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Genome sequence of the human malaria parasite Plasmodium falciparum
Open accessAbstract
The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.
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“we calculated that 1 μg of P. falciparum DNA is equal to 4.067 × 107 genome copies or one genome copy in 24.6 fg of DNA.”
From Real-Time PCR for Detection and Identification of Plasmodium spp (2005) · cites this paper as [11]
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“The 18S rRNA gene was chosen as the target since it contains both highly conserved and variable regions, and at least five copies of the gene are dispersed on separate chromosomes of the Plasmodium genome (11, 20).”
From Real-Time PCR for Detection and Identification of Plasmodium spp (2005) · cites this paper as [11]
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“By targeting a gene with multiple copies dispersed throughout the Plasmodium genome (11), the sensitivity of this assay is greater than if a single-copy gene was chosen.”
From Real-Time PCR for Detection and Identification of Plasmodium spp (2005) · cites this paper as [11]
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Quantitative insertion-site sequencing (QIseq) for high throughput phenotyping of transposon mutantsPreprint
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“Plasmodia are complex eukaryotic parasites with large genomes (5,300 genes) and transform through multiple life cycle stages with stage-specific gene (antigen) expression (2).”
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Malaria Genomics in the Era of Eradication.
Neafsey, D., & Volkman, S. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025544 · Cited by 40
“Consequently, thousands of parasite and vector genomes have been sequenced since the original Plasmodium falciparum reference genome assembly in 2002 (Gardner et al. 2002).”
BackgroundNagasundaram, N., Doss, C., Chakraborty, C., Karthick, V., Kumar, D. T., Balaji, V., Siva, R., Lu, A.-P., Ge, Z., & Zhu, H. (2016) · Scientific Reports · doi:10.1038/srep30106 · Cited by 40
A redesigned CRISPR/Cas9 system for marker-free genome editing in Plasmodium falciparum
Lu, J., Tong, Y., Pan, J., Yang, Y.-J., Liu, Q., Tan, X., Zhao, S., Qin, L.-M., & Chen, X.-P. (2016) · Parasites & Vectors · doi:10.1186/s13071-016-1487-4 · Cited by 40
“It has been reported that none of the proteins required for the canonical non-homologous end joining (C-NHEJ) pathway have been identified in Pf [7 – 9].”
Cheeseman, I. H., McDew‐White, M., Phyo, A. P., Sriprawat, K., Nosten, F. H., & Anderson, T. J. C. (2014) · Molecular Biology and Evolution · doi:10.1093/molbev/msu397 · Cited by 37
“We followed the manufacturer’s instructions for genotyping except for the annealing stage which we extended from 2 to 16 h, to account for the high AT content of the P. falciparum genome (Gardner et al. 2002).”
MethodNovel approaches to identify protective malaria vaccine candidates
Chia, W. N., Goh, Y. S., & Rénia, L. (2014) · Frontiers in Microbiology · doi:10.3389/fmicb.2014.00586 · Cited by 33
“These genome sequencing initiatives, by The Wellcome Trust Sanger Institute and The Institute for Genomic Research, have provided a wealth of data for the identification of protective antigens (Carlton et al., 2002; Gardner et al., 2002).”
BackgroundMethodReid, A. J. (2014) · Parasitology · doi:10.1017/s0031182014001528 · Cited by 39
Malaria Adhesins: Structure and Function
Malpede, B., & Tolia, N. (2014) · Cellular Microbiology · doi:10.1111/cmi.12276 · Cited by 40
“falciparum contains approximately 60 unique variants in each haploid parasite genome, of which one variant is predominantly expressed at a given time (Chen et al., 1998; Scherf et al., 1998; Gardner et al., 2002).”
BackgroundCornillot, E., Dassouli, A., Garg, A., Pachikara, N. D., Randazzo, S., Depoix, D., Carcy, B., Delbecq, S., Frutos, R., Silva, J. C., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072657 · Cited by 40
Heneberg, P. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712799828274 · Cited by 40
Deshmukh, A. S., Srivastava, S., Herrmann, S., Gupta, A., Mitra, P., Gilberger, T., & Dhar, S. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks202 · Cited by 40
“The orientation of transcription of subtelomeric upsA, upsD and upsE var genes is opposite to upsB var genes (24,25).”
Total synthesis, stereochemical assignment, and antimalarial activity of gallinamide A.
Conroy, T., Guo, J. T., Linington, R., Hunt, N., & Payne, R. (2011) · Chemistry · doi:10.1002/chem.201102538 · Cited by 40
Plasmodium falciparum serine repeat antigen 5 (SE36) as a malaria vaccine candidate.
Palacpac, N., Arisue, N., Tougan, T., Ishii, K., & Horii, T. (2011) · Vaccine · doi:10.1016/j.vaccine.2011.06.052 · Cited by 40
Substitution scoring matrices for proteins ‐ An overview
Trivedi, R., & Nagarajaram, H. A. (2020) · Protein Science · doi:10.1002/pro.3954 · Cited by 52
“57,58 Only proteins having either annotated non-Plasmodia orthologs or have been classified as hypothetical with no known orthologs in non-Plasmodia species were considered to study residue compositional bias in Plasmodium species.”
BackgroundObeng-Adjei, N., Larremore, D. B., Turner, L., Ongoïba, A., Li, S., Doumbo, S., Yazew, T., Kayentao, K., Miller, L. H., Traoré, B., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.137262 · Cited by 42
Lee, V. V., Judd, L. M., Jex, A. R., Holt, K. E., Tonkin, C. J., & Ralph, S. A. (2021) · mSystems · doi:10.1128/msystems.01081-20 · Cited by 47
Self-citationKojom, L., & Singh, V. (2020) · Malaria Journal · doi:10.1186/s12936-019-3090-6 · Cited by 39
Barcons-Simon, A., Cordon-Obras, C., Guizetti, J., Bryant, J. M., & Scherf, A. (2020) · mBio · doi:10.1128/mbio.03054-19 · Cited by 39
The Biochemistry and Evolution of the Dinoflagellate Nucleus
Gornik, S. G., Hu, I., Lassadi, I., & Waller, R. F. (2019) · Microorganisms · doi:10.3390/microorganisms7080245 · Cited by 49
“The closely related apicomplexan parasites Plasmodium falciparum and Babesi bovis, on the other hand, contain only 14 chromosomes [36] and four”
BackgroundClaessens, A., Harris, L. M., Stanojčić, S., Chappell, L., Stanton, A., Kuk, N., Veneziano-Broccia, P., Sterkers, Y., Rayner, J., & Merrick, C. J. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007490 · Cited by 39
Carey, M. A., Papin, J. A., & Güler, J. L. (2017) · BMC Genomics · doi:10.1186/s12864-017-3905-1 · Cited by 36
“genes) [43, 75, 76]; iPfal17 accounts for the function of 987 metabolites, 730 enzymatic reactions, 1195 total reactions, and 488 genes (Table 1).”
BackgroundResisting resistance: is there a solution for malaria?
Verlinden, B. K., Louw, A. I., & Birkholtz, L. (2016) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2016.1154037 · Cited by 40
“[94] The genome of the malaria parasite is ~80% AT bp [95] and is substantially different from the human genome, which may provide opportunities to use sequence-specific inhibitors to target the parasite’s genome.”
BackgroundOwusu-Ofori, S., Kusi, J., Owusu-Ofori, A., Freimanis, G., Olver, C., Martinez, C. R., Wilkinson, S., Mundt, J. M., Keil, S., Goodrich, R., et al. (2015) · Shock · doi:10.1097/shk.0000000000000280 · Cited by 39
“The qPCR results only give an indication of the DNA damage to a small 2,316-bp target region out of the total 23 Mb gEq (23), whereas the culture result measures the infectivity of the organism.”
Towards genome-wide experimental genetics in the in vivo malaria model parasite Plasmodium berghei
Matz, J. M., & Kooij, T. (2015) · Pathogens and Global Health · doi:10.1179/2047773215y.0000000006 · Cited by 39
Functional Analysis of Sirtuin Genes in Multiple Plasmodium falciparum Strains
Merrick, C. J., Jiang, R. H. Y., Skillman, K. M., Samarakoon, U., Moore, R. M., Dzikowski, R., Ferdig, M. T., & Duraisingh, M. T. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118865 · Cited by 38
“There are 63 var genes in the sequenced 3D7 strain, with the majority located sub-telomerically and a subset arranged in tandem arrays at chromosome-internal locations [6].”
BackgroundGupta, A., Shah, P., Haider, A., Gupta, K., Siddiqi, M., Ralph, S. A., & Habib, S. (2014) · Open Biology · doi:10.1098/rsob.140045 · Cited by 39
“Initial analysis of sequenced Plasmodium nuclear DNA fragments and expressed sequence tags (ESTs), then later assembly of the entire Plasmodium falciparum nuclear genome, revealed many more ribosomal proteins with apicoplast and mitochondrial targeting sequences [2,23] that are post-translationally processed for targe…”
BackgroundSelf-citationSynthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials
Cui, H.-Q., Carrero-Lérida, J., Silva, A. P. G., Whittingham, J., Brannigan, J., Ruiz-Pérez, L., Read, K., Wilson, K., González-Pacanowska, D., & Gilbert, I. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301328h · Cited by 39
Kafsack, B. F. C., Painter, H. J., & Llinás, M. (2012) · Malaria Journal · doi:10.1186/1475-2875-11-187 · Cited by 39
“falciparum strain 3D7 reference genome [3], oligonucleotide-based arrays quickly followed and provided an unprecedented in-depth view of transcriptional changes during asexual development in red blood cells [9,10].”
Characterization of Plasmodium liver stage inhibition by halofuginone
Derbyshire, E., Mazitschek, R., & Clardy, J. (2012) · ChemMedChem · doi:10.1002/cmdc.201200045 · Cited by 39
Tan, X., Traoré, B., Kayentao, K., Ongoïba, A., Doumbo, S., Waisberg, M., Doumbo, O. K., Felgner, P. L., Fairhurst, R. M., & Crompton, P. D. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir638 · Cited by 42
PLP-dependent enzymes as potential drug targets for protozoan diseases.
Kappes, B., Tews, I., Binter, A., & Macheroux, P. (2011) · Biochimica et Biophysica Acta · doi:10.1016/j.bbapap.2011.07.018 · Cited by 39
6-oxopurine phosphoribosyltransferase: a target for the development of antimalarial drugs.
de Jersey, J., Holý, A., Hocková, D., Naesens, L., Keough, D., & Guddat, L. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611796575911 · Cited by 39
“Today, with the sequencing of the Pv [18] and Pf genomes [19] and through the use of advanced scientific approaches such as the screening of large chemical libraries [20], we are now in an unprecedented position to design and develop drugs to specifically target and treat malaria.”
Djokić, V., Rocha, S. C., & Parveen, N. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.685239 · Cited by 39
“Out of 60 species, P. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi, P. cynomolgi, and P. simium infect humans to cause malaria (Milner, 2018; Garrido-Cardenas et al., 2019), while four others, P. chabaudi, P. berghei, P. vinckei, and P. yoelii, infect rodents (De Niz and Heussler, 2018).”
Genomic Advances in Avian Malaria Research
Videvall, E. (2019) · Trends in Parasitology · doi:10.1016/j.pt.2018.12.005 · Cited by 46
Diversity and Evolution of Sensor Histidine Kinases in Eukaryotes
Kabbara, S., Hérivaux, A., de Bernonville, T. D., Courdavault, V., Clastre, M., Gastebois, A., Osman, M., Hamzé, M., Cock, J. M., Schaap, P., et al. (2018) · Genome Biology and Evolution · doi:10.1093/gbe/evy213 · Cited by 43
Vaccines to Accelerate Malaria Elimination and Eventual EradicationPreprint
Healer, J., Cowman, A. F., Kaslow, D. C., & Birkett, A. J. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025627 · Cited by 37
“Publication of the P. falciparum (Gardner et al. 2002) and P. vivax (Carlton et al. 2008) genomes revealed many novel potential candidate antigens.”
BackgroundStanton, A., Harris, L. M., Graham, G., & Merrick, C. J. (2016) · BMC Genomics · doi:10.1186/s12864-016-3183-3 · Cited by 43
“The P. knowlesi genome is also quite abundant in non-ITS PQSs, since its genome bias is very different from P. falciparum at 62.5 % A/T [39] pir gene 3 0 0 Upstream (within 2 kb) 0 1 2 8 Downstream (within 2 kb) 0 1 6 Total pir sequences 226 a 528 a 299 Pir genes 189 a 351 a 217 Fragments/ pseudogenes 0/37 a 118/59 a…”
BackgroundInfluential
Metadata
- Authors
- Gardner, M. J., Hall, N., Fung, E., White, O., Berriman, M., Hyman, R. W., Carlton, J. M., Pain, A., Nelson, K. E., Bowman, S., Paulsen, I. T., James, K., Eisen, J. A., Rutherford, K., Salzberg, S. L., Craig, A., Kyes, S., Chan, M.-S., Nene, V., Shallom, S. J., Suh, B., Peterson, J., Angiuoli, S., Pertea, M., Allen, J., Selengut, J., Haft, D., Mather, M. W., Vaidya, A. B., Martin, D. M. A., Fairlamb, A. H., Fraunholz, M. J., Roos, D. S., Ralph, S. A., McFadden, G. I., Cummings, L. M., Subramanian, G. M., Mungall, C., Venter, J. C., Carucci, D. J., Hoffman, S. L., Newbold, C., Davis, R. W., Fraser, C. M., & Barrell, B.
- Affiliations
- J. Craig Venter Institute (US)
- Corresponding author
- Gardner, Malcolm J.
- ORCID
- Gardner, Malcolm J.
- Hall, Neil
- Fung, Eula
- White, Owen
- Berriman, Matthew
- Hyman, Richard W.
- Carlton, Jane M.
- Pain, Arnab
- Paulsen, Ian T.
- Eisen, Jonathan A.
- Rutherford, Kim
- Salzberg, Steven L.
- Craig, Alister
- Nene, Vishvanath
- Pertea, Mihaela
- Allen, Jonathan
- Haft, Daniel
- Mather, Michael W.
- Vaidya, Akhil B.
- Martin, David M. A.
- Fairlamb, Alan H.
- Fraunholz, Martin J.
- Roos, David S.
- Ralph, Stuart A.
- McFadden, Geoffrey I.
- Mungall, Chris
- Venter, J. Craig
- Hoffman, Stephen L.
- Newbold, Chris
- Davis, Ronald W.
- Fraser, Claire M.
- Venue
- Nature
- Published
- 2002-10
- Volume
- 419
- Issue
- 6906
- Pages
- 498-511
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3836256
- OpenAlex
- W2019851585
- Cited by
- 4,407
- References
- 170
- Citations by year
- 2026: 68 · 2025: 107 · 2024: 112 · 2023: 107 · 2022: 154 · 2021: 151 · 2020: 148 · 2019: 140 · 2018: 150 · 2017: 160 · 2016: 183 · 2015: 166 · 2014: 213 · 2013: 191 · 2012: 211
- FWCI
- 272.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Burroughs Wellcome Fund
- Global Fund to Fight AIDS, Tuberculosis and Malaria
- Wellcome Trust (061524)
- Stanford Bio-X
- National Institute of Allergy and Infectious Diseases (R01AI028398)
- Medical Research and Materiel Command
- Naval Medical Research Center
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Immunology and Microbiology › Parasitology › Bird parasitology and diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- Plasmodium falciparum, Plasmodium, genome sequence, nuclear genome, antigenic variation, subtelomeric regions, immune evasion, host-parasite interactions, apicoplast, isoprenoid metabolism, gene content, drug and vaccine targets
- MeSH terms
- Animals, DNA Repair, DNA Replication, Humans, Molecular Sequence Data, Plasmodium falciparum, Recombination, Genetic, Protozoan Proteins, DNA, Protozoan, Malaria, Falciparum, Sequence Analysis, DNA, Malaria Vaccines, Plastids, Genome, Protozoan, Evolution, Molecular, Proteome, Chromosome Structures, Membrane Transport Proteins
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