The Plasmodium genome database

Kissinger, Jessica C.; Brunk, Brian P.; Crabtree, Jonathan; Fraunholz, Martin; Gajria, Bindu; Milgram, Arthur J.; Pearson, David; Schug, Jonathan; Bahl, Amit; Diskin, Sharon J.; Ginsburg, Hagaï; Grant, Gregory R.; Gupta, Dinesh; Labo, Philip T.; Li, Li; Mailman, Matthew D.; McWeeney, Shannon K.; Whetzel, Patricia L.; Stoeckert, Christian J.; Roos, David S.

doi:10.1038/419490a

Cited by 152 publications

(98 citation statements)

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“…Querying the Gene Ontology (GO; Ashburner et al 2000) annotations in PlasmoDB (Kissinger et al 2002) with the word 'transcription' identified 45 sequences involved with transcriptional control, all of which were identifed by the above HMM searches and TRIBE-MCL clustering. Thus, this combined strategy using two complementary sequence-searching methods has facilitated the retrieval of proteins from two databases with different contents and annotation levels, and involved in all aspects of the transcriptional process.…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomics of Transcriptional Control in the Human Malaria Parasite Plasmodium falciparum

Coulson¹,

Hall²,

Ouzounis³

2004

Genome Res.

241

255

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The life cycle of the parasite Plasmodium falciparum, responsible for the most deadly form of human malaria, requires specialized protein expression for survival in the mammalian host and insect vector. To identify components of processes controlling gene expression during its life cycle, the malarial genome-along with seven crown eukaryote group genomes-was queried with a reference set of transcription-associated proteins (TAPs). Following clustering on the basis of sequence similarity of the TAPs with their homologs, and together with hidden Markov model profile searches, 156 P. falciparum TAPs were identified. This represents about a third of the number of TAPs usually found in the genome of a free-living eukaryote. Furthermore, the P. falciparum genome appears to contain a low number of sequences, which are highly conserved and abundant within the kingdoms of free-living eukaryotes, that contribute to gene-specific transcriptional regulation. However, in comparison with these other eukaryotic genomes, the CCCH-type zinc finger (common in proteins modulating mRNA decay and translation rates) was found to be the most abundant in the P. falciparum genome. This observation, together with the paucity of malarial transcriptional regulators identified, suggests Plasmodium protein levels are primarily determined by posttranscriptional mechanisms.

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Section: Resultsmentioning

confidence: 99%

Comparative Genomics of Transcriptional Control in the Human Malaria Parasite Plasmodium falciparum

Coulson¹,

Hall²,

Ouzounis³

2004

Genome Res.

241

255

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“…Our estimates of the selective pressures across the P. falciparum genome will be useful for understanding host-pathogen interactions and for developing appropriately targeted vaccines 21 . The Figure 2 The distribution of volatility P values across all genes in the M. tuberculosis and P. falciparum genomes.…”

mentioning

confidence: 99%

Detecting selection using a single genome sequence of M. tuberculosis and P. falciparum

Plotkin¹,

Dushoff

Fraser

2004

Nature

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Selective pressures on proteins are usually measured by comparing nucleotide sequences 1 . Here we introduce a method to detect selection on the basis of a single genome sequence. We catalogue the relative strength of selection on each gene in the entire genomes of Mycobacterium tuberculosis and Plasmodium falciparum. Our analysis confirms that most antigens are under strong selection for amino-acid substitutions, particularly the PE/PPE family 2 of putative surface proteins in M. tuberculosis and the EMP1 family 3 of cytoadhering surface proteins in P. falciparum. We also identify many uncharacterized proteins that are under strong selection in each pathogen. We provide a genome-wide analysis of natural selection acting on different stages of an organism's life cycle: genes expressed in the ring stage 4 of P. falciparum are under stronger positive selection than those expressed in other stages of the parasite's life cycle. Our method of estimating selective pressures requires far fewer data than comparative sequence analysis, and it measures selection across an entire genome; the method can readily be applied to a large range of sequenced organisms.Historically, the study of natural selection has been pursued under a comparative paradigm 5 . Genes under selection are identified by comparing homologous nucleotide sequences sampled either from different individuals within a species (for example, nucleotide polymorphism studies) or from different species (for example, phylogenetic analysis). The widely used non-synonymous to synonymous substitution ratio (dN/dS) falls within this model 6 , as do all other existing methods for detecting natural selection on coding sequences [7][8][9] . Within the comparative paradigm, it would be impossible to measure selective pressures on the basis of a genome sequence from a single individual.Here we present a method for rapidly detecting differential selective pressures on genes by inspecting a single genome sequence for a footprint of non-synonymous substitutions. Our method rests on a simple observation: if a protein coding region of a nucleotide sequence has undergone an excess number of amino-acid substitutions, then the region will on average contain an overabundance of 'volatile' codons, compared with the genome as a whole. For each of the 61 sense codons, we define its volatility as the proportion of its point-mutation neighbours that encode different amino acids (see Fig. 1). The volatility of a codon will be used to quantify the chance that the most recent nucleotide mutation to that codon caused an amino-acid substitution.Using the concept of codon volatility, we can scan an entire genome to find genes that show significantly more, or less, pressure for amino-acid substitutions than the genome as a whole. If a gene contains many residues under pressure for amino-acid replacements, then the resulting codons in that gene will on average exhibit elevated volatility, because its ancestor codons encoded different amino acids from those encoded by the current codons. Simila...

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“…18, 19 One such emerging target is PfPK7, an 'orphan' plasmodial kinase which is distantly related to the MAPKK family of kinases (mitogen-activated protein kinase kinase). 20, 21 Disruption of the pfpk7 gene suggests that PfPK7 is involved in a pathway regulating cell proliferation and development: P. falciparum clones in which the PfPK7 locus has been inactivated are viable, but their asexual growth rate is about half that observed in wild-type parasites. 22 This phenotype suggests that PFPK7 inactivation through chemical inhibition would be expected to slow parasite growth and, hence, decrease the virulence of infection.…”

Section: Biological Evaluation Of Inhibitors Towards the Plasmodium Fmentioning

confidence: 99%

Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chemistry: potential inhibitors of the Plasmodium falciparum PfPK7 protein kinase

et al. 2009

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Efficient routes to 3-(1,2,3-triazol-1-yl)-and 3-(1,2,3-triazol-4-yl)pyrazolo [3,4-d]pyrimidin-4-amines using a one-pot two-step reaction are presented. The two routes give easy access to two different isomers of 1,4-disubstituted triazoles and the target compounds are obtained from a variety of readily available aromatic and aliphatic halides without isolation of potentially unstable organic azide intermediates. Two compounds show activity towards the PfPK7 kinase (IC 50 10-20 mM) of P. falciparum, the organism responsible for the most virulent form of malaria, and can be regarded as hits useful for further development into lead compounds.

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The Plasmodium genome database

Cited by 152 publications

References 0 publications

Comparative Genomics of Transcriptional Control in the Human Malaria Parasite Plasmodium falciparum

Comparative Genomics of Transcriptional Control in the Human Malaria Parasite Plasmodium falciparum

Detecting selection using a single genome sequence of M. tuberculosis and P. falciparum

Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chemistry: potential inhibitors of the Plasmodium falciparum PfPK7 protein kinase

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