Harnessing genomics and genome biology to understand malaria biology

Nature Reviews Genetics

Volumn 13, Issue 5, 2012, Pages 315-328

  Volkman, Sarah K ^a,b,c   Neafsey, Daniel E ^b   Schaffner, Stephen F ^b   Park, Daniel J ^b,d   Wirth, Dyann F ^a,b  

^a HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^b BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^c SIMMONS COLLEGE   (United States)

^d HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APICAL MEMBRANE ANTIGEN 1; MEROZOITE SURFACE PROTEIN 1;

AFRICA; ANOPHELES; ANTIBIOTIC RESISTANCE; BALANCING SELECTION; BIOINFORMATICS; CAMEROON; CONGO; COPY NUMBER VARIATION; DIRECTIONAL SELECTION; DISEASE TRANSMISSION; DNA BARCODING; GENE LOCUS; GENE SEQUENCE; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOMICS; HOST SELECTION; INDEL MUTATION; LINKAGE ANALYSIS; MICROSATELLITE INSTABILITY; NONHUMAN; PHENOTYPE; PLASMODIUM FALCIPARUM; POPULATION SIZE; POPULATION STRUCTURE; PRIORITY JOURNAL; PROTOZOAL GENETICS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SOUTH AND CENTRAL AMERICA; SOUTHEAST ASIA; UGANDA; ZIMBABWE;

ANIMALS; ANOPHELES; ANTIMALARIALS; DRUG RESISTANCE; FEMALE; GENETIC LINKAGE; GENETIC LOCI; GENOME, PROTOZOAN; GENOMICS; HUMANS; MALARIA; MALE; PLASMODIUM FALCIPARUM; SELECTION, GENETIC;

PLASMODIUM FALCIPARUM;

EID: 84859905492     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg3187     Document Type: Review

References (129)

1. WHO. in World Malaria Report 2011 (World Health Organization, Switzerland, 2011).
2. Trape, J. F. et al. Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study. Lancet Infect. Dis. 11, 925-932 (2011).
3. Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498-511 (2002).
4. Carlton, J. M. et al. Comparative genomics of the neglected human malaria parasite Plasmodium vivax. Nature 455, 757-763 (2008).
5. Carlton, J. M. et al. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii. Nature 419, 512-519 (2002).
6. Hall, N. et al. A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses. Science 307, 82-86 (2005).
7. Dharia, N. V. et al. Whole-genome sequencing and microarray analysis of ex vivo Plasmodium vivax reveal selective pressure on putative drug resistance genes. Proc. Natl Acad. Sci. USA 107, 20045-20050 (2010).
8. Anderson, T., Nkhoma, S., Ecker, A. & Fidock, D. How can we identify parasite genes that underlie antimalarial drug resistance? Pharmacogenomics 12, 59-85 (2011). This is a comprehensive review article that outlines genome-scale approaches for identifying genetic variants that contribute to drug resistance.
9. Escalante, A. A., Cornejo, O. E., Rojas, A., Udhayakumar, V. & Lal, A. A. Assessing the effect of natural selection in malaria parasites. Trends Parasitol. 20, 388-395 (2004).
10. Weedall, G. D. & Conway, D. J. Detecting signatures of balancing selection to identify targets of antiparasite immunity. Trends Parasitol. 26, 363-369 (2010). This review describes population genetic approaches for identifying signatures of balancing selection and the use of new genomic information to discover new potential vaccine candidates.
11. Ghedin, E. et al. Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution. Nature 437, 1162-1166 (2005).
12. Jeffares, D. C. et al. Genome variation and evolution of the malaria parasite Plasmodium falciparum. Nature Genet. 39, 120-125 (2007).
13. Mu, J. et al. Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome. Nature Genet. 39, 126-130 (2007).
14. Volkman, S. K. et al. A genome-wide map of diversity in Plasmodium falciparum. Nature Genet. 39, 113-119 (2007).
15. Cheeseman, I. H. et al. Gene copy number variation throughout the Plasmodium falciparum genome. BMC Genomics 10, 353 (2009).
16. Dharia, N. V. et al. Use of high-density tiling microarrays to identify mutations globally and elucidate mechanisms of drug resistance in Plasmodium falciparum. Genome Biol. 10, R21 (2009).
17. Jiang, H. et al. Detection of genome-wide polymorphisms in the AT-rich Plasmodium falciparum genome using a high-density microarray. BMC Genomics 9, 398 (2008).
18. Kidgell, C. et al. A systematic map of genetic variation in Plasmodium falciparum. PLoS Pathog. 2, e57 (2006).
19. Neafsey, D. E. et al. Genome-wide SNP genotyping highlights the role of natural selection in Plasmodium falciparum population divergence. Genome Res. 9, R171 (2008).
20. Tan, J. C. et al. Optimizing comparative genomic hybridization probes for genotyping and SNP detection in Plasmodium falciparum. Genomics 93, 543-550 (2009).
21. Westenberger, S. J. et al. A systems-based analysis of Plasmodium vivax lifecycle transcription from human to mosquito. PLoS Negl. Trop. Dis. 4, e653 (2010).
22. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860-921 (2001).
23. Liu, W. et al. Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature 467, 420-425 (2010).
24. Mu, J. et al. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nature Genet. 42, 268-271 (2010).
25. Van Tyne, D. et al. Identification and functional validation of the novel antimalarial resistance locus PF10-0355 in Plasmodium falciparum. PLoS Genet. 7, e1001383 (2011). This was the first demonstration of a GWAS in P. falciparum that included functional follow-up of a novel locus identified using this approach.
26. Mu, J. et al. Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol. 3, e335 (2005).
27. Anderson, T. J. et al. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol. Biol. Evol. 17, 1467-1482 (2000).
28. Pumpaibool, T. et al. Genetic diversity and population structure of Plasmodium falciparum in Thailand, a low transmission country. Malaria J. 8, 155 (2009).
29. Conway, D. J. et al. Extreme geographical fixation of variation in the Plasmodium falciparum gamete surface protein gene Pfs48/45 compared with microsatellite loci. Mol. Biochem. Parasitol. 115, 145-156 (2001).
30. Nkhoma, S. C. et al. Close kinship within multiplegenotype malaria parasite infections. Proc. R. Soc. B 7 Mar 2012 (doi:10.1098/rspb.2012.0113).
31. Takala, S. L. et al. Dynamics of polymorphism in a malaria vaccine antigen at a vaccine-testing site in Mali. PLoS Med. 4, e93 (2007).
32. Thera, M. A. et al. A field trial to assess a blood-stage malaria vaccine. N. Engl. J. Med. 365, 1004-1013 (2011).
33. Smith, J. M. & Haigh, J. The hitch-hiking effect of a favourable gene. Genet. Res. 23, 23-35 (1974).
34. Conway, D. J. et al. High recombination rate in natural populations of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 96, 4506-4511 (1999).
35. Jiang, H. et al. High recombination rates and hotspots in a Plasmodium falciparum genetic cross. Genome Biol. 12, R33 (2011).
36. Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832-837 (2002).
37. Laufer, M. K. et al. Return of chloroquine-susceptible falciparum malaria in Malawi was a reexpansion of diverse susceptible parasites. J. Infect. Dis. 202, 801-808 (2010).
38. Wootton, J. C. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418, 320-323 (2002).
39. Nair, S. et al. A selective sweep driven by pyrimethamine treatment in southeast asian malaria parasites. Mol. Biol. Evol. 20, 1526-1536 (2003).
40. Foote, S. J., Thompson, J. K., Cowman, A. F. &Kemp, D. J. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of P. falciparum. Cell 57, 921-930 (1989).
41. Wilson, C. M. et al. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 244, 1184-1186 (1989).
42. Nair, S. et al. Adaptive copy number evolution in malaria parasites. PLoS Genet. 4, e1000243 (2008).
43. Yuan, J. et al. Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets. Science 333, 724-729 (2011). This study used a chemical screen and GWASs to identify a number of antimalarial compounds and confirms the involvement of the identified SNPs in response to drugs using both linkage analysis and genetically modified parasites. Demonstrates that most of these activities are associated with only three previously identified genes and that combinations of drugs targeting the pfcrt locus may be clinically useful.
44. Ponts, N. et al. Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence. PLoS ONE 3, e2386 (2008).
45. Nguitragool, W. et al. Malaria parasite clag3 genes determine channel-mediated nutrient uptake by infected red blood cells. Cell 145, 665-677 (2011). This paper shows that the plasmodial surface anion channel (PSAC) is an anti-malarial target of compounds inhibiting nutrient uptake. The authors localize this response to the clag3 locus, which is previously assumed to function in cytoadherence. This work demonstrates that surface molecules can alter cell permeability to diverse solutes, including drugs.
46. Su, X. Z., Mu, J. & Joy, D. A. The 'Malaria's Eve' hypothesis and the debate concerning the origin of the human malaria parasite Plasmodium falciparum. Microbes Infect. 5, 891-896 (2003).
47. Sabeti, P. C. et al. Positive natural selection in the human lineage. Science 312, 1614-1620 (2006). This is a review of the different genomic patterns left by positive natural selection and the many methods and tests used to detect them.
48. Hartl, D. L. The origin of malaria: mixed messages from genetic diversity. Nature Rev. Microbiol. 2, 15-22 (2004).
49. Hartl, D. L. et al. The paradoxical population genetics of Plasmodium falciparum. Trends Parasitol. 18, 266-272 (2002).
50. Gutenkunst, R. N., Hernandez, R. D., Williamson, S. H. & Bustamante, C. D. Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data. PLoS Genet. 5, e1000695 (2009).
51. Li, J. et al. Joint analysis of demography and selection in population genetics: where do we stand and where could we go? Mol. Ecol. 21, 28-44 (2012).
52. Trager, W. & Jensen, J. B. Human malaria parasites in continuous culture. Science 193, 673-675 (1976).
53. Ferdig, M. T. et al. Dissecting the loci of low-level quinine resistance in malaria parasites. Mol. Microbiol. 52, 985-997 (2004). This paper describes the use of quantitative trait analysis to identify the pfnhe-1 locus, which is related to quinine resistance. It also demonstrates the power of linkage studies to locate genes contributing to drug resistance.
54. Hayton, K. & Su, X. Z. Drug resistance and genetic mapping in Plasmodium falciparum. Curr. Genet. 54, 223-239 (2008).
55. Nkrumah, L. J. et al. Probing the multifactorial basis of Plasmodium falciparum quinine resistance: evidence for a strain-specific contribution of the sodium-proton exchanger PfNHE. Mol. Biochem. Parasitol. 165, 122-131 (2009).
56. Sa, J. M. et al. Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proc. Natl Acad. Sci. USA 106, 18883-18889 (2009).
57. Sanchez, C. P., Mayer, S., Nurhasanah, A., Stein, W. D. & Lanzer, M. Genetic linkage analyses redefine the roles of PfCRT and PfMDR1 in drug accumulation and susceptibility in Plasmodium falciparum. Mol. Microbiol. 82, 865-878 (2011).
58. Wellems, T. E., Walker-Jonah, A. & Panton, L. J. Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7. Proc. Natl Acad. Sci. USA 88, 3382-3386 (1991).
59. Hayton, K. et al. Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion. Cell Host Microbe 4, 40-51 (2008).
60. Vaidya, A. B. et al. A genetic locus on Plasmodium falciparum chromosome 12 linked to a defect in mosquito-infectivity and male gametogenesis. Mol. Biochem. Parasitol. 69, 65-71 (1995).
61. Su, X. et al. A genetic map and recombination parameters of the human malaria parasite Plasmodium falciparum. Science 286, 1351-1353 (1999).
62. Dharia, N. V. et al. Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites. Genome Res. 20, 1534-1544 (2010). This study used genome scanning to reveal an almost clonal population structure for P. falciparum parasites from Peru, which suggests that these parasites could be useful in linkage or quantitative trait locus analyses. It also identifies mutations in the apicoplast that confer resistance to clindamycin, which is used in Peru in combination with quinine to treat pregnant women and infants.
63. Griffing, S. M. et al. South American Plasmodium falciparum after the malaria eradication era: clonal population expansion and survival of the fittest hybrids. PLoS ONE 6, e23486 (2011).
64. Anderson, T. J. et al. High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. J. Infect. Dis. 201, 1326-1330 (2010).
65. Anderson, T. J. et al. Inferred relatedness and heritability in malaria parasites. Proc. Biol. Sci. 277, 2531-2540 (2010).
66. de Bakker, P. I. et al. Efficiency and power in genetic association studies. Nature Genet. 37, 1217-1223 (2005).
67. Pulit, S. L., Voight, B. F. & de Bakker, P. I. Multiethnic genetic association studies improve power for locus discovery. PLoS ONE 5, e12600 (2010).
68. Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881-888 (2008).
69. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997-1004 (1999).
70. Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet. 38, 904-909 (2006).
71. Pritchard, J. K., Stephens, M., Rosenberg, N. A. &Donnelly, P. Association mapping in structured populations. Am. J. Hum. Genet. 67, 170-181 (2000).
72. Kang, H. M. et al. Variance component model to account for sample structure in genome-wide association studies. Nature Genet. 42, 348-354 (2010).
73. Kang, H. M. et al. Efficient control of population structure in model organism association mapping. Genetics 178, 1709-1723 (2008).
74. Price, A. L., Zaitlen, N. A., Reich, D. & Patterson, N. New approaches to population stratification in genome-wide association studies. Nature Rev. Genet. 11, 459-463 (2010). This is a Review of GWAS methods that deal with population structure, focusing mostly on mixed-model approaches.
75. Thornton, T. & McPeek, M. S. ROADTRIPS: case-control association testing with partially or completely unknown population and pedigree structure. Am. J. Hum. Genet. 86, 172-184 (2010).
76. Ochola, L. I. et al. Allele frequency-based and polymorphism-versus- divergence indices of balancing selection in a new filtered set of polymorphic genes in Plasmodium falciparum. Mol. Biol. Evol. 27, 2344-2351 (2010).
77. Dvorin, J. D. et al. A plant-like kinase in Plasmodium falciparum regulates parasite egress from erythrocytes. Science 328, 910-912 (2010).
78. Istvan, E. S. et al. Validation of isoleucine utilization targets in Plasmodium falciparum. Proc. Natl Acad. Sci. USA 108, 1627-1632 (2011). This study takes a pharmacogenomic approach to select for P. falciparum parasites by using compounds that interfere with isoleucine use, which must be obtained by the parasite exogenously. Resistant parasites had mutations in isoleucyl-tRNA synthetase, showing that this approach can be used to elucidate new targets for drug development.
79. McNamara, C. & Winzeler, E. A. Target identification and validation of novel antimalarials. Future Microbiol. 6, 693-704 (2011).
80. Meister, S. et al. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372-1377 (2011).
81. Nam, T. G. et al. A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor. ACS Chem. Biol. 6, 1214-1222 (2011).
82. Rottmann, M. et al. Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 1175-1180 (2010).
83. Alonso, P. L. et al. A research agenda to underpin malaria eradication. PLoS Med. 8, e1000406 (2011).
84. Farnert, A. et al. Genotyping of Plasmodium falciparum infections by PCR: a comparative multicentre study. Trans. R. Soc. Trop. Med. Hyg. 95, 225-232 (2001).
85. Juliano, J. J. et al. Exposing malaria in-host diversity and estimating population diversity by capturerecapture using massively parallel pyrosequencing. Proc. Natl Acad. Sci. USA 107, 20138-20143 (2010). This study used high-throughput sequencing to characterize malaria parasite diversity among patients and to evaluate parasite populations before and after drug treatment. These data are combined with computational strategies to study the evolution of drug resistance.
86. Snounou, G. et al. Biased distribution of msp1 and msp2 allelic variants in Plasmodium falciparum populations in Thailand. Trans. R. Soc. Trop. Med. Hyg. 93, 369-374 (1999).
87. Daniels, R. et al. A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking. Malar J. 7, 223 (2008). This paper describes the generation of TaqMan assays for 24 SNPs that have a high minor-allele frequency to distinguish individual parasite genomes.
88. Agnandji, S. T. et al. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N. Engl. J. Med. 365, 1863-1875 (2011).
89. Alloueche, A. et al. Protective efficacy of the RTS,S/AS02 Plasmodium falciparum malaria vaccine is not strain specific. Am. J. Trop. Med. Hyg. 68, 97-101 (2003).
90. Bojang, K. A. et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet 358, 1927-1934 (2001).
91. Enosse, S. et al. RTS,S/AS02A malaria vaccine does not induce parasite CSP T cell epitope selection and reduces multiplicity of infection. PLoS Clin. Trials 1, e5 (2006).
92. Waitumbi, J. N. et al. Impact of RTS,S/AS02A and RTS,S/AS01B on genotypes of P. falciparum in adults participating in a malaria vaccine clinical trial. PLoS ONE 4, e7849 (2009).
93. Bozdech, Z. et al. The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol. 1, E5 (2003).
94. Le Roch, K. G. et al. Discovery of gene function by expression profiling of the malaria parasite life cycle. Science 301, 1503-1508 (2003).
95. Duraisingh, M. T. et al. Heterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium falciparum. Cell 121, 13-24 (2005).
96. Foth, B. J., Zhang, N., Mok, S., Preiser, P. R. &Bozdech, Z. Quantitative protein expression profiling reveals extensive post-transcriptional regulation and post-translational modifications in schizont-stage malaria parasites. Genome Biol. 9, R177 (2008).
97. Freitas-Junior, L. H. et al. Telomeric heterochromatin propagation and histone acetylation control mutually exclusive expression of antigenic variation genes in malaria parasites. Cell 121, 25-36 (2005). This paper describes the use of high-throughput RNA sequencing approaches to detect novel P. falciparum transcripts, to correct gene models, to propose alternative splicing events and to predict untranslated regions. Differential expression patterns across the developmental life cycle were connected with DNA microarray analysis to advance our understanding of gene expression substantially.
98. Otto, T. D. et al. New insights into the blood-stage transcriptome of Plasmodium falciparum using RNAseq. Mol. Microbiol. 76, 12-24 (2010).
99. Raabe, C. A. et al. A global view of the nonprotein-coding transcriptome in Plasmodium falciparum. Nucleic Acids Res. 38, 608-617 (2010).
100. Daily, J. P. et al. Distinct physiological states of Plasmodium falciparum in malaria-infected patients. Nature 450, 1091-1095 (2007).
101. Lemieux, J. E. et al. Statistical estimation of cell-cycle progression and lineage commitment in Plasmodium falciparum reveals a homogeneous pattern of transcription in ex vivo culture. Proc. Natl Acad. Sci. USA 106, 7559-7564 (2009).
102. Mackinnon, M. J. et al. Comparative transcriptional and genomic analysis of Plasmodium falciparum field isolates. PLoS Pathog. 5, e1000644 (2009).
103. Mok, S. et al. Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription. BMC Genomics 12, 391 (2011). DNA microarrays were used in this study to show that parasites that are obtained from patients exhibiting delayed clearance rates under artemisinin drug treatment show decreased metabolic activities in the ring stages. The data also suggest that the increased protein metabolism in the schizont stage may protect against oxidative stress and other effects of artemisinin.
104. De Silva, E. K. et al. Specific DNA-binding by apicomplexan AP2 transcription factors. Proc. Natl Acad. Sci. USA 105, 8393-8398 (2008).
105. Balaji, S., Babu, M. M., Iyer, L. M. & Aravind, L. Discovery of the principal specific transcription factors of Apicomplexa and their implication for the evolution of the AP2-integrase DNA binding domains. Nucleic Acids Res. 33, 3994-4006 (2005).
106. Aravind, L., Iyer, L. M., Wellems, T. E. & Miller, L. H. Plasmodium biology: genomic gleanings. Cell 115, 771-785 (2003).
107. Coleman, B. I. & Duraisingh, M. T. Transcriptional control and gene silencing in Plasmodium falciparum. Cell. Microbiol. 10, 1935-1946 (2008).
108. Hakimi, M. A. & Deitsch, K. W. Epigenetics in Apicomplexa: control of gene expression during cell cycle progression, differentiation and antigenic variation. Curr. Opin. Microbiol 10, 357-362 (2007).
109. Horrocks, P., Wong, E., Russell, K. & Emes, R. D. Control of gene expression in Plasmodium falciparum - ten years on. Mol. Biochem. Parasitol. 164, 9-25 (2009).
110. Iyer, L. M., Anantharaman, V., Wolf, M. Y. & Aravind, L. Comparative genomics of transcription factors and chromatin proteins in parasitic protists and other eukaryotes. Int. J. Parasitol. 38, 1-31 (2008).
111. Cui, L. & Miao, J. Chromatin-mediated epigenetic regulation in the malaria parasite Plasmodium falciparum. Eukaryot. Cell 9, 1138-1149 (2010).
112. Broadbent, K. et al. A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs. Genome Biol. 12, R56 (2011). Uses a high-resolution DNA-tiling microarray to identify long non-coding RNAs (lncRNAs) localized to the telomeres, where they are proposed to have a role in telomere maintenance, virulence gene regulation and potentially in other processes that are related to chromosome end biology in the parasite.
113. Bright, A. T. & Winzeler, E. A. Noncoding RNA, antigenic variation, and the virulence genes of Plasmodium falciparum. BMC Biol. 9, 50 (2011).
114. Su, X., Hayton, K. & Wellems, T. E. Genetic linkage and association analyses for trait mapping in Plasmodium falciparum. Nature Rev. Genet. 8, 497-506 (2007).
115. Florens, L. et al. A proteomic view of the Plasmodium falciparum life cycle. Nature 419, 520-526 (2002).
116. Khan, S. M. et al. Proteome analysis of separated male and female gametocytes reveals novel sexspecific Plasmodium biology. Cell 121, 675-687 (2005).
117. Lasonder, E. et al. Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry. Nature 419, 537-542 (2002).
118. Lasonder, E. et al. Proteomic profiling of Plasmodium sporozoite maturation identifies new proteins essential for parasite development and infectivity. PLoS Pathog. 4, e1000195 (2008).
119. Patra, K. P., Johnson, J. R., Cantin, G. T., Yates, J. R. &Vinetz, J. M. Proteomic analysis of zygote and ookinete stages of the avian malaria parasite Plasmodium gallinaceum delineates the homologous proteomes of the lethal human malaria parasite Plasmodium falciparum. Proteomics 8, 2492-2499 (2008).
120. Sinden, R. E. Reality check for malaria proteomics. Genome Biol. 10, 211 (2009).
121. Wuchty, S., Adams, J. H. & Ferdig, M. T. A comprehensive Plasmodium falciparum protein interaction map reveals a distinct architecture of a core interactome. Proteomics 9, 1841-1849 (2009).
122. Besteiro, S., Vo Duy, S., Perigaud, C., Lefebvre-Tournier, I. & Vial, H. J. Exploring metabolomic approaches to analyse phospholipid biosynthetic pathways in Plasmodium. Parasitology 137, 1343-1356 (2010).
123. Olszewski, K. L. et al. Branched tricarboxylic acid metabolism in Plasmodium falciparum. Nature 466, 774-778 (2010).
124. Olszewski, K. L. et al. Host-parasite interactions revealed by Plasmodium falciparum metabolomics. Cell Host Microbe 5, 191-199 (2009).
125. Teng, R. et al. Metabolite profiling of the intraerythrocytic malaria parasite Plasmodium falciparum by 1H NMR spectroscopy. NMR Biomed. 22, 292-302 (2009).
126. Nsobya, S. L., Kiggundu, M., Joloba, M., Dorsey, G. & Rosenthal, P. J. Complexity of Plasmodium falciparum clinical samples from Uganda during short-term culture. J. Infect. Dis. 198, 1554-1557 (2008).
127. Pologe, L. G. & Ravetch, J. V. Large deletions result from breakage and healing of P. falciparum chromosomes. Cell 55, 869-874 (1988).
128. Venkatesan, M. et al. Using CF11 cellulose columns to inexpensively and effectively remove human DNA from Plasmodium falciparum-infected whole blood samples. Malar J. 11, 41 (2012).
129. Melnikov, A. et al. Hybrid selection for sequencing pathogen genomes from clinical samples. Genome Biol. 12, R73 (2011). This paper describes the use of the hybrid selection process to capture P. falciparum DNA from a DNA sample derived from patient blood samples containing a mixture of human and P. falciparum DNA.