Phylogenomic analyses of malaria parasites and evolution of their exported proteins

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it>is the most malignant agent of human malaria. It belongs to the taxon Laverania, which includes other ape-infecting <it>Plasmodium </it>species. The origin of the Laverania is still debated. <it>P. falciparum </it>exports pathogenicity-related proteins into the host cell using the <it>Plasmodium </it>export element (PEXEL). Predictions based on the presence of a PEXEL motif suggest that more than 300 proteins are exported by <it>P. falciparum</it>, while there are many fewer exported proteins in non-Laverania.</p> <p>Results</p> <p>A whole-genome approach was applied to resolve the phylogeny of eight <it>Plasmodium </it>species and four outgroup taxa. By using 218 orthologous proteins we received unanimous support for a sister group position of Laverania and avian malaria parasites. This observation was corroborated by the analyses of 28 exported proteins with orthologs present in all <it>Plasmodium </it>species. Most interestingly, several deviations from the <it>P. falciparum </it>PEXEL motif were found to be present in the orthologous sequences of non-Laverania.</p> <p>Conclusion</p> <p>Our phylogenomic analyses strongly support the hypotheses that the Laverania have been founded by a single <it>Plasmodium </it>species switching from birds to African great apes or <it>vice versa</it>. The deviations from the canonical PEXEL motif in orthologs may explain the comparably low number of exported proteins that have been predicted in non-Laverania.</p

Genetic Association Study Identifies HSPB7 as a Risk Gene for Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10−6, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10−5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10−3, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10−3, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10−4, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10−13, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage