Bréhélin et al. BMC Genomics 2010, 11:35 http://www.biomedcentral.com/1471-2164/11/35 turned out to correspond to a nucleolar small ribo- somal subunit assembling protein similar to YPL217C, with an e-value = 1.4e-45. Likewise, the pairing of two contiguous P. falciparum genes, PF14_0436 and PF14_0437, with distinct parts of the same yeast gene YNL112W involved in ribosomal biogenesis and assembly, allowed us to propose a revised gene structure at the corresponding P. falci- parum locus (Additional File 8). Additional File 9 is a series of other remarkable pairings between P. falciparum and S. cerevisiae or P. falciparum and D. melanogaster that were discov- ered. Apart from the pair (PFL1345c; YPL095C) that allowed us to propose a refined annotation as a “his- tone S-adenosyl methyltransferase, putative” for PFL1345c, and the pair (PF14_0178; YGR048W), that led to a new annotation as a “polyubiquitinated pro- tein - 26S proteasome guiding protein, putative” for PF14_0178, most of these pairs were only found in only one co-coexpression analysis. For example, see the P. falciparum gene PFC0100c, now proposed to be involved in “Golgi organisation and biogenesis” (pair (PFC0100c; FBgn0030365) in BO-PI analysis). On the whole, the biological functions attributed to the gene of the reference species in the output gene pairs show that a limited number of cellular processes are represented. In particular, genes coding for ribosome constituents are extremely abundant, for example in cluster pairs #13, #14 and #18 of the LR-GA analysis, or in cluster pairs #14 and #24 of the BO-GA analysis. Pro- teins involved in ribosomal biogenesis and assembly and rRNA metabolism and processing, most of which are annotated as nucleolar proteins in Yeast and/or Droso- phila, are also frequently returned in co-coexpressed clusters (such as in cluster pair #2 of the BO-GA analy- sis). To a lesser extent, genes encoding proteins playing roles in histone modifications, cytoskeleton dynamics, Golgi organization and biogenesis, proteasome, and cell cycle regulation (see Discussion below) are also discovered. Discussion Ribosomal proteins and potential drug targets Many gene pairs highlighted in the present study com- prise genes coding for ribosomal proteins or involved in ribosome biogenesis and assembly. Whereas the struc- ture of malarial ribosomal RNAs has attracted consider- able attention and has been analysed in many comparative studies, no census of ribosomal proteins was undertaken in the first large scale expert annotation of P. falciparum [4,31] and annotations have not been seriously revised since. The results of the present study, combined with other published data [32] and an analysis Page 8 of 14 by Akhil Vaidya group (Philadelphia, USA), were there- fore used to propose a revised annotation for the future versions of the GeneDB and PlasmoDB public databases. The annotation presented here was transferred to the PlasmoDB database before the submission of this article and was used in a recent study by Mishra et al. (2009) [33]. This re-annotation potentially involves promising drug targets. Many of the drugs used in clinical medicine to treat infectious diseases interfere with protein synthesis by targeting the pathogen ribosomes, e.g. macrolides, ketolides, lincosamides, oxazolidinones, aminoglycosides and tetracyclines [34]. Many teams have studied Plasmo- dium ribosomal RNAs as targets for antimalarial drugs, including thiostrepton, known to bind the apicoplast large ribosomal subunit rRNA [35,36], clindamycin, shown to also act on the large ribosomal subunit rRNA in Toxoplasma [37] and tetracycline, whose antimalarial effect is likely due to its binding to the mitochondrial and/or apicoplast small subunit rRNA [38]. Whereas recent studies focused on the ribonucleic constituents of ribosomes, i.e. rRNAs, as a promising target for innova- tive drugs [39], ribosomal proteins are also candidates of choice in the search for antimalarial drugs. Sidhu et al. (2007) [40] reported, for instance, that azithromycin, a broad spectrum antibiotic macrolide, could bind the api- coplast ribosomal protein L4 (PFCOMPIRB-rpl4; see Add. File 6), a polypeptide suspected to interact with the apicoplast ribosomal protein L22 (PF14_0642, anno- tated from our analysis as an organelle ribosomal pro- tein L22/L17 precursor, putative; see Add. File 6) and the apicoplast large RNA subunit. In general, the main problem in contemporary drug development is toxicity [34]. Concerning the uses of ribosomes as drug targets, the characterization of structural domains that diverge between a pathogen and its host, and the identification of residues whose polymorphism might be related to drug resistance, are crucial in the search for new drug candidates. The present study, which allows prediction of ribosomal proteins with low or very low sequence conservation, points to regions of the ribosomes that likely bind specific small molecules that would not inter- fere with the host ribosomes. Proteins involved in cell cycle regulation Molecular mechanisms and proteins involved in the control of P. falciparum cell cycle are largely unknown [41]. We focused on this biological process as a case study, and attempted to uncover some related malarial genes, by paying special attention to the Bozdech data sets in which the cell cycle was synchronized. 38 genes were proposed to be involved in cell cycle regulation by Tienda-Luna et al. (2008) [42], and 97 P. falciparum kinase genes were reported by Ward et al. (2004) [43] as representative of the malarial kinome. From these genes,