Biochemical Genetics

, Volume 43, Issue 5–6, pp 229–237 | Cite as

Local Base Order Influences the Origin of ccr5 Deletions Mediated by DNA Slip Replication

Article
Received:
Accepted:

Abstract

CCR5 is a seven-transmembrane G-protein-coupled receptor that binds the CC-chemokines including RANTES, eotaxin, MIP-1α and β. CCR5 serves as an essential coreceptor for cell entry of R5 (macrophage-tropic, nonsyncytium-inducing) strains of HIV-1. To date, four deletions have been found in human and primate ccr5. There is little evidence, however, on how these deletion mutations occur. In the present study, we analyzed ccr5 sequences of both mutants and wild type and found that direct repeats flanked the breakpoints of the deletions, suggesting that these deletions resulted from slipped mispairing during DNA replication. Of particular interest was the location of these deletions in or near the regions with higher negative FORS-D values. High negative FORS-D values stand for high stem-loop potential determined by base order and influence mainly the formation of stem-loop structures. Therefore, the particular location of these deletions suggests that the local sequence of bases might be important in the initiation of deletions mediated by DNA slip replication in concert with direct repeats.

Key Words

ccr5 deletion direct repeats stem-loop potential slip replication 

Abbreviations

CCR5

CC-chemokine receptor 5

RANTES

regulated on activation, normal T cell expressed and secreted

MIP

macrophage inflammatory protein

HIV-1

human immunodeficiency virus type 1

ORF

open reading frame

AIDS

acquired immunodeficiency syndrome

FORS-D

folding of randomized sequence difference

FONS

folding of natural sequence

FORS-M

folding of randomized sequence mean

This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahne, A., Muller-Derlich, J., Merlos-Lange, A. M., Kanbay, F., Wolf, K., and Lang, B. F. (1988). Two distinct mechanisms for deletion in mtDNA of Schizosaccharomyces pombe mutator strains: Slipped mispairing mediated by direct repeats and erroneous intron splicing. J. Mol. Biol. 202:725–734.CrossRefPubMedGoogle Scholar
  2. Ansari-Lari, M. A., Liu, X. M., Metzter, M. L., Rut, A. R., and Gibbs, R. A. (1997). The extent of genetic variation in the CCR5 gene. Nat. Genet. 16:221–222.CrossRefPubMedGoogle Scholar
  3. Baggiolini, M., Dewald, B., and Moser, B. (1997). Human chemokines: An update. Annu. Rev. Immunol. 15:675–705.CrossRefPubMedGoogle Scholar
  4. Carrington, M., Kissner, T., Gerrard, B., Ivanov, S., O'Brien, S. J., and Michael, D. (1997). Novel alleles of the chemokine-receptor gene CCR5. Am. J. Hum. Genet. 61:1261–1267.CrossRefPubMedGoogle Scholar
  5. Chen, Z. W., Kwon, D., Jin, Z. Q., Monard, S., Telfer, P., Jones, M. S., Lu, C. Y., Aguilar, R. F., Ho, D. D., and Marx, P. A. (1998). Natural infection of a homozygous delta24 CCR5 red-capped mangabey with an R2b-tropic simian immunodeficiency virus. J. Exp. Med. 188:2057–2065.CrossRefPubMedGoogle Scholar
  6. Dean, M., Carrington, M., Winkler, C., Huttley, G. A., Smith, M. W., Allikmets, R., Goedert, J. J., Buchbinder, S. P., Vittinghoff, E., Gomperts, E., Donfield, S., Vlahov, D., Kaslow, R., Saah, A., Rinaldo, C., Detels, R., and O'Brien, S. J. (1996). Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273:1856–1862.PubMedGoogle Scholar
  7. Forsdyke, D. R. (1995a). A stem-loop “kissing” model for the initiation of recombination and the origin of introns. Mol. Biol. Evol. 12:949–958.Google Scholar
  8. Forsdyke, D. R. (1995b). Conservation of stem-loop potential in introns of snake venom phospholipase A2 genes: An application of FORS-D analysis. Mol. Biol. Evol. 12:1157–1165.Google Scholar
  9. Forsdyke, D. R. (1996). Stem-loop potential in MHC genes: A new way of evaluating positive Darwinian selection? Immunogenetics 43:182–189.PubMedGoogle Scholar
  10. Forsdyke, D. R. (1998). An alternative way of thinking about stem-loops in DNA: A case study of the human GOS2 gene. J. Theor. Biol. 192:489–504.CrossRefPubMedGoogle Scholar
  11. Huang, Y., Paxton, W. A., Wolinsky, S. M., Neumann, A. V., Zhang, L., He, T., Kang, S., Ceradini, D., Jin, Z., Yazdanbakhsh, K., Kunstman, K., Erickson, D., Dragon, E., Landau, N. R., Phair, J., Ho, D. D., and Koup, R. A. (1996). The role of a mutant CCR5 allele in HIV-I transmission and disease progression. Nat. Med. 2:1240–1243.CrossRefPubMedGoogle Scholar
  12. Jeanmougin, F., Thompson, J. D., Gouy, M., Higgins, D. G., and Gibson, T. J. (1998). Multiple sequence alignment with Clustal X. Trends Biochem. Sci. 23:403–405.CrossRefPubMedGoogle Scholar
  13. Littman, D. R. (1998). Chemokine receptors: Keys to AIDS pathogenesis? Cell 93:677–680.CrossRefPubMedGoogle Scholar
  14. Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., MacDonald, M. E., Stuhlmann, H., Koup, R. A., and Landau, N. R. (1996). Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86:367–377.CrossRefPubMedGoogle Scholar
  15. Martinson, J. J., Chapman, N. H., Rees, D. C., Liu, Y. T., and Clegg, J. B. (1997). Global distribution of the CCR5 gene 32-basepair deletion. Nat. Genet. 16:100–103 (Letter).CrossRefPubMedGoogle Scholar
  16. Mathews, D. H., Sabina, J., Zuker, M., and Turner, D. H. (1999). Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. J. Mol. Biol. 288:911–940.CrossRefPubMedGoogle Scholar
  17. Schaaper, R. M., Danforth, B. N., and Glickman, B. W. (1986). Mechanisms of spontaneous mutagenesis: An analysis of the spectrum of spontaneous mutation in the Escherichia coli lacI gene. J. Mol. Biol. 189:273–284.CrossRefPubMedGoogle Scholar
  18. Schon, E. A., Rizzuto, R., Moraes, C. T., Nakase, H., Zeviani, M., and DiMauro, S. (1989). A direct repeat is a hotspot for large-scale deletion of human mtDNA. Science 244:346–349.PubMedGoogle Scholar
  19. Shoffner, J. M., Lott, M. T., Voljavec, A. S., Soueidan, S. A., Costigan, D. A., and Wallace, D. C. (1989). Spontaneous Kearns–Sayre/chronic external ophthalmoplegia plus syndrome associated with a mtDNA deletion: A slip-replication model and metabolic therapy. Proc. Natl. Acad. Sci. U.S.A. 86:7952–7956.PubMedGoogle Scholar
  20. Stephens, J. C., Reich, D. E., Goldstein, D. B., Shin, H. D., Smith, M. W., Carrington, M., Winkler, C., Huttley, G. A., Allikmets, R., Schriml, L., Gerrard, B., Malasky, M., Ramos, M. D., Morlot, S., Tzetis, M., Oddoux, C., di Giovine, F. S., Nasioulas, G., Chandler, D., Aseev, M., Hanson, M., Kalaydjieva, L., Glavac, D., Gasparini, P., Kanavakis, E., Claustres, M., Kambouris, M., Ostrer, H., Duff, G., Baranov, V., Sibul, H., Metspalu, A., Goldman, D., Martin, N., Duffy, D., Schmidtke, J., Estivill, X., O'Brien, S. J., and Dean, M. (1998). Dating the origin of the CCR5-Ll32 AIDS-resistance allele by the coalescence of haplotypes. Am. J. Hum. Genet. 62:1507–1515.CrossRefPubMedGoogle Scholar
  21. Zeviani, M., Servidei, S., Gellera, C., Bertini, E., DiMauro, S., and DiDonato, S. (1989). An autosomal dominant disorder with multiple deletions of mtDNA starting at the D-loop region. Nature 339:309–311.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Allergy and Inflammation Research InstituteMedical College of Shantou UniversityShantou, GuangdongP.R. China
  2. 2.Department of Biochemistry and Molecular Biology, School of Medical TechnologyJiangsu UniversityZhenjiang, JiangsuP.R. China

Personalised recommendations