* Centre for Bioinformatics and Biological Computing, School of Information Technology, Murdoch University, Murdoch, Western Australia; and Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1143, Japan
Correspondence: E-mail: jkulski{at}murdoch.edu.au.
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Abstract |
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Key Words: segmental tandem duplications MHC genes retrotransposons rhesus macaque comparative genomics
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Introduction |
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The human MHC class I gene organization has been explained by chromosomal rearrangements that have involved a series of imperfect tandem duplications and various deletion events (Dawkins et al. 1999; Kulski et al. 1999b, Kulski, Gaudieri, and Dawkins 2000a). Different duplication models have been proposed, such as single-gene duplications (Hughes 1995), block duplications (Geraghty et al. 1992; Leelayuwat, Pinelli, and Dawkins 1995; Klein, Sato, and O'hUigin 1998), single-unit and biunit segmental duplications with transpositions (Shiina et al. 1999b), and serial unigenic and multigenic tandem duplications (Dawkins et al. 1999; Kulski et al. 1999b; Kulski, Anzai, and Inoko 2004) or metamerismatic duplications (Kulski, Gaudieri, and Dawkins 2000a). Detailed analyses of duplicon structures, organization, and phylogeny suggest segmental or tandem block duplication models are the most likely explanation for the MHC class I gene organization (Gaudieri et al. 1999a; Kulski et al. 1997, 1999b). Indels are a major pathway to genomic divergence of duplicated segments (Gaudieri et al. 1999b, 2000; Anzai et al. 2003) often by way of retrotransposons acting as recombination hotspots (Kulski et al. 1999a, 1999b). Therefore, an analysis of retrotransposons within genomic duplicated segments is a key to gaining useful insights into the time and nature of duplication events and genomic rearrangements.
The human MHC class I duplication unit (duplicon) consists of at least an ERV16 element (Kulski and Dawkins 1999) and some other subfamily members of retrotransposons and DNA transposons, and a class I gene with or without an adjoining MIC gene (Geraghty et al. 1992; Avoustin et al. 1994, Dawkins et al. 1999; Kulski et al. 1999b; Shiina et al. 1999b). The genomic organization of the 10 to 11 HLA class I genes within the human alpha block was further categorized into four distinct duplicons based on the characteristic features of the HLA class I genes, retroelements, and their phylogenies (Kulski et al. 1999b). The four categories of the duplicons were used to reconstruct a duplication history that required only five tandem duplication steps, starting from a single MHC class I duplicon, to explain the organization of the 10 alternating MHC class I genes within the human and chimpanzee MHC class I alpha block (Kulski et al. 1999b, Kulski, Anzai, and Inoko 2004). A duplication-transposition model based on seven duplications and four transpositions of MHC class I genes has also been proposed (Shiina et al. 1999b).
Recently, the entire genomic sequence of the rhesus macaque MHC class I region was completed, annotated, and compared with the corresponding human and chimpanzee region (Shiina et al. unpublished data). The rhesus macaque MHC class I region was found to be markedly different to the human and chimpanzee MHC class I gene organization, with a complex organization of at least 20 additional class I genes within the alpha block and 17 additional class I genes within the beta block. Although there are no inverted MHC class I genes within the alpha block of the chimpanzee and the human, there are nine in the rhesus macaque. In this study, we examined in greater detail the organization of the rhesus macaque MHC class I genes within the alpha block and identified certain transposons and retroelements within the segmental genomic duplicon structures with a view to reconstructing their duplication history. This paper shows that the complex arrangement of 31 class I genes within the rhesus macaque MHC class I alpha block can be explained parsimoniously by a series of unigenic and multigenic tandem duplications, tandem duplications with inversions, and deletions and recombinations based on a previous model developed for humans (Kulski et al. 1999b).
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Materials and Methods |
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Dot-plot matrix analyses were performed using the programs Dotter (Sonnhammer and Durbin 1995) or HarrPlot version 2.1.0 as part of the GENETYX version 11 program (Shiina et al. 1999b) as required. The programs RepeatMasker (http//ftp.genome.washington.edu/cgi-bin/RepeatMasker, A.F.A. Smit and P. Green pesonal communication) or CENSOR (Jurka et al. 1996b) were used to identify DNA transposons and retrotransposons within the contiguous sequences. BlastN (NCBI) confirmed gene loci within the genomic sequences. Sequence alignments were performed using ClustalW (Baylor College of Medicine) or ClustalX version 1.81 (Thompson et al. 1997), and the phylogenetic analysis was performed using the Neighbor-Joining (NJ) method within Clustal at DDBJ (http://www.ddbj.nig.ac.jp/E-mail/clustalw-e.html) or the programs PAUP* (Swofford 1998) or MEGA version 2.1 (Kumar et al. 2001). The sequences flanking Alu repeats within different duplicated segments were aligned and examined for homology to confirm their paralogous location by using ClustalW and a spreadsheet program (Excel, Microsoft). Each paralogous Alu element within the alpha block was given a code name and number following the subfamily designation (e.g., AluJ1 and AluJ2 or AluS1, and AluS2) as previously described by Kulski et al. (1999b). The same number was used for each Alu element found within a paralogous location of duplicated segments unless specified otherwise.
The nomenclature used in this report for the Mamu MIC and Mamu class I genes within the alpha block (fig. 1) is the same as that used by Shiina et al. (unpublished data). The Mamu-80 (eight copies), Mamu-G (six copies), Mamu-A (three copies), Mamu-70 (one copy) and Mamu-75 (three copies) are equivalent to the Patr/HLA-80, -G, -A, -70, and -75 genes, respectively. Mamu-AG (five copies) is also closely related to either the HLA-A or HLA-H genes. Mamu-MICG (eight copies) and Mamu-MICD are equivalent to the human MICG and MICD genes, respectively. Mamu-59 is also called Mamu-J and is equivalent to HLA-59 or HLA-J. We also refer to some deleted Mamu-75 genes here as Mamu-Del75a (or Del75a) and Mamu-Del75b (or Del75b) and a deleted Mamu-AG gene as Mamu-AGdel (or AGdel). The three class I S series genes, SD, SE-1, and SE-2 have low identity (<70%) at exon 4 with HLA-A, -B, -C, -E, -F, and -G, and their strongest similarity is with mouse class I T region genes (Shiina et al. unpublished data).
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Results and Discussion |
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The rhesus macaque genes within the expanded region 1 (ER1) and D1 region of figure 1 are in the same direction and have a similar organization to the human genes. Mamu-F, like the Patr/HLA-F gene orthologs, is located at the very telomeric end of the rhesus macaque alpha block. In the expanded region 2 (ER2), telomeric of the Mamu-75-1 gene, there are six genomic inversions. ER2 has 18 class I genes and four MIC genes, with 11 of the 18 class I genes in the opposite direction to the 13 class I genes centromeric of ER2. In contrast to the rhesus macaque genomic sequence, all of the human and chimpanzee class I genes and MIC genes within each respective gene group are oriented in the same direction. In addition, the rhesus macaque appears to have lost the human HLA-90 ortholog (or the Mamu-80 paralogous gene) in the D1 region and within the five duplicated locations of the ER2. Thus, the rhesus macaque ER1 and D1 are similar in organization to the human and chimpanzee alpha block region, whereas the ER2 of the rhesus macaque has no equivalent structure in the human and chimpanzee. Figure 1 also shows the duplicon categories, A to D, that have been deleted, inverted and/or duplicated within the inverted and noninverted segments of the rhesus macaque ER2. The four distinct duplication regions (D1 to D4) that were deduced to have been involved in the formation of the rhesus macaque ER2 are shown in figure 1 and discussed in more detail in the following sections.
Structural Categories of MHC Class I Duplicons
To better understand the genomic organization and duplication history of the rhesus macaque alpha block, the duplicated genomic segments (duplicons) were classified into four categories, A to D, on the basis of the types of duplicated retrotransposons and transposons that are linked to a particular class I and/or MIC gene within each segment (Kulski et al. 1999b, 2002). Figures 2 and 3 show the structural features for each of the rhesus macaque A to D duplicated segments. The nomenclature for the duplicated genomic segments in rhesus macaque is the same as in the human (Kulski et al. 1999b) and chimpanzee (Kulski, Anzai, and Inoko 2004), except that here we have called the previously labeled category B' genomic segment as D for greater emphasis and clarity. A summary of the common transposons and retrotransposons found within each of the duplicon categories A, B, C, and D are presented in Table 1. The repeat elements identified within the duplicons include DNA transposons (MER5A, MER5B, MER20, MER30, CHARLIE1, CHARLIE 9, TIGGER1), LTRs (MER9, MER21B, MER41B), SINES (Alu, MIR), LINEs (L1, L2), members of a superfamily of Mammalian apparent-LTR retrotransposons (MaLRs) such as MSTs and MLTs (Smit 1993; Jurka et al. 1996a; Smit 1996, 1999; Smit and Riggs 1996) and different ERV families (Kulski et al. 1999a; Jurka 2000). ERV16 is present usually as a fragmented sequence in most of the duplicated segments of the alpha block.
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The basic features and genomic structure of the eight category B duplicons are shown in figure 2B and figure 3. In comparison, there are only four category B genomic duplicons, J, 70, G, and F, in the human and chimpanzee (Kulski, Anzai, and Inoko 2004). The category B duplicons are characterized by the presence of the distinctive AluJ3 and AluJ4 elements that are absent from the category A duplicons. Except for duplicon F, the category B duplicons in the rhesus macaque are 18 kb or more in length, and they all have a fragment of the MIC genes and the LTR71B/ERV71 sequences. Only one of the category B duplicons (Mamu-G3) is located in the opposite direction to the other category B duplicons. In addition, there appear to be at least two category B hybrid duplicons, Mamu G2 and Mamu A3, where a portion of the category B duplicon has been recombined with a category D (fig. 2D) and C duplicon (fig. 3), respectively.
The category C duplicons have the AluJ3 and the AluY1 sequences and the Mamu-A or Mamu-AG genes (fig. 2C and 3). In humans and chimpanzees, the category C duplicons carry the Patr/HLA-A and Patr/HLA-H genes. Moreover, six inversion breakpoints were found between the category C and D duplicons in rhesus macaque but not in the human or the chimpanzee. Overall, there are nine category C duplicons in the rhesus macaque compared with only two in the human and chimpanzee (Patr/HLA-A and Patr/HLA-H). Five of the category C duplicons in the rhesus macaque contain the Mamu-AG genes (AG1 to AG5), one duplicon (AGDel) has a deleted Mamu-AG gene (fig. 2C), and three others have the Mamu-A1, -A2, and -A3 genes (fig. 3). Four of the category C duplicons (AG1, AG3, AG4, AG5) are inverted in relation to the direction of most of the other class I genes.
The category D duplicons that are linked with the Mamu-75 genes in the rhesus macaque, are shown in figure 2D. There is a full-length L1PA6 retrotransposon (6,140 bp), inserted within the one human (Kulski et al. 1999b) and the six rhesus macaque category D duplicons (fig. 2D) that is missing from the chimpanzee (Kulski, Anzai, and Inoko 2004). The two open reading frames, one coding for a RNA-binding protein and the other coding for a protein with an endonuclease and reverse transcriptase domains (Feng et al. 1996), are highly disrupted by numerous premature stop codons within all of the Mamu-L1PA6 sequences. A Charlie9 fragment and a L1ME3B or MLT1E3 fragment usually flank the insertion site for the L1PA6 sequence, and it appears to be the same site for both the human and rhesus macaque sequences. The L1PA6 sequence in the orthologous location of duplicon 75-1 of the rhesus macaque and the human duplicon 75 suggests that it was most likely deleted from the chimpanzee duplicon 75. The human L1PA6 insertion however, has a species-specific flanking telomeric duplication of a genomic sequence that contains the category B segmental elements, AluJ4 and AluJ3. On the other hand, the region between HLA-75 and the L1PA6 contains AluJ3 but lacks AluJ4, similar to the category C duplicons (Kulski et al. 1999b). The corresponding regions within duplicons 75 of the chimpanzee and rhesus macaque also lack the category AluJ4 element. The category D duplicons are similar to the category C duplicons, except that they have the L1PA6 insertion but not the AluY1 insertion. In addition, all category D duplicons have an AluS insertion within the ERV16 sequences and a MLT sequence adjoining the LTR16B inversion breakpoint. Nevertheless, the structural and sequence similarity of the category D duplicon with the C duplicons suggest that it is an intermediate structure between the category B and category C duplicons and the likely precursor to the category C duplicons.
Because of the L1PA6 insertion, the human and rhesus macaque duplicons 75 are referred to here as category D duplicons (previously called B' or B [Kulski, Anzai, and Inoko 2004]). In human, there is only one category D duplicon (contains the HLA-75 gene), whereas in the rhesus macaque, there are six. Three category D duplicons have the genes Mamu-75-1, -75-2, and -75-3, whereas two others have had their Mamu-75 genes completely deleted and are referred to here as the Mamu-Del75a and -Del75b duplicons (fig. 2D). Another of the D duplicons appears to be a hybrid structure between a category B and a category D duplicon because it has a fully intact category B gene (Mamu-G2) instead of the category D Mamu-75 fragmented gene (exons 1 to 3). The remainder of this hybrid duplicon is typically category D with the full-length L1PA6 insertion at the expected location. Two of the category D duplicons have been inverted, and all of the telomeric ends of the category D duplicons in the vicinity of the ERV16 and LTR16B sequences form an inversion breakpoint. This inversion breakpoint is linked to the category C duplicons that have the Mamu-AG genes.
Breakpoints and BALSL Complexes
The ER2 has six inverted subregions providing 12 breakpoints, as shown in figure 1. The breakpoints for the original inversions are difficult to ascertain because they may have been masked by the subsequent duplications, insertions, deletions, and other rearrangements. Nevertheless, there are four discernable inversion breakpoints (fig. 1): (1) the ERV16 breakpoint at positions 1, 2, 3, 4, 5, and 6, (2) the breakpoint between Mamu-G3 and Mamu-G4 at position 6, (3) the breakpoint near the BALSL 5' ends at positions 2, 4, and 8, and (4) the breakpoint at positions 10 and 12 that are between the Mamu-SE1/Mamu-SE2 and Mamu-AG4/Mamu-AG5 genes, respectively. Presumably, most of the inversion breakpoints, such as the ERV16 breakpoints, have resulted from duplications rather than actual inversions.
There are a collection of duplicated retroelements located between the ERV16 sequences and the MIC genes within the category B duplicons of Patr/HLA-J to Patr/HLA-80, Patr/HLA-H to Patr/HLA-G, and Patr/HLA-75 to Patr/HLA-F. This collection of duplicated retroelements, which we have termed the "breakpoint-associated LTR-sine-line" complex, or BALSL for short, has been modified slightly in the rhesus macaque alpha block. Figure 4 shows a majority of the BALSL retroelements and transposon sequences that adjoin the six breakpoint locations of the rhesus macaque in comparison with the similar group of elements that were detected within the two human duplicons linked with HLA-H and HLA-75, respectively. The human duplicon with HLA-J also has some of the elements, such as LTR16B/ERV16, L2, MLT1E2, Tigger 1, MIR, MLTB1, and MER5. The genomic ends close to L2/MLT1E2 or MIR of BALSL2-4 form the terminal ends with the breakpoints within the adjoining retroelements that are downstream from Mamu-806 to Mamu-808. On the other hand, the MIR/MLTB1 sequences of BALSL5-6 form the terminal ends with the breakpoints located closely to Mamu-SE1 and Mamu-SE2. The 584-bp sequence between Mamu-SD1 and BALSL1 appears to contain the breakpoint position for the start of the duplication D2a region that is shown in figure 1. The LTR16B/ERV16 sequences that are present within the human BALSL-like sequences appear to have been completely lost from the rhesus macaque BALSL complexes, presumably as part of the duplication process D2 that had first involved BALSL1. In addition, the MIC genes in the human BALSL-like sequences appear to have been replaced by the endogenous retroviral LTR sequences, MER9, within the rhesus macaque BALSL complex. This further differentiates the rhesus macaque duplicated BALSL complex from the structurally similar complex in human and chimpanzee (fig. 4).
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Phylogeny of Genes and Retrotransposons Within MHC Class I Duplicons
Figure 5 shows the separate NJ trees of the Mamu exons 2 and 3. In general, the exon sequences clustered into groups according to their duplicon categories, A to D. The exception was the Mamu-A2 exon 3 that grouped with the category B sequences. The category A to D sequences from the duplication regions D2, D3, and D4 (fig. 1) paired closely together in the NJ trees, suggesting they had evolved more recently than the sequences from the D1 and ER1 regions.
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Figure 6B shows the distance tree for the 5' and 3' LTR16B sequences. The 5' and 3' LTR16B, supposedly identical in sequence when first inserted into the alpha block, have separated into there own distinct clusters. This suggests that after ERV16 was first inserted into the ancestral duplicon, the 5' LTR (L5) and 3' LTR (L3) had already diverged before any of the subsequent duplication events. Consequently, the 5' and 3' LTR do not group together as would be expected if the ERV16 sequences were the products of recent and separate insertions. Relatively few 5' LTR16B sequences (six sequences) compared with the 3' LTR16B sequences (29 sequences) have remained within the duplicons of the alpha block, suggesting a bias towards the retention of the 3' LTR16B. This was confirmed by the alignment of 32 ERV16 sequences (data not shown). Of the 32 ERV16 sequences, 29 had at least one LTR remaining. Only six ERV16 sequences had both of their 3' and 5' LTR16B left intact, although partially fragmented. There were seven solitary LTR16B sequences, and the other LTR16B sequences had a portion of their internal ERV16 sequences linked with its LTR so that they could be easily distinguished as either a 5' or 3' LTR. The seven solitary LTR16B sequences were classified as 3' LTR on the basis of their topology within the NJ trees (fig. 6B).
The six 5' LTR16B are part of the category D and category B duplicons, whereas the 29 3' LTR16B belong to all four duplicon categories, A to D. The category B to category D sequences grouped together to form a lineage separately from the category A sequences. In category A, the LTR16B sequences near the MICG4 to MICG8 gene fragments grouped together to reveal that they are indeed part of the category A duplicons that have had their Mamu-80 gene fragment completely deleted, as indicated in figure 1. Other LTR16B sequences from the two duplicons with deleted Mamu genes have grouped as expected; that is, Mamu-Del75a and -Del75b grouped with the category D duplicons and Mamu-AGdel grouped with the category C duplicons. The 5' and 3' LTR16B sequences within the Mamu G2 duplicon grouped with the other sequences from the category D duplicons, confirming the hybrid nature of the G2 duplicon. The sequences taken from the genomic regions that were predicted to be the most recent duplication sites (i.e., D3 and D4) generally clustered as pairs; for example, AG4L3 paired with AG5L3, G5L3 paired with G6L3, and Del75b.L5 paired with Del75a.L5 (fig. 6B). This tree also supports the view that the LTR16B sequences located within the duplicons of ER1 and D1 originated before those in the ER2. It is noteworthy that the solitary LTR16B sequence from the duplicon carrying the Mamu-F gene sequence is well separated from the other category B, C, and D duplicons. Therefore, this topology supports the prediction of the earlier evolutionary duplication models that duplicon F was probably fixed within the alpha block without contributing to any further duplications at a time well before the formation of most of the other MHC class I genes from the category B, C, and D duplicons (Kulski et al. 1999b; Kulski, Anzai, and Inoko 2004).
Evolution of MHC Class I Duplicons by Tandem Duplications and Inversions
The first detailed model for the evolution of the MHC class I duplicons by serial tandem duplications of multigenic units within the alpha block was proposed on the basis of a structural and phylogenetic analysis of duplicons and their organization within the human alpha block (Kulski et al. 1999b). It was more parsimonious than other models, such as the duplication-transition model (Shiina et al. 1999b), in that it required fewer duplication steps and no transposition events. In addition, the MHC tandem-duplication model proposed that HLA-75 was the ancestor of HLA-A and -H, and HLA-90 was the ancestor of HLA-80 and -16. The duplication-transposition model also proposed a lineage for the same genes, but in the opposite direction.
The following five assumptions were made in reconstructing the evolutionary history of the MHC class I gene clusters by tandem duplication of the genomic segments or duplicons. (1) Tandem duplications are preferred to duplications that are associated with transpositions. (2) In reconstructing the most-parsimonious tandem duplication steps, a single block duplication of a multigenic duplication unit (polyduplicons) is preferred to a series of duplications of monogenic units. (3) The sequential order of segmental duplications should be based as much as possible on the duplicon structural features, organization, phylogeny, and evolutionary time. (4) The sequence identity and divergence between duplicons is time dependent. Presumably, two newly generated duplicons are almost identical in sequence soon after the duplication event. Deletions, insertions, point mutations, and other rearrangements will eventually create diversity within and between duplicons over time. (5) Recent tandem duplication steps will be more evident within the same species or between closely related species (e.g., human and chimpanzee) than between more distantly related species (e.g., human and rhesus macaque).
On the basis of the structure and phylogeny of the genes and retrotransposons within the four duplicon categories A to D, a duplication history for the evolution of the alpha block within the MHC of the rhesus macaque, chimpanzee, and human was reconstructed as outlined in figures 7 and 8. In the rhesus macaque, the duplicons G, 80, and 75 within the D1 region are inferred to be the progenitors of the duplications within the ER1 (fig. 7). Following on from the evolution of ER1, the duplicons A, G, 80, and 75 were then the progenitors for the duplication events within the ER2 (fig. 8).
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Figure 8 shows the inferred expansion of ER2 within the alpha block of the rhesus macaque. This is shown as nine distinct steps (11 to 19), starting from duplication and inversion of the category ACBD combination in step 11 of the previous figure. Essentially, six tandem duplications, two of which also include inversions, explain the formation of 15 new class I genes in the macaque ER2. The first tandem duplication is derived from the conserved region (D1), with the duplication and inversion of ACBD resulting in the inverted AC and loss of the inverted BD as shown in the figure. The origin of duplications has been boxed by dashed lines and labeled as D1 because this is the first critical duplication and inversion that leads to the expansion of region 2; that is, ACBD is duplicated but with an inversion (DBCA) of one of its products. All other duplication, inversion, and deletion steps result from the duplication unit composed of the four duplicon units, BD(AC)inv, as shown in steps 14 to 19 of the figure. The MHC orthologous class I F gene is shown as the single F duplicon or F tail on the right-handed end (the telomeric end) of MHC class I duplicons at each step.
Only two inversion steps needed to be postulated to account for all of the inverted regions or nine inverted duplicons (figs. 1 and 8). Tandem duplications of the first two inverted regions can then account for the other four inverted regions. Therefore, the model in figure 7 infers two tandem duplications with an associated inversion and four tandem duplications with no inversions to account for 19 genes within D1 and the ER2. Overall, there appear to have been 12 tandem duplications (with or without inversions) and 12 deletions to explain the presence of at least 28 class I genes within the alpha block of the rhesus macaque, beginning with either a category A or category B progenitor duplicon and class I gene. In addition, this tandem duplication/inversion model helps to explain the organization of the six deleted category A duplicons, the deleted category C gene (Mamu-AGdel), and the two deleted category D genes (Mamu-Del75a and -Del75b), as seen within the dot-plot (fig. 1) and the Alu and LTR16B phylogenetic trees (fig. 6). In comparison, five tandem duplications and two deletions appear to be sufficient to explain the organization of the 10 to 11 MHC class I genes and duplicons within the alpha block of the human and the chimpanzee (Kulski, Anzai, and Inoko 2004).
The key step in explaining the presence of nine inverted class 1 genes and duplicons within the ER2 (fig. 1) is the duplication/inversion of the category ACBD duplicons within the D1 region and the deletion of the category BD duplicons from within the inversion (steps 12 and 13 in figure 8). Thereafter, the duplicon block combination of BDCA is inferred to have undergone five duplications whereby one of the duplications included an inversion and at least three single duplicons were deleted. Thus, two separate inversion steps are sufficient to explain the presence of nine inverted duplicons out of the total of 28 MHC class I duplicons within the alpha block of the rhesus macaque.
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Conclusion |
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Acknowledgements |
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Footnotes |
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References |
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