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MHC-linked and un-linked class I genes in the wallaby.

Siddle HV, Deakin JE, Coggill P, Hart E, Cheng Y, Wong ES, Harrow J, Beck S, Belov K - BMC Genomics (2009)

Bottom Line: MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions.The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens.The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia. h.siddle@usyd.edu.au

ABSTRACT

Background: MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions. However, there is a fundamental difference between the organization of class I genes in mammals and non-mammals. Non-mammals have a single classical gene responsible for antigen presentation, which is linked to the antigen processing genes, including TAP. This organization allows co-evolution of advantageous class Ia/TAP haplotypes. In contrast, mammals have multiple classical genes within the MHC, which are separated from the antigen processing genes by class III genes. It has been hypothesized that separation of classical class I genes from antigen processing genes in mammals allowed them to duplicate. We investigated this hypothesis by characterizing the class I genes of the tammar wallaby, a model marsupial that has a novel MHC organization, with class I genes located within the MHC and 10 other chromosomal locations.

Results: Sequence analysis of 14 BACs containing 15 class I genes revealed that nine class I genes, including one to three classical class I, are not linked to the MHC but are scattered throughout the genome. Kangaroo Endogenous Retroviruses (KERVs) were identified flanking the MHC un-linked class I. The wallaby MHC contains four non-classical class I, interspersed with antigen processing genes. Clear orthologs of non-classical class I are conserved in distant marsupial lineages.

Conclusion: We demonstrate that classical class I genes are not linked to antigen processing genes in the wallaby and provide evidence that retroviral elements were involved in their movement. The presence of retroviral elements most likely facilitated the formation of recombination hotspots and subsequent diversification of class I genes. The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens. The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function.

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Promoter elements of MHC-linked and MHC-unlinked class I genes. 180 base pairs of sequence upstream from the TATA box is shown for all wallaby class I genes, with the exception of Maeu-UK and Maeu-UP, for which promoter elements could not be identified. The promoter elements for Modo-UA are also included. The boxed elements are, Enhancer A, an IFN stimulated response element (ISRE), S, X and Y motifs, a CAAT element and TATA box within 50 base pairs of the start site for each gene.
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Figure 4: Promoter elements of MHC-linked and MHC-unlinked class I genes. 180 base pairs of sequence upstream from the TATA box is shown for all wallaby class I genes, with the exception of Maeu-UK and Maeu-UP, for which promoter elements could not be identified. The promoter elements for Modo-UA are also included. The boxed elements are, Enhancer A, an IFN stimulated response element (ISRE), S, X and Y motifs, a CAAT element and TATA box within 50 base pairs of the start site for each gene.

Mentions: Putative class I promoter elements were identified within 200 base pairs of the start codon for the class I genes and included TATA and CAAT sites, the S, X and Y regulatory motif, an interferon stimulated response element (ISRE) and an enhancer A site (Figure 4). The promoter elements of the MHC un-linked class I genes are highly similar to each other, sharing between 66–95% nucleotide identity in the 290 base pairs upstream of the gene start site. The promoter elements of the MHC un-linked class I are also similar to the regulatory elements of Modo-UA, sharing 57–70% nucleotide identity. However, Maeu-UJ is missing a TATA site and appears to have a truncated enhancer A element and Maeu-UH and Maeu-UI have no enhancer A element. These variations may account for the lack of evidence of transcription of Maeu-UJ and Maeu-UI. The upstream sequence of the class Ib, MHC-linked class I genes shared between 32–50% nucleotide identity with the MHC un-linked class I, 35–79% with one another and only 39–51% with the promoter sequence of Modo-UA, consistent with the more divergent nature of the coding sequence of these genes. However, it was still possible to identify the TATA, CAAT and SXY motifs in these genes, with the exception of Maeu-UK and Maeu-UP. Putative enhancer A and ISRE elements of the class Ib genes were identified with less confidence due to the lower sequence identity in the upstream sequence observed for these genes.


MHC-linked and un-linked class I genes in the wallaby.

Siddle HV, Deakin JE, Coggill P, Hart E, Cheng Y, Wong ES, Harrow J, Beck S, Belov K - BMC Genomics (2009)

Promoter elements of MHC-linked and MHC-unlinked class I genes. 180 base pairs of sequence upstream from the TATA box is shown for all wallaby class I genes, with the exception of Maeu-UK and Maeu-UP, for which promoter elements could not be identified. The promoter elements for Modo-UA are also included. The boxed elements are, Enhancer A, an IFN stimulated response element (ISRE), S, X and Y motifs, a CAAT element and TATA box within 50 base pairs of the start site for each gene.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719672&req=5

Figure 4: Promoter elements of MHC-linked and MHC-unlinked class I genes. 180 base pairs of sequence upstream from the TATA box is shown for all wallaby class I genes, with the exception of Maeu-UK and Maeu-UP, for which promoter elements could not be identified. The promoter elements for Modo-UA are also included. The boxed elements are, Enhancer A, an IFN stimulated response element (ISRE), S, X and Y motifs, a CAAT element and TATA box within 50 base pairs of the start site for each gene.
Mentions: Putative class I promoter elements were identified within 200 base pairs of the start codon for the class I genes and included TATA and CAAT sites, the S, X and Y regulatory motif, an interferon stimulated response element (ISRE) and an enhancer A site (Figure 4). The promoter elements of the MHC un-linked class I genes are highly similar to each other, sharing between 66–95% nucleotide identity in the 290 base pairs upstream of the gene start site. The promoter elements of the MHC un-linked class I are also similar to the regulatory elements of Modo-UA, sharing 57–70% nucleotide identity. However, Maeu-UJ is missing a TATA site and appears to have a truncated enhancer A element and Maeu-UH and Maeu-UI have no enhancer A element. These variations may account for the lack of evidence of transcription of Maeu-UJ and Maeu-UI. The upstream sequence of the class Ib, MHC-linked class I genes shared between 32–50% nucleotide identity with the MHC un-linked class I, 35–79% with one another and only 39–51% with the promoter sequence of Modo-UA, consistent with the more divergent nature of the coding sequence of these genes. However, it was still possible to identify the TATA, CAAT and SXY motifs in these genes, with the exception of Maeu-UK and Maeu-UP. Putative enhancer A and ISRE elements of the class Ib genes were identified with less confidence due to the lower sequence identity in the upstream sequence observed for these genes.

Bottom Line: MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions.The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens.The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia. h.siddle@usyd.edu.au

ABSTRACT

Background: MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions. However, there is a fundamental difference between the organization of class I genes in mammals and non-mammals. Non-mammals have a single classical gene responsible for antigen presentation, which is linked to the antigen processing genes, including TAP. This organization allows co-evolution of advantageous class Ia/TAP haplotypes. In contrast, mammals have multiple classical genes within the MHC, which are separated from the antigen processing genes by class III genes. It has been hypothesized that separation of classical class I genes from antigen processing genes in mammals allowed them to duplicate. We investigated this hypothesis by characterizing the class I genes of the tammar wallaby, a model marsupial that has a novel MHC organization, with class I genes located within the MHC and 10 other chromosomal locations.

Results: Sequence analysis of 14 BACs containing 15 class I genes revealed that nine class I genes, including one to three classical class I, are not linked to the MHC but are scattered throughout the genome. Kangaroo Endogenous Retroviruses (KERVs) were identified flanking the MHC un-linked class I. The wallaby MHC contains four non-classical class I, interspersed with antigen processing genes. Clear orthologs of non-classical class I are conserved in distant marsupial lineages.

Conclusion: We demonstrate that classical class I genes are not linked to antigen processing genes in the wallaby and provide evidence that retroviral elements were involved in their movement. The presence of retroviral elements most likely facilitated the formation of recombination hotspots and subsequent diversification of class I genes. The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens. The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function.

Show MeSH
Related in: MedlinePlus