, Volume 57, Issue 11, pp 805–815 | Cite as

Extensive genomic and functional polymorphism of the complement control proteins

  • Craig A. McLure
  • Joseph F. Williamson
  • Louise A. Smyth
  • Suraksha Agrawal
  • Susan Lester
  • John A. Millman
  • Peter J. Keating
  • Brent J. Stewart
  • Roger L. DawkinsEmail author
Original Paper


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).


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



Ancestral haplotype


Arthritis Research Laboratory controls


Complement control proteins


Complement receptor 1


Complement receptor 1-like


Complement receptor 2


Genomic matching technique




Haplospecific geometric element




Membrane cofactor protein


Membrane cofactor protein-like


Major histocompatibility complex


Polymerase chain reaction


Polymorphic frozen block


Psoriasis vulgaris


Regulators of complement activation


Recurrent spontaneous abortion


Recurrent spontaneous abortion controls


Recurrent spontaneous abortion patients


Suraksha Agrawal


Systemic lupus erythematosus


Sjogren’s syndrome



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.


  1. Bell, E (2000) Murine embryonic survival depends on regulation of complement. Immunology Today 21:109Google 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 108:531–538CrossRefPubMedGoogle 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 167:275–304PubMedCrossRefGoogle Scholar
  4. Dhiman N, Jacobson R, Poland G (2004) Measles virus receptors: SLAM and CD46. Reviews in Medical Virology 14:217–229CrossRefPubMedGoogle 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 62:279–285CrossRefPubMedGoogle 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 45:422–427CrossRefPubMedGoogle Scholar
  7. Hourcade D, Holers VM, and Atkinson JP (1989) The regulators of complement activation (RCA) gene cluster. Advances in Immunology 45:381–416PubMedCrossRefGoogle 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)Google Scholar
  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 40:831–840CrossRefPubMedGoogle Scholar
  10. Longman-Jacobsen N, Williamson JF, Dawkins RL, Gaudieri S (2003) In polymorphic genomic regions indels cluster with nucleotide polymorphism: quantum genomics. Gene 312:257–261CrossRefPubMedGoogle 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 59:143–157CrossRefPubMedGoogle 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 56:631–638CrossRefPubMedGoogle 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 66:258–273CrossRefPubMedGoogle 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 97:2879–2885CrossRefPubMedGoogle 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)Google Scholar
  16. Sonnhammer E, Durbin R (1995) A dot-matrix program with dynamic threshold control suited for genomic DNA and protein sequence analysis. Gene 167:GC1–10CrossRefPubMedGoogle 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 61:85–91CrossRefPubMedGoogle 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 163:4939–4945PubMedGoogle 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 287:498–501CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Craig A. McLure
    • 1
    • 2
  • Joseph F. Williamson
    • 1
  • Louise A. Smyth
    • 1
  • Suraksha Agrawal
    • 3
  • Susan Lester
    • 1
    • 4
  • John A. Millman
    • 1
    • 5
  • Peter J. Keating
    • 1
  • Brent J. Stewart
    • 1
    • 2
  • Roger L. Dawkins
    • 1
    • 2
    Email author
  1. 1.CY O’Connor ERADE VillageWestern AustraliaAustralia
  2. 2.Centre for Molecular Immunology and Instrumentation, University of Western AustraliaWestern AustraliaAustralia
  3. 3.Department of Medical GeneticsSanjay Gandhi Institute of Medical SciencesLucknowIndia
  4. 4.Arthritis Research LaboratoryHanson InstituteAdelaide, South AustraliaAustralia
  5. 5.TAFEWA Swan CampusBentley, Western AustraliaAustralia

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