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Evolutionary Histories of HLA-DRB Haplotypes

M.Tevfik Dorak, MD PhD

Phylogeny and evolutionary history of any gene group can be worked out by determining nucleotide substitutions to construct phylogenetic trees and to estimate divergence times; or a set of insertions (mostly Alu elements, L1 repeats, retroviral insertions and others) that reveal the order of splitting of duplicated genes; or the presence of homologous genes in different taxa with known evolutionary histories mainly from their fossil records. When these data are applied to human HLA-DRB genes, depending on the method used or in the case of sequencing studies, depending on the part of the gene used, different scenarios emerge. There are, however, some consistent findings. The ancestor of the human DRB genes appears to have been HLA-DRB1*04-like 1,2. The ancestor of the DRB1*03 cluster (DRB1*03, DRB1*15, DRB3) is believed to have diverged from the ancestral HLA-DRB1*04 lineage 2,3. Both DRB1*04-like ancestor and the ancestor of the DRB1*03 cluster have been estimated to be older than 85 my 1. This estimate derives from the fact that DRB1*04 alleles are found in prosimian species (note that the mouse lineage separated 75-80 Mya). It is possible that DRB2 (on DR52 haplotypes), DRB4 (on DR53 haplotypes and most closely resembles DRB2), and DRB6 (on DR51 haplotypes) might be the diverged copies of a single ancestral DRB gene 4-6. The common ancestry of DR51 and DR52 haplotypes is also suggested by a common ERV9 LTR insertion about 40-60 million years old 4. Phylogenetic analyses of introns 1, 4, 5 of HLA-DRB genes suggest that the present-day HLA-DR haplotypes were derived from three principal ancestral haplotypes: DRB1-DRB2 (DR52 group), DRB1-DRB5 (DR51 group), and DRB1-DRB7 (DR53 group) 2,3. Therefore, the main allelic lineages appear to be: an ancestral DRB1*04 (DR53 group) gene (the exon 2 motif: 9EQVKH13) giving rise to DRB1*03 lineage (DR52 group) (the exon 2 motif: 9EYSTS13), and DR51 group (represented by DRB1*15) diverging from the DR52 group later on.


The DRB4 gene may have arisen 46 Mya by a deletion from the DRB1 and DRB2 genes 2. The DRB1 and DRB4 genes of the DR53 haplotypes have distinct evolutionary histories 7. The DRB9 locus is about 58 million years old 8 and the pseudogenes DRB7 and DRB8 arose after DRB9 9. The remaining HLA-DR haplotypes, the DR1/10 and DR8 groups, probably evolved from the DR51 and DR52 haplotypes, respectively, after more recent deletion events 4,10. The DRB1 genes in the DR1 and DR51 haplotypes contain similar ERV9 LTR elements located at the same positions as in the expressed DRB genes in the DR8 and DR52 haplotypes 4,6,10. These ERV9 LTRs are missing at these positions in the DR53 haplotypes. All DR53 haplotypes carry the DRB1, DRB4, DRB7, DRB8 and DRB9 genes. Of these, DRB4, DRB7 and DRB8 are exclusive to this group. The two DRB pseudogenes DRB7 and DRB8 in the DR53 haplotypes do not cluster with other DRB genes. The DRB8 gene also exists in the gorilla and seems to have appeared 18-26 Mya 11. The DR10 haplotype has a composite origin: a mixture of segments from DR1, DR3 and independent parts can be detected 12. Interestingly, its HV3 epitope sequence is shared by HLA-DR53 and -DR1 13,14.

Since DR51 (incl. DR1/10) and DR52 (incl. DR8) haplotypes seem to share a common ancestry, it is possible to divide all HLA-DR haplotypes into two evolutionarily related groups: DR53 group and non-DR53 group as direct descendants of the two primordial DRB genes, i.e., HLA-DRB1*04 and HLA-DRB1*03, respectively 10. The exclusive features of the DR53 haplotypes are: their unique DRB gene composition, the lack of ERV9 LTRs in introns 4 and 5 but the presence of distinct Alu repeats 6, and the 110 - 160 kb extra DNA content (irrespective of the DRB1 type) 15,16. The other main branch is characterised by the ERV9 LTR insertions at identical positions in the intron 5 of the expressed DRB genes (DRB1*01, DRB1*15, DRB1*0301, DRB3*0101, DRB1*08021) 4,10. In summary, two main, evolutionarily old branches of DR haplotypes exist in the human population. The DR53 haplotypic group represents one main branch. The second branch consists of the other DR haplotypes 4,6,10.


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2. Satta Y, Mayer WE, Klein J. HLA-DRB intron 1 sequences: implications for the evolution of HLA-DRB genes and haplotypes. Human Immunology 1996;51:1-12.

3. Satta Y, Mayer WE, Klein J. Evolutionary relationship of HLA-DRB genes inferred from intron sequences. Journal of Molecular Evolution 1996;42:648-57.

4. Svensson AC, Setterblad N, Pihlgren U, Rask L, Andersson G. Evolutionary relationship between human major histocompatibility complex HLA-DR haplotypes. Immunogenetics 1996;43:304-14.

5. Vincek V, Klein D, Figueroa F, Hauptfeld V, Kasahara M, O'hUigin C, Mach B, Klein J. The evolutionary origin of the HLA-DR3 haplotype. Immunogenetics 1992;35:263-71.

6. Svensson AC, Setterblad N, Sigurdardottir S, Rask L, Andersson G. Primate DRB genes from the DR3 and DR8 haplotypes contain ERV9 LTR elements at identical positions. Immunogenetics 1995;41:74-82.

7. Gorski J, Rollini P, Mach B. Structural comparison of the genes of two HLA-DR supertypic groups: the loci encoding DRw52 and DRw53 are not truly allelic. Immunogenetics 1987;25:397-402.

8. Gongora R, Figueroa F, Klein J. The HLA-DRB9 gene and the origin of HLA-DR haplotypes. Human Immunology 1996;51:23-31.

9. Arvidsson AK, Svensson AC, Widmark E, Andersson G, Rask L, Larhammar D. Characterization of three separated exons in the HLA class II DR region of the human major histocompatibility complex. Human Immunology 1995;42:254-64.

10. Svensson AC, Andersson G. Presence of retroelements reveal the evolutionary history of the human DR haplotypes. Hereditas 1997;127:113-24.

11. Klein D, Vincek V, Kasahara M, Schonbach C, O'hUigin C, Klein J. Gorilla major histocompatibility complex-DRB pseudogene orthologous to HLA-DRBVIII. Human Immunology 1991;32:211-20.

12. Gongora R, Figueroa F, Klein J. Complex origin of the HLA-DR10 haplotype. Journal of Immunology 1997;159:6044-51.

13. Auger I, Roudier J. Influence of the QKRAA/QRRAA/RRRAA motifs of the third hypervariable region of HLA-DRB1 in the development of rheumatoid arthritis. Journal of Rheumatology 1997;24:227-8.

14. Seyfried CE, Mickelson E, Hansen JA, Nepom GT. A specific nucleotide sequence defines a functional T-cell recognition epitope shared by diverse HLA-DR specificities. Human Immunology 1988;21:289-99.

15. Kendall E, Todd JA, Campbell RD. Molecular analysis of the MHC class II region in DR4, DR7, and DR9 haplotypes. Immunogenetics 1991;34:349-57.

16. Niven MJ, Hitman GA, Pearce H, Marshall B, Sachs JA. Large haplotype-specific differences in inter-genic distances in human MHC shown by pulsed field electrophoresis mapping of healthy and type 1 diabetic subjects. Tissue Antigens 1990;36:19-24.

M.Tevfik Dorak, MD, PhD

Last updated on Sept 1, 2004

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