Skip to main content
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Jul;17(7):3679–3686. doi: 10.1128/mcb.17.7.3679

Expression of var genes located within polymorphic subtelomeric domains of Plasmodium falciparum chromosomes.

K Fischer 1, P Horrocks 1, M Preuss 1, J Wiesner 1, S Wünsch 1, A A Camargo 1, M Lanzer 1
PMCID: PMC232219  PMID: 9199301

Abstract

Plasmodium falciparum var genes encode a diverse family of proteins, located on the surfaces of infected erythrocytes, which are implicated in the pathology of human malaria through antigenic variation and adhesion of infected erythrocytes to the microvasculature. We have constructed a complete representative telomere-to-telomere yeast artificial chromosome (YAC) contig map of the P. falciparum chromosome 8 for studies on the chromosomal organization, distribution, and expression of var genes. Three var gene loci were identified on chromosome 8, two of which map close to the telomeres at either end of the chromosome. Analysis of the previously described chromosome 2 contig map and random P. falciparum telomeric YAC clones revealed that most, if not all, 14 P. falciparum chromosomes contain var genes in a subtelomeric location. Mapping the chromosomal location of var genes expressed in a long-term culture of the P. falciparum isolate Dd2 revealed that four of the five different expressed var genes identified map within subtelomeric locations. Expression of var genes from a chromosomal domain known for frequent rearrangements has important implications for the mechanism of var gene switching and the generation of novel antigenic and adhesive phenotypes.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aley S. B., Sherwood J. A., Howard R. J. Knob-positive and knob-negative Plasmodium falciparum differ in expression of a strain-specific malarial antigen on the surface of infected erythrocytes. J Exp Med. 1984 Nov 1;160(5):1585–1590. doi: 10.1084/jem.160.5.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baruch D. I., Gormely J. A., Ma C., Howard R. J., Pasloske B. L. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3497–3502. doi: 10.1073/pnas.93.8.3497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baruch D. I., Pasloske B. L., Singh H. B., Bi X., Ma X. C., Feldman M., Taraschi T. F., Howard R. J. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell. 1995 Jul 14;82(1):77–87. doi: 10.1016/0092-8674(95)90054-3. [DOI] [PubMed] [Google Scholar]
  4. Biggs B. A., Anders R. F., Dillon H. E., Davern K. M., Martin M., Petersen C., Brown G. V. Adherence of infected erythrocytes to venular endothelium selects for antigenic variants of Plasmodium falciparum. J Immunol. 1992 Sep 15;149(6):2047–2054. [PubMed] [Google Scholar]
  5. Borst P., Rudenko G. Antigenic variation in African trypanosomes. Science. 1994 Jun 24;264(5167):1872–1873. doi: 10.1126/science.7516579. [DOI] [PubMed] [Google Scholar]
  6. Camargo A. A., Fischer K., Lanzer M. Construction and rapid screening of a representative yeast artificial chromosome library from the Plasmodium falciparum strain Dd2. Parasitol Res. 1997;83(1):87–89. doi: 10.1007/s004360050214. [DOI] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Corcoran L. M., Forsyth K. P., Bianco A. E., Brown G. V., Kemp D. J. Chromosome size polymorphisms in Plasmodium falciparum can involve deletions and are frequent in natural parasite populations. Cell. 1986 Jan 17;44(1):87–95. doi: 10.1016/0092-8674(86)90487-3. [DOI] [PubMed] [Google Scholar]
  9. Corcoran L. M., Thompson J. K., Walliker D., Kemp D. J. Homologous recombination within subtelomeric repeat sequences generates chromosome size polymorphisms in P. falciparum. Cell. 1988 Jun 3;53(5):807–813. doi: 10.1016/0092-8674(88)90097-9. [DOI] [PubMed] [Google Scholar]
  10. Gardner J. P., Pinches R. A., Roberts D. J., Newbold C. I. Variant antigens and endothelial receptor adhesion in Plasmodium falciparum. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3503–3508. doi: 10.1073/pnas.93.8.3503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gottschling D. E., Aparicio O. M., Billington B. L., Zakian V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell. 1990 Nov 16;63(4):751–762. doi: 10.1016/0092-8674(90)90141-z. [DOI] [PubMed] [Google Scholar]
  12. Hernandez-Rivas R., Mattei D., Sterkers Y., Peterson D. S., Wellems T. E., Scherf A. Expressed var genes are found in Plasmodium falciparum subtelomeric regions. Mol Cell Biol. 1997 Feb;17(2):604–611. doi: 10.1128/mcb.17.2.604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hinterberg K., Mattei D., Wellems T. E., Scherf A. Interchromosomal exchange of a large subtelomeric segment in a Plasmodium falciparum cross. EMBO J. 1994 Sep 1;13(17):4174–4180. doi: 10.1002/j.1460-2075.1994.tb06735.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Horrocks P., Jackson M., Cheesman S., White J. H., Kilbey B. J. Stage specific expression of proliferating cell nuclear antigen and DNA polymerase delta from Plasmodium falciparum. Mol Biochem Parasitol. 1996 Aug;79(2):177–182. doi: 10.1016/0166-6851(96)02657-6. [DOI] [PubMed] [Google Scholar]
  15. Lanzer M., Fischer K., Le Blancq S. M. Parasitism and chromosome dynamics in protozoan parasites: is there a connection? Mol Biochem Parasitol. 1995 Mar;70(1-2):1–8. doi: 10.1016/0166-6851(95)00021-r. [DOI] [PubMed] [Google Scholar]
  16. Lanzer M., de Bruin D., Ravetch J. V. Transcriptional differences in polymorphic and conserved domains of a complete cloned P. falciparum chromosome. Nature. 1993 Feb 18;361(6413):654–657. doi: 10.1038/361654a0. [DOI] [PubMed] [Google Scholar]
  17. Lanzer M., de Bruin D., Wertheimer S. P., Ravetch J. V. Organization of chromosomes in Plasmodium falciparum: a model for generating karyotypic diversity. Parasitol Today. 1994 Mar;10(3):114–117. doi: 10.1016/0169-4758(94)90012-4. [DOI] [PubMed] [Google Scholar]
  18. Leech J. H., Barnwell J. W., Miller L. H., Howard R. J. Identification of a strain-specific malarial antigen exposed on the surface of Plasmodium falciparum-infected erythrocytes. J Exp Med. 1984 Jun 1;159(6):1567–1575. doi: 10.1084/jem.159.6.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. MacPherson G. G., Warrell M. J., White N. J., Looareesuwan S., Warrell D. A. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985 Jun;119(3):385–401. [PMC free article] [PubMed] [Google Scholar]
  20. Magowan C., Wollish W., Anderson L., Leech J. Cytoadherence by Plasmodium falciparum-infected erythrocytes is correlated with the expression of a family of variable proteins on infected erythrocytes. J Exp Med. 1988 Oct 1;168(4):1307–1320. doi: 10.1084/jem.168.4.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marsh K., Otoo L., Hayes R. J., Carson D. C., Greenwood B. M. Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. Trans R Soc Trop Med Hyg. 1989 May-Jun;83(3):293–303. doi: 10.1016/0035-9203(89)90478-1. [DOI] [PubMed] [Google Scholar]
  22. Mendis K. N., Carter R. Clinical disease and pathogenesis in malaria. Parasitol Today. 1995 May;11(5):PTI1–PT16. doi: 10.1016/0169-4758(95)80143-x. [DOI] [PubMed] [Google Scholar]
  23. Miller L. H., Good M. F., Milon G. Malaria pathogenesis. Science. 1994 Jun 24;264(5167):1878–1883. doi: 10.1126/science.8009217. [DOI] [PubMed] [Google Scholar]
  24. Pace T., Ponzi M., Scotti R., Frontali C. Structure and superstructure of Plasmodium falciparum subtelomeric regions. Mol Biochem Parasitol. 1995 Feb;69(2):257–268. doi: 10.1016/0166-6851(94)00206-3. [DOI] [PubMed] [Google Scholar]
  25. Peterson D. S., Miller L. H., Wellems T. E. Isolation of multiple sequences from the Plasmodium falciparum genome that encode conserved domains homologous to those in erythrocyte-binding proteins. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7100–7104. doi: 10.1073/pnas.92.15.7100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pologe L. G., Ravetch J. V. Large deletions result from breakage and healing of P. falciparum chromosomes. Cell. 1988 Dec 2;55(5):869–874. doi: 10.1016/0092-8674(88)90142-0. [DOI] [PubMed] [Google Scholar]
  27. Pongponratn E., Riganti M., Punpoowong B., Aikawa M. Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. Am J Trop Med Hyg. 1991 Feb;44(2):168–175. doi: 10.4269/ajtmh.1991.44.168. [DOI] [PubMed] [Google Scholar]
  28. Roberts D. J., Craig A. G., Berendt A. R., Pinches R., Nash G., Marsh K., Newbold C. I. Rapid switching to multiple antigenic and adhesive phenotypes in malaria. Nature. 1992 Jun 25;357(6380):689–692. doi: 10.1038/357689a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rubio J. P., Thompson J. K., Cowman A. F. The var genes of Plasmodium falciparum are located in the subtelomeric region of most chromosomes. EMBO J. 1996 Aug 1;15(15):4069–4077. [PMC free article] [PubMed] [Google Scholar]
  30. Rubio J. P., Triglia T., Kemp D. J., de Bruin D., Ravetch J. V., Cowman A. F. A YAC contig map of Plasmodium falciparum chromosome 4: characterization of a DNA amplification between two recently separated isolates. Genomics. 1995 Mar 20;26(2):192–198. doi: 10.1016/0888-7543(95)80200-6. [DOI] [PubMed] [Google Scholar]
  31. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  32. Sim B. K., Orlandi P. A., Haynes J. D., Klotz F. W., Carter J. M., Camus D., Zegans M. E., Chulay J. D. Primary structure of the 175K Plasmodium falciparum erythrocyte binding antigen and identification of a peptide which elicits antibodies that inhibit malaria merozoite invasion. J Cell Biol. 1990 Nov;111(5 Pt 1):1877–1884. doi: 10.1083/jcb.111.5.1877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Smith J. D., Chitnis C. E., Craig A. G., Roberts D. J., Hudson-Taylor D. E., Peterson D. S., Pinches R., Newbold C. I., Miller L. H. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell. 1995 Jul 14;82(1):101–110. doi: 10.1016/0092-8674(95)90056-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Su X. Z., Heatwole V. M., Wertheimer S. P., Guinet F., Herrfeldt J. A., Peterson D. S., Ravetch J. A., Wellems T. E. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell. 1995 Jul 14;82(1):89–100. doi: 10.1016/0092-8674(95)90055-1. [DOI] [PubMed] [Google Scholar]
  35. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  36. Triglia T., Peterson M. G., Kemp D. J. A procedure for in vitro amplification of DNA segments that lie outside the boundaries of known sequences. Nucleic Acids Res. 1988 Aug 25;16(16):8186–8186. doi: 10.1093/nar/16.16.8186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Triglia T., Wellems T. E., Kemp D. J. Towards a high-resolution map of the Plasmodium falciparum genome. Parasitol Today. 1992 Jul;8(7):225–229. doi: 10.1016/0169-4758(92)90118-l. [DOI] [PubMed] [Google Scholar]
  38. Vernick K. D., Walliker D., McCutchan T. F. Genetic hypervariability of telomere-related sequences is associated with meiosis in Plasmodium falciparum. Nucleic Acids Res. 1988 Jul 25;16(14B):6973–6985. doi: 10.1093/nar/16.14.6973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. White N. J., Ho M. The pathophysiology of malaria. Adv Parasitol. 1992;31:83–173. doi: 10.1016/s0065-308x(08)60021-4. [DOI] [PubMed] [Google Scholar]
  40. de Bruin D., Lanzer M., Ravetch J. V. Characterization of yeast artificial chromosomes from Plasmodium falciparum: construction of a stable, representative library and cloning of telomeric DNA fragments. Genomics. 1992 Oct;14(2):332–339. doi: 10.1016/s0888-7543(05)80223-x. [DOI] [PubMed] [Google Scholar]
  41. de Bruin D., Lanzer M., Ravetch J. V. The polymorphic subtelomeric regions of Plasmodium falciparum chromosomes contain arrays of repetitive sequence elements. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):619–623. doi: 10.1073/pnas.91.2.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. van Dijk M. R., Janse C. J., Waters A. P. Expression of a Plasmodium gene introduced into subtelomeric regions of Plasmodium berghei chromosomes. Science. 1996 Feb 2;271(5249):662–665. doi: 10.1126/science.271.5249.662. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES