Extensive genomic and functional polymorphism of the complement control proteins

Abstract

Using combinations of genomic markers, we describe more than 20 distinct ancestral haplotypes (AH) of complement control proteins (CCPs), located within the regulators of complement activation (RCA) alpha block at 1q32. This extensive polymorphism, including functional sites, is important because CCPs are involved in the regulation of complement activation whilst also serving as self and viral receptors. To identify haplotypes, we used the genomic matching technique (GMT) based on the pragmatic observation that extreme nucleotide polymorphism is packaged with duplicated sequences as polymorphic frozen blocks (PFB). At each PFB, there are many alternative sequences (haplotypes) which are inherited faithfully from very remote ancestors. We have compared frequencies of RCA haplotypes and report differences in recurrent spontaneous abortion (RSA) and psoriasis vulgaris (PV).

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Abbreviations

AH:

Ancestral haplotype

ARL-C:

Arthritis Research Laboratory controls

CCP:

Complement control proteins

CR1:

Complement receptor 1

CR1-L:

Complement receptor 1-like

CR2:

Complement receptor 2

GMT:

Genomic matching technique

HCT:

Haemochromatosis

HE:

Haplospecific geometric element

Indels:

Insertions/deletions

MCP:

Membrane cofactor protein

MCP-L:

Membrane cofactor protein-like

MHC:

Major histocompatibility complex

PCR:

Polymerase chain reaction

PFB:

Polymorphic frozen block

PV:

Psoriasis vulgaris

RCA:

Regulators of complement activation

RSA:

Recurrent spontaneous abortion

RSA-C:

Recurrent spontaneous abortion controls

RSA-P:

Recurrent spontaneous abortion patients

SA:

Suraksha Agrawal

SLE:

Systemic lupus erythematosus

SS:

Sjogren’s syndrome

References

  1. Bell, E (2000) Murine embryonic survival depends on regulation of complement. Immunology Today 21:109

    Google Scholar 

  2. Birmingham DJ, Chen W, Liang G, Schmitt HC, Gavit K, Nagaraja HN (2003) A CR1 polymorphism associated with constitutive erythrocyte CR1 levels affects binding to C4b but not C3b. Immunology 108:531–538

    Article  PubMed  CAS  Google Scholar 

  3. Dawkins R, Leelayuwat C, Gaudieri S, Tay G, Hui J, Cattley S, Martinez P, Kulski J (1999) Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease. Immunological Reviews 167:275–304

    PubMed  Article  CAS  Google Scholar 

  4. Dhiman N, Jacobson R, Poland G (2004) Measles virus receptors: SLAM and CD46. Reviews in Medical Virology 14:217–229

    Article  PubMed  CAS  Google Scholar 

  5. Gaudieri S, Longman-Jacobsen N, Tay GK, Dawkins RL (2001) Sequence analysis of the MHC class I region reveals the basis of the genomic matching technique. Human Immunology 62:279–285

    Article  PubMed  CAS  Google Scholar 

  6. Heine-Suner D, Diaz-Guillen M, de Villena F, Robledo M, Benitez J, Rodriguez de Cordoba S (1997) A high-resolution map of the regulator of the complement activation gene cluster on 1q32 that integrates new genes and markers. Immunogenetics 45:422–427

    Article  PubMed  CAS  Google Scholar 

  7. Hourcade D, Holers VM, and Atkinson JP (1989) The regulators of complement activation (RCA) gene cluster. Advances in Immunology 45:381–416

    PubMed  CAS  Article  Google Scholar 

  8. Korendowych E, Williamson JF, Berry JA, Blasczyk R, Dupont E, Goldberg AC, Marin MLC, Hohler T, McHugh NJ, Novelli G, Dawkins RL Haplotypes associated with psoriasis, psoriatic arthritis and haemochromatosis. IHWG, Seattle (in press)

  9. Logar CM, Chen W, Schmitt H, Yu CY, Birmingham DJ (2004) A human CR1-like transcript containing sequence for a binding protein for iC4 is expressed in hematopoietic and fetal lymphoid tissue. Molecular Immunology 40:831–840

    Article  PubMed  CAS  Google Scholar 

  10. Longman-Jacobsen N, Williamson JF, Dawkins RL, Gaudieri S (2003) In polymorphic genomic regions indels cluster with nucleotide polymorphism: quantum genomics. Gene 312:257–261

    Article  PubMed  CAS  Google Scholar 

  11. McLure C, Dawkins R, Williamson J, Davies R, Berry J, Longman-Jacobsen N, Laird R, Gaudieri S (2004a) Amino acid patterns within short consensus repeats define conserved duplicons shared by genes of the RCA complex. Journal of Molecular Evolution 59:143–157

    Article  PubMed  CAS  Google Scholar 

  12. McLure C, Williamson J, Stewart B, Keating P, Dawkins R (2004b) Genomic analysis reveals a duplication of eight rather than seven SCRs in primate CR1 and CR1L: evidence for an additional set shared between CR1 and CR2. Immunogenetics 56:631–638

    Article  PubMed  CAS  Google Scholar 

  13. McLure C, Williamson J, Stewart B, Keating P, Dawkins R (2005) Indels and imperfect duplication have driven the evolution of human CR1 and CR1-like from their precursor CR1 alpha: importance of functional sets. Hum Immunol 66:258–273

    Article  PubMed  CAS  Google Scholar 

  14. Moulds JM, Zimmerman PA, Doumbo OK, Kassambara L, Sagara I, Diallo DA, Atkinson JP, Krych-Goldberg M, Hauhart RE, Hourcade DE, McNamara DT, Birmingham DJ, Rowe JA, Moulds JJ, Miller LH (2001) Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1. Blood 97:2879–2885

    Article  PubMed  CAS  Google Scholar 

  15. Nath SK, Harley JB, Lee YH (2005) Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Hum Genet (in press)

  16. Sonnhammer E, Durbin R (1995) A dot-matrix program with dynamic threshold control suited for genomic DNA and protein sequence analysis. Gene 167:GC1–10

    Article  PubMed  CAS  Google Scholar 

  17. Witt C, Sayer D, Trimboli F, Saw M, Herrmann R, Cannell P, Baker D, Christiansen F (2000) Unrelated donors selected prospectively by block-matching have superior bone marrow transplant outcome. Human Immunology 61:85–91

    Article  PubMed  CAS  Google Scholar 

  18. Xiang L, Rundles JR, Hamilton DR, Wilson JG (1999) Quantitative alleles of CR1: coding sequence analysis and comparison of haplotypes in two ethnic groups. J Immunol 163:4939–4945

    PubMed  CAS  Google Scholar 

  19. Xu C, Mao D, Holers M, Palanca B, Cheng A, Molina H (2000) A critical role for murine complement regulator crry in fetomaternal tolerance. Science 287:498–501

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to Dr. D Sayer and Royal Perth Hospital for the sequencing of the products, Dr. Peter Kesners for advice and Ms. Wendy Ford for administration. The samples designated RSA-C and RSA-P are from the Sanjay Gandhi Institute of Medical Sciences (SA). Those designated ARL-C, SLE-P and SS are from the Arthritis Research Laboratory, Hanson Institute (SL) with acknowledgements to Dr. Maureen Rischmueller of Rheumatology, Queen Elizabeth Hospital, Adelaide. The HCT and PV samples were described previously (Korendowych et al. 2002). Supported by Australian Research Council, CY O’Connor Village Foundation and Genetic Technologies, Fitzroy, Victoria 3065, Australia. Collectively, the authors associated with the CY O’Connor ERADE Village have an interest in Genetic Technologies.

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Correspondence to Roger L. Dawkins.

Additional information

Nucleotide sequence data reported are available in the GenBank database under the accession numbers DQ007054–DQ007076. Manuscript number 0408 of the Centre for Molecular Immunology and Instrumentation of the University of Western Australia and the CY O’Connor ERADE Village

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McLure, C.A., Williamson, J.F., Smyth, L.A. et al. Extensive genomic and functional polymorphism of the complement control proteins. Immunogenetics 57, 805–815 (2005). https://doi.org/10.1007/s00251-005-0049-2

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Keywords

  • Ancestral haplotypes
  • Complement control proteins
  • Autoimmunity
  • Genomic matching technique
  • Regulators of complement activation