure 2B).

Canine MHC

Two supercontigs, which encode the entire canine MHCsequences defined as sequence-encoding genes from HKETthrough UBD, plus 3 olfactory receptor genes were obtainedand analyzed. One supercontig, 38195, which is 9 472 360 bpin size includes two-thirds of the MHC genes (SYNGAP1 toTRIM39 ) in the 2.9-Mbp region. The other supercontig,40588, which is 2 661 921 bp in size includes the restof the MHC genes (TRIM26 to olfactory receptor genes).

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Detailed gene contents and gene order were presented inFigure 3A,B, where canine MHCs split into 2 DNA frag-ments at the point where the feline MHC split occurred be-tween TRIM39 and TRIM26. Two-thirds of canine MHCs(SYNGAP1 to TRIM39 ) are located on or near the centro-meric border of canine chromosome 12 and acquired 4 genes

(ARG1, CRSP3, ATP5L, and ENPP3) from the HSA 6p13region.

The remaining canine MHCs (500 kbp from TRIM26 toolfactory receptor genes) were found on the telomeric regionof canine chromosome 35 and have acquired 4 processedpseudogenes (DSG3, EEF1A2, MGC35023, MGC35023)

Figure 1. (A) Locations ofTRIM39, 26, 15, 10 genes in HLA, H2, compared with gene contents and order in FLA. BAC clone

329i22 and 46j10 encode TRIM39, class I-Rp, and -S genes and TRIM26, TRIM15, and TRIM10 genes, respectively. BAC

clone 329i22 and 46j10 were labeled with digoxigenin and FITC, respectively, and hybridized on feline chromosome (fcaB2). BAC

sequence coordinates are shown. Location of BAC clone 329i22 and 46j10, indicating each location on telomere of the short arm

and centromere of the long arm of fcaB2. (B) G-banding of feline chromosome B2 and schematic views of fcaB2 and its synthenic

cfa chromosomes, cfa35, 12, 1. (C ) Schematic view of gene contents and order in FLA. The FLA class I region spans

approximately 1700 kbp not including (peri)centromeric and (sub)telomeric repeats. A break point was indicated by double slashes.

Left and right sides of the double slashes are pericentromeric and subtelomeric regions, respectively, and rearranged by

a chromosomal inversion.

Yuhki et al. Comparative Genomic Structure of Human, Dog, and Cat MHCs

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near the telomere region. No class I gene or gene fragmentswere identified in this region.

Dotplot Comparison ofHLA and DLA

In order to reveal the difference of genomic structure, a directsequence comparison of 2 MHCs, HLA and DLA, dotplotanalysis (Erik et al. 1995) was attempted. Intersperse repeatsequences were first masked, and every 100-bp sequencesegments were compared against the other sequence. The se-quence similarity was color graded (white, gray, and black)

and placed on the field. This process was continued in both xand y axes to fill out the entire sequence comparison filed.As results, contiguously similar sequences of x and y axes were recognized as positive 45-degree solid lines andsequence inversion events were recognized as negative 45-degree solid lines. Sequence insertion was recognized as dis-continuity of one axis but not the other. Discontinuity ofsolid lines suggests rapid sequence divergence (i.e., species-specific sequence amplification in each species) in thoseregions. Results indicated a mosaic structure of highly con-served and species-specific unique regions throughout theMHC. Figure 4 shows a combination of 45-degree straightlines (sharp boxes) and disrupted lines (fuzzy boxes) inthe dotplot between 4.6-Mbp HLA (x axis) and 2.9-Mb(cfa12) and 1.0-Mb (cfa35) DLA (yaxis). From right to left,blue boxes represent extended class II region, class III region,and central class I framework regions in comparison betweenHLA and cfa12 DLA. Three relatively short conservedregions in comparison between HLA and cfa35 DLA rep-resent 2 class I framework gene regions adjacent to the miss-ing HLA-A corresponding region shown as a straight redline, plus an additional conserved region beyond olfactoryreceptor gene clusters. Three types of disrupted patterns wereobserved. First, the class II region has recognizable shortstraight lines with gaps and shifts, suggesting gene amplifica-tions and deletions. Second, unrecognizable conserved pat-terns, suggesting species-unique evolution, were found inHLA-B and -C class I gene regions, near centromeric andtelomeric regions in DLA and olfactory receptor gene clus-ters. Third, 2 conserved lines (2 sharp boxes) were located without a gap in y axis but with a gap in x axis, indicatinga large deletion of HLA-A class I corresponding region inDLA.

Discussion

Here we report 2 unique MHC genomic structures of the fe-line and canine MHC regions. Two-color FISH clearly indi-cated that the MHC break occurred within the TRIM genefamily region, specifically between TRIM39 and TRIM26(Figure 1A). The same MHC break was also found in thecanine MHC from 2 supercontigs of 7x WGS assembly(Figure 3A,B). These results can also be visualized as

FLA, DLA, and HLA class I gene contents in Figure 6. Be-cause the split of felids and canids are reported to be most

ancient in Carnivora species, 55 million years ago (MYA)(Murphy et al. 2001), this split MHC structure may be a com-mon form in Carnivora species. We have attempted to com-pare G-banding patterns of the feline chromosome (fcaB2)and canine chromosomes (cfa35, 12, 1). The result showedrecognizable similar G-banding pattern in the location of theMHC (Figure 1B). Similar conclusions are made by examin-ing the G-banding patterns of Carnivora chromosomes(Nash et al. 2001; OBrien et al. 2006).

Genomic structure of 9 mammalian MHCs was presentedin Figure 5. Though this is a rough sketch of the MHC struc-ture, it is clear that chromosome breaks/inversion/centro-

Figure 2. (A) Self-dotplot analysis of BAC 329i22 sequence.

A105 270-bp sequence was compared with self-using dotter

program. Arrows indicate 3 clusters of feline alpha satellite

repeats (FASAT). (B) Self-dotplot analysis of BAC 46j10

sequence. A54 599-bp sequence was compared with self-using

dotter program, detecting both FASAT and 47 units of

telomeric repeats (TTAGGG).

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Figure 3. (A) The 3000-kb DLA region from supercontig 38195 and its gene contents and gene order. This 3-Mbp DLA spans

from SYNGAP1 through TRIM39plus gene contents transduced from HSA 6q13 near centromere of cfa12. Coordinates from 7x

canine whole-genome shotgun sequence are shown in (A) and (B). (B) The 500-kb DLA region from supercontig 40588 and its

gene contents and gene order. This 500-kbp DLA spans from RAN to TRIM26 plus 4 pseudogenes near telomere of cfa35.

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mere invasion occurred in the MHC region during evolutionof each species. For example, nearly all mammalian MHCclass II regions retain DP, DQ, and DRsubregions; however,DP regions tends to become nonfunctional as observed indog DLA, cat FLA, and equine MHC. In FLA, the entireDQ region was deleted after the split of canids and felids.Moreover, in bovine BoLA, DNA break in the class II regionfollowed by the DNA inversion caused the loss and gain ofDP and DY/DI class II regions, respectively (Band et al.1998). Other notable examples are shown in this paper;

the feline MHC split occurred once more than 55 MYAand was located near the centromere and telomere regionsby a chromosomal inversion (fcaB2). In canids, the same seg-ments found in the FLA are located near centromere andtelomere of 2 separate chromosomes (cfa12 and 35). In swineMHC, centromere invasion was found in the border of theclass II and III regions (Renard et al. 2006). Recent mousegenome assembly also shows that a segmental break in itsMHC occurred in the distal class I region, where approxi-mately 2.8-Mbp segments from TRIM27 (RFP ) to SCGNgenes are located on chromosome mmu13, apartfrom mmu17 where the rest of the MHCs are located

(Mouse Genome Sequencing Consortium 2002). Thus, an in-tegrity of the MHC defined by HLA (SYNGAP1 throughSCGN ) is shown in a few exceptional cases in mammalianMHC.

The direct sequence comparison between HLA andDLA performed by the PIPMAKER program shows themosaic structure of several hundred conserved and noncon-served kilobase segments. In nonconserved regions, the classII region was clearly reorganized by gene amplificationand deletion as described elsewhere (Debenham et al.2005). The class I region was probably rearranged by geneamplification of a small amplicon (i.e., class I gene plus

MIC in HLA (Shiina et al. 1999) and class I gene plusBAT1 in FLA, unknown in DLA) in species-specific fashion.A similar pattern was observed in the olfactory receptor genecluster, suggesting that the gene amplification seen in class Igenes may have taken place in this cluster. It is noteworthy todescribe the gene organization near heterochromatinregions, where ancient chromosome break points have notremained the same clear-cut sequences as the original ones,but rather this region functions as a vacuum of new genes/rearrangements.

Figure 4. Dotplot analysis of the HLA 4.6 Mbp and 2 DLA fragments, 2.9 Mbp and 1.0 Mbp. Conserved and nonconserved

regions are sharp and fuzzy boxed, respectively. Approximate borders of class II, III, and I regions are shown above and to the right

of the graph.

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In the HLA class I region, HLA-A is the largest class Iregion compared with the HLA-B, -C, -E regions, spanning550 kbp from HTEX4 to MOG, including at least 11 class Igenes (HLA-A, -G, -Fas functional genes). In FLA, HTEX4to MOG spans only 55 kbp, and no class I gene/gene seg-ments were found. The HLA-E gene is also missing in

FLA. In DLA, the HLA-A corresponding region and theHLA-E-92 genes are also deleted.

The HLA-B, -C regions occupy in a short segment ofhuman HLA; however both FLA and DLA have a multiplenumber of class I genes (5 DLA [Wagner et al. 2005] and 17

FLA class I genes).It is clear by sequence comparisons that each FLA and

DLA class I genes were amplified in species-specific mannersand are not orthologous to HLA class I genes. Remarkably,

FLA has at least one full-length class I gene at the break pointnear TRIM39, where mouse H2, M1M10 class I genes,which may function as an escort molecule for pheromonereceptors, are located (Loconto et al. 2003). In DLA, 2 otherclass I genes (Wagner 2003), ctpg26 and DLA-79, are located

on 2 additional chromosomes, cfa7 and cfa18. Though cptg26appeared to be a processed pseudogene, DLA-79has a mod-erate level of polymorphism, suggesting this may encodea functional class I antigen. In addition, a number of olfactoryreceptor-like genes plus an OCT3-like gene were linked withDLA-79 on cfa18 (Figure 6).

Of the19 class I genes in FLA, at least 3 genes have con-served amino acid residues in the peptide-binding region(data not shown). This may suggest that FLA has 3 peptide-presenting class I genes, like human and mouse MHCs. Atleast 4 MHC class Irelated (MIC ) gene homologues werefound in FLA HLA-B/C region; however, no MIC-likesequences were found in DLA HLA-B/Ccorrespondingregion. This may suggest distinct NK control mechanismsin dog and cat.

Funding

National Cancer Institute, National Institutes of Health(N01-CO-12400).

Figure 5. A schematic view of 9 mammalian MHCs. Two major mammalian groups, Euarchontoglires including primates

(Human [MHC Sequencing Consortium 1999], chimpanzee [Anzai et al. 2003], rhesus macaque [Daza-Vamenta et al. 2004], and

rodents [mouse {Kumanovics et al. 2003}, rat {Hurt et al. 2004}]) and Laurasiatheria including carnivores (cat and dog),

Perissodactyla (horse [Gustafson et al. 2003]), and Certartiodactyla (pig [Renard et al. 2006], cattle [Lewin et al. 1999]) are shown.

Cat and dog separated 55 MYA represent the most ancient split in carnivores. Carnivores and Perissodactyla separated 80 MYA. In

class II region, DQ/DR are highly conserved, except FLA (DQ deletion), whereas in class I region, HLA-B, -C are highly

conserved.

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Figure 6. Comparison of gene content and order in class I region of FLA, DLA, and HLA. Orthologous genes in FLA, DLA, and HL

class I genes in HLA-B, -Cregions, plus 2 class I genes in HLA-92region, whereas HLA-E, -A regions are deleted. DLA has 5 class I genes

are found in HLA-E, -92, -A regions. Two class I genes, one in cfa7 and another in cfa18 (cptg26, DLA-79 ) are found. Triangle indicat

subregions (HLA-E, -92, -A).

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Acknowledgments

The authors thank Lisa Maslan for her technical support. Neither does the

content of this publication necessarily reflect the views or policies of the

Department of Health and Human Services nor does mention of trade

names, commercial products, or organizations imply endorsement by the

US Government.

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This work was presented in poster form at the Third InternationalConference on Advances in Canine and Feline Genomics andInherited Diseases, Davis, CA, August 2006.

Corresponding Editor: Urs Giger

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Documents

Comp Genomic Sructure HLA DLA FLA