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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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“The homologous genes for enzymatic components involved in cyclic nucleotide-based signaling like adenylyl cyclase (AC), guanylyl cyclase (GC), cGMP-dependent protein kinase [protein kinase G (PKG)], and a regulatory and catalytic subunit of cAMP-dependent protein kinase, and nucleotide phosphodiesterase (PDE) have bee…”
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“Much of our understanding of how apicoplasts work came through predicting their proteome on the basis of understanding how nucleus-encoded proteins are targeted into the organelle across its four bounding membranes [6, 9, 10].”
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Moreira, C. K., Naissant, B., Coppi, A., Bennett, B. L., Aime, E., Franke-Fayard, B., Janse, C., Coppens, I., Sinnis, P., & Templeton, T. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152510 · Cited by 20
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A brief review on biomarkers and proteomic approach for malaria research.
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“PfEMP1 is encoded by ∼60 var genes per haploid genome that undergo clonal antigenic variation (3).”
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“falciparum, as over 60% of the predicted open reading frames (ORFs) were annotated as “hypothetical” without functional assignment [5].”
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“PlmV, PlmIX and PlmX are expressed concurrently with PlmI to PlmIV but are not transported to the DV. Recently, it has been reported that PlmV licenses Pf proteins for export into the host erythrocyte, therefore, it is essential for parasite viability [41].”
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Dacon, C., Moskovitz, R., Swearingen, K. E., Pereira, L. D. S., Flores-Garcia, Y., Aleshnick, M. A., Kanatani, S., Flynn, B., Molina-Cruz, A., Wollenberg, K., et al. (2025) · Science · doi:10.1126/science.adr0510 · Cited by 18
The protist Aurantiochytrium has universal subtelomeric rDNAs and is a host for mirusviruses
Collier, J. L., Rest, J. S., Gallot-Lavallée, L., Lavington, E., Kuo, A., Jenkins, J. W., Plott, C., Pangilinan, J. L., Daum, C. G., Grigoriev, I. V., et al. (2023) · Current Biology · doi:10.1016/j.cub.2023.10.009 · Cited by 20
“24 The 5S and 18S-28S coding regions in the nanopore assembly of A. limacinum are more closely spaced than is usual for organisms where this linkage occurs but not as tightly linked as in the brown alga (stramenopile) Scytosiphon lomentaria and some other protists, where the 5S is just downstream…”
Niaré, K., Greenhouse, B., & Bailey, J. (2023) · Malaria Journal · doi:10.1186/s12936-023-04632-0 · Cited by 18
“Second, sequence data from natural malaria infections present an additional challenge, often containing an unknown number of clones (complexity of infection, COI) at unknown relative abundances [5, 11, 12].”
BackgroundAkinnusi, P. A., Olubode, S. O., Adebesin, A. O., Osadipe, T. J., Nwankwo, D. O., Adebisi, A. D., Bisi-Adeniyi, T. I., Alo, Y. M., Owoloye, A. J., & Oyebola, K. M. (2023) · Informatics in Medicine Unlocked · doi:10.1016/j.imu.2023.101206 · Cited by 18
Histone Modification Landscapes as a Roadmap for Malaria Parasite Development
Connacher, J., von Grüning, H., & Birkholtz, L. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.848797 · Cited by 18
Shared Mechanisms for Mutually Exclusive Expression and Antigenic Variation by Protozoan Parasites
Florini, F., Visone, J. E., & Deitsch, K. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.852239 · Cited by 24
“falciparum genome, which has <20% GC-content (Gardner et al., 2002; Upadhyay et al., 2005).”
BackgroundPeculiarities of Plasmodium falciparum Gene Regulation and Chromatin Structure
Watzlowik, M. T., Das, S., Meissner, M., & Längst, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105168 · Cited by 18
“With regard to genome size, Pf displays unusually large intergenic regions (mean of 1700 bp) and introns with an average length of 180 bp, which is rather long for protists but very short in comparison to higher eukaryotes [6].”
BackgroundInfluentialG-quadruplex RNA motifs influence gene expression in the malaria parasite Plasmodium falciparum
Dumetz, F., Chow, E. Y., Harris, L. M., Liew, S. W., Jensen, A., Umar, M. I., Chung, B., Chan, T., Merrick, C. J., & Kwok, C. K. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1095 · Cited by 17
“falciparum, which has an unusual genome with an extreme A/T-bias of ∼81% A/T (2).”
BackgroundElahi, R., Ray, W., Dapper, C. H., Dalal, S., Helm, R. F., & Klemba, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-54009-0 · Cited by 18
Ibrahim, M. A. A., Abdelrahman, A. H. M., & Hassan, A. M. A. (2019) · Comput. Biol. Chem. · doi:10.1016/j.compbiolchem.2019.03.010 · Cited by 18
Grabias, B. M., Essuman, E. E., Quakyi, I. A., & Kumar, S. (2019) · Malaria Journal · doi:10.1186/s12936-019-2743-9 · Cited by 20
Epopa, P. S., Maiga, H., Hien, D. F. D. S., Dabiré, R., Lees, R., Giles, J., Tripet, F., Baldet, T., Damiens, D., & Diabaté, A. (2018) · Malaria Journal · doi:10.1186/s12936-018-2530-z · Cited by 18
Kaur, H., Sehgal, R., Goyal, K., Makkar, N., Yadav, R., Bharti, P. K., Singh, N., Sarmah, N., Mohapatra, P. K., Mahanta, J., et al. (2017) · Tropical medicine & international health · doi:10.1111/tmi.12990 · Cited by 18
Nikolaeva, D., Illingworth, J. J., Miura, K., Alanine, D. G. W., Brian, I. J., Li, Y., Fyfe, A. J., Da, D. F., Cohuet, A., Long, C. A., et al. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra117.000036 · Cited by 17
“falciparum genome in 2002 identified all possible targets across the sexual-stages (16), and has been followed by numerous global studies of protein expression (17–19).”
BackgroundMeissner, K. A., Lunev, S., Wang, Y., Linzke, M., Batista, F. D. A., Wrenger, C., & Groves, M. R. (2016) · Current Drug Targets · doi:10.2174/1389450117666160201115003 · Cited by 13
“falciparum, which facilitates functional genomic studies has been available since 2002 [19], although Wu and colleges already succeeded in transfecting the parasite in 1995 [20].”
InfluentialFrequent GU wobble pairings reduce translation efficiency in Plasmodium falciparum
Chan, S. C.-L., Ch’ng, J.-H., Wahlgren, M., & Thutkawkorapin, J. (2017) · Scientific Reports · doi:10.1038/s41598-017-00801-9 · Cited by 23
Dara, A., Drábek, E. F., Travassos, M. A., Moser, K. A., Delcher, A. L., Su, Q., Hostelley, T. L., Coulibaly, D. M., Daou, M., Dembélé, A., et al. (2017) · Genome Medicine · doi:10.1186/s13073-017-0422-4 · Cited by 19
“Each complete var gene consists of two exons, the first of which, at 2500– 10,500 bp, is longer and much more variable in length than the second (1000–1500 bp) [34].”
Self-citationInferring Strain Mixture within Clinical Plasmodium falciparum Isolates from Genomic Sequence Data
O’Brien, J., Iqbal, Z., Wendler, J., & Amenga-Etego, L. N.-K. (2016) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004824 · Cited by 31
“Each SNP xcall provides the number of reference and non-reference read counts observed at each variant position within the genome, ascertained against the the 3D7 reference [36].”
Liang, M., Raley, C., Zheng, X. M., Kutty, G., Gogineni, E., Sherman, B. T., Sun, Q., Chen, X., Skelly, T., Jones, K. M., et al. (2016) · BioData Mining · doi:10.1186/s13040-016-0090-8 · Cited by 19
“…members) in Trypanosoma brucei [6], the variant surface protein ( vsp ) gene family (~235 – 275 members) in Giardia lamblia [7], the var gene family (~60 members) in Plasmodium falciparum [8], and the major surface glycoprotein ( msg ) gene family (estimated ~80 members) in Pneumocystis [9 – 11].”
BackgroundAlves, E., Maluf, F. V., Bueno, V. B., Guido, R. V. C., Oliva, G., Singh, M. K., Scarpelli, P. H., Costa, F., Sartorello, R., Catalani, L. H., et al. (2016) · Scientific Reports · doi:10.1038/srep22093 · Cited by 17
Targeting kinases in Plasmodium and Schistosoma: Same goals, different challenges.
Doerig, C., & Grevelding, C. (2015) · Biochimica et Biophysica Acta · doi:10.1016/j.bbapap.2015.03.002 · Cited by 18
Carlton, J., Volkman, S., Uplekar, S., Hupalo, D. N., Alves, J. M., Cui, L.-W., Donnelly, M., Roos, D., Harb, O., Acosta, M. M., et al. (2015) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.15-0049 · Cited by 18
Self-citationHan, J.-H., Li, J., Wang, B., Lee, S.-K., Nyunt, M. H., Na, S.-H., Park, J.-H., & Han, E. (2015) · Korean Journal of Parasitology · doi:10.3347/kjp.2015.53.4.403 · Cited by 18
“Although the exact function of the PF3D7_0305200 has not yet been defined, it has the expected high antigenicity [13,41-43].”
BackgroundUnique features of apicoplast DNA gyrases from Toxoplasma gondii and Plasmodium falciparum
Nagano, S., Lin, T., Edula, J. R., & Heddle, J. G. (2014) · BMC Bioinformatics · doi:10.1186/s12859-014-0416-9 · Cited by 20
“falciparum genome [28] and is localized to the apicoplast.”
BackgroundThe impact of genomics on population genetics of parasitic diseases
Hupalo, D. N., Bradic, M., & Carlton, J. (2014) · Current Opinion in Microbiology · doi:10.1016/j.mib.2014.11.001 · Cited by 18
“They vary in properties such as nucleotide bias, for example the extremely AT-rich Plasmodium falciparum genome [6], or”
BackgroundSelf-citationBiomedical research, a tool to address the health issues that affect African populations
Peprah, E., & Wonkam, A. (2013) · Globalization and Health · doi:10.1186/1744-8603-9-50 · Cited by 18
“Fieldwork ha s allowed sample collection resulting in the genomes of Plasmodium falciparum [23], Trypansoma brucei [24], Leishmania major [25], and Schistosoma mansoni [26] being sequenced with additional molecular, biochemical and bioinformatics analyses [27].”
BackgroundWagner, J., Goldfless, S. J., Ganesan, S. M., Lee, M. C. S., Fidock, D., & Niles, J. C. (2013) · Malaria Journal · doi:10.1186/1475-2875-12-373 · Cited by 18
“First, the parasite’s genome is extremely (A + T)-rich (80-90%) [3], and extended regions of low complexity sequence are common [4,5].”
BackgroundIn silico docking studies of bioactive natural plant products as putative DHFR antagonists
Kumar, M., Dagar, A., Gupta, V. K., & Sharma, A. (2013) · Medicinal Chemistry Research · doi:10.1007/s00044-013-0654-9 · Cited by 24
Malaria Diagnostics and Surveillance in the Post-Genomic Era
Lucchi, N., Oberstaller, J., Kissinger, J., & Udhayakumar, V. (2013) · Public Health Genomics · doi:10.1159/000345607 · Cited by 18
“The genome sequence for the most lethal human malaria parasite Plasmodium falciparum ( ∼ 23 Mb) was first published in 2002 [2] based on the laboratory-adapted parasite isolate 3D7.”
Insights into the genome structure and copy-number variation of Eimeria tenella
Lim, L., Tay, Y.-L., Alias, H., Wan, K., & Dear, P. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-389 · Cited by 18
“The genomes of several apicomplexans have been extensively studied [1-5] in an”
BackgroundMugasa, J. P., Qi, W., Rusch, S., Rottmann, M., & Beck, H. (2012) · Malaria Journal · doi:10.1186/1475-2875-11-230 · Cited by 17
“falciparum derived proteins on the surface of infected erythrocytes that play a key role as both virulence factors and as targets of naturally acquired immunity [4,5].”
BackgroundSmith, M., Campino, S., Gu, Y., Clark, T., Otto, T., Maslen, G., Manske, M., Imwong, M., Dondorp, A., Kwiatkowski, D., et al. (2012) · The Open Genomics Journal · doi:10.2174/1875693x01205010018 · Cited by 18
“This neutrality makes the amplification and sequencing easier than for many pathogens that have extreme GC contents, for example the Plasmodium genome contains less than 20% GC bases [1].”
BackgroundA cross sectional investigation of malaria epidemiology among seven tea estates in Assam, India
Rabha, B., Goswami, D., Dhiman, S., Das, N., Talukdar, P. K., Nath, M., Baruah, I., Bhola, R., & Singh, L. K. (2012) · Journal of Parasitic Diseases · doi:10.1007/s12639-011-0070-3 · Cited by 18
Mesplet, M., Palmer, G., Pedroni, M., Echaide, I., Florin-Christensen, M., Schnittger, L., & Lau, A. O. T. (2011) · Molecular and biochemical parasitology (Print) · doi:10.1016/j.molbiopara.2011.06.005 · Cited by 18
ULTRA-effective labeling of tandem repeats in genomic sequence
Olson, D. R., & Wheeler, T. J. (2024) · Bioinformatics Advances · doi:10.1093/bioadv/vbae149 · Cited by 14
Kormos, A., Dimopoulos, G., Bier, E., Lanzaro, G. C., Marshall, J. M., & James, A. A. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1261123 · Cited by 17
Plasmodium falciparum Development from Gametocyte to Oocyst: Insight from Functional Studies
Ouologuem, D., Dara, A., Koné, A., Ouattara, A., & DJIMDÉ, A. A. (2023) · Microorganisms · doi:10.3390/microorganisms11081966 · Cited by 24
Lessons from the deep: mechanisms behind diversification of eukaryotic protein complexes
Prokopchuk, G., Butenko, A., Dacks, J. B., Speijer, D., Field, M. C., & Lukeš, J. (2023) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12988 · Cited by 21
“In yeast, some plants, and myzozoans, there is a complete loss of complex I combined with alternative electron entry points (De Vries & Marres, 1987; Gardner et al ., 2002; Petersen et al ., 2015).”
BackgroundDirect tests of cytochrome c and c 1 functions in the electron transport chain of malaria parasites
Espino-Sanchez, T. J., Wienkers, H., Marvin, R. G., Nalder, S.-A., García-Guerrero, A. E., VanNatta, P. E., Jami‐Alahmadi, Y., Blackwell, A. M., Whitby, F. G., Wohlschlegel, J. A., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2301047120 · Cited by 20
“The P. falciparum genome is highly reduced, and all genes are expected to enhance parasite fitness at some point in the Plasmodium life cycle and/or under specific growth conditions or stresses (63, 72, 73).”
Background
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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