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Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children
Get PDFBACKGROUND:
Cerebral malaria (CM) represents a severe outcome of the Plasmodium falciparum infection. Recent genetic studies have correlated human genes with severe malaria susceptibility, but there is little data on genetic variants that increase the risk of developing specific malaria clinical complications. Nevertheless, susceptibility to experimental CM in the mouse has been linked to host genes including Transforming Growth Factor Beta 2 (TGFB2) and Heme oxygenase-1 (HMOX1). Here, we tested whether those genes were governing the risk of progressing to CM in patients with severe malaria syndromes.
METHODOLOGY/PRINCIPAL FINDINGS:
We report that the clinical outcome of P. falciparum infection in a cohort of Angolan children (n = 430) correlated with nine TGFB2 SNPs that modify the risk of progression to CM as compared to other severe forms of malaria. This genetic effect was explained by two haplotypes harboring the CM-associated SNPs (Pcorrec. = 0.035 and 0.036). In addition, one HMOX1 haplotype composed of five CM-associated SNPs increased the risk of developing the CM syndrome (Pcorrec. = 0.002) and was under-transmitted to children with uncomplicated malaria (P = 0.036). Notably, the HMOX1-associated haplotype conferred increased HMOX1 mRNA expression in peripheral blood cells of CM patients (P = 0.012).
CONCLUSIONS/SIGNIFICANCE:
These results represent the first report on CM genetic risk factors in Angolan children and suggest the novel hypothesis that genetic variants of the TGFB2 and HMOX1 genes may contribute to confer a specific risk of developing the CM syndrome in patients with severe P. falciparum malaria. This work may provide motivation for future studies aiming to replicate our findings in larger populations and to confirm a role for these genes in determining the clinical course of malaria
A Genomic Signature and the Identification of New Sporulation Genes
Get PDFBacterial endospores are the most resistant cell type known to humans, as they are able to withstand extremes of temperature, pressure, chemical injury, and time. They are also of interest because the endospore is the infective particle in a variety of human and livestock diseases. Endosporulation is characterized by the morphogenesis of an endospore within a mother cell. Based on the genes known to be involved in endosporulation in the model organism Bacillus subtilis, a conserved core of about 100 genes was derived, representing the minimal machinery for endosporulation. The core was used to define a genomic signature of about 50 genes that are able to distinguish endospore-forming organisms, based on complete genome sequences, and we show this 50-gene signature is robust against phylogenetic proximity and other artifacts. This signature includes previously uncharacterized genes that we can now show are important for sporulation in B. subtilis and/or are under developmental control, thus further validating this genomic signature. We also predict that a series of polyextremophylic organisms, as well as several gut bacteria, are able to form endospores, and we identified 3 new loci essential for sporulation in B. subtilis: ytaF, ylmC, and ylzA. In all, the results support the view that endosporulation likely evolved once, at the base of the Firmicutes phylum, and is unrelated to other bacterial cell differentiation programs and that this involved the evolution of new genes and functions, as well as the cooption of ancestral, housekeeping functions.FCT grant: (PEst-OE/EQB/LA0004/2011), FCT Ph.D. fellowship: (SFRH/BPD/36328/2007), FCT postdoc fellowship: (SFRH/BPD/65605/2009), Instituto Gulbenkian de Ciência research fellowship
An experimental test on the probability of extinction of new genetic variants
Get PDFIn 1927, J.B.S. Haldane reasoned that the probability of fixation of new beneficial alleles is twice their fitness effect. This result, later generalized by M. Kimura, has since become the cornerstone of modern population genetics. There is no experimental test of Haldane's insight that new beneficial alleles are lost with high probability. Here we demonstrate that extinction rates decrease with increasing initial numbers of beneficial alleles, as expected, by performing invasion experiments with inbred lines of the nematode Caenorhabditis elegans. We further show that the extinction rates of deleterious alleles are higher than those of beneficial alleles, also as expected. Interestingly, we also find that for these inbred lines, when at intermediate frequencies, the fate of invaders might not result in their ultimate fixation or loss but on their maintenance. Our study confirms the key results from classical population genetics and highlights that the nature of adaptation can be complex.Human Frontiers Science Program grant: (RGP0045/2010)
Telomerase Is Required for Zebrafish Lifespan
Get PDFTelomerase activity is restricted in humans. Consequentially, telomeres shorten in most cells throughout our lives. Telomere dysfunction in vertebrates has been primarily studied in inbred mice strains with very long telomeres that fail to deplete telomeric repeats during their lifetime. It is, therefore, unclear how telomere shortening regulates tissue homeostasis in vertebrates with naturally short telomeres. Zebrafish have restricted telomerase expression and human-like telomere length. Here we show that first-generation tert(-/-) zebrafish die prematurely with shorter telomeres. tert(-/-) fish develop degenerative phenotypes, including premature infertility, gastrointestinal atrophy, and sarcopaenia. tert(-/-) mutants have impaired cell proliferation, accumulation of DNA damage markers, and a p53 response leading to early apoptosis, followed by accumulation of senescent cells. Apoptosis is primarily observed in the proliferative niche and germ cells. Cell proliferation, but not apoptosis, is rescued in tp53(-/-)tert(-/-) mutants, underscoring p53 as mediator of telomerase deficiency and consequent telomere instability. Thus, telomerase is limiting for zebrafish lifespan, enabling the study of telomere shortening in naturally ageing individuals.FCT fellowships, Howard Hughes Medical Institute
The Genetic Basis of Escherichia coli Pathoadaptation to Macrophages
Get PDFAntagonistic interactions are likely important driving forces of the evolutionary process underlying bacterial genome complexity and diversity. We hypothesized that the ability of evolved bacteria to escape specific components of host innate immunity, such as phagocytosis and killing by macrophages (MΦ), is a critical trait relevant in the acquisition of bacterial virulence. Here, we used a combination of experimental evolution, phenotypic characterization, genome sequencing and mathematical modeling to address how fast, and through how many adaptive steps, a commensal Escherichia coli (E. coli) acquire this virulence trait. We show that when maintained in vitro under the selective pressure of host MΦ commensal E. coli can evolve, in less than 500 generations, virulent clones that escape phagocytosis and MΦ killing in vitro, while increasing their pathogenicity in vivo, as assessed in mice. This pathoadaptive process is driven by a mechanism involving the insertion of a single transposable element into the promoter region of the E. coli yrfF gene. Moreover, transposition of the IS186 element into the promoter of Lon gene, encoding an ATP-dependent serine protease, is likely to accelerate this pathoadaptive process. Competition between clones carrying distinct beneficial mutations dominates the dynamics of the pathoadaptive process, as suggested from a mathematical model, which reproduces the observed experimental dynamics of E. coli evolution towards virulence. In conclusion, we reveal a molecular mechanism explaining how a specific component of host innate immunity can modulate microbial evolution towards pathogenicity.LAO/ITQB, FC
Female and Male Perspectives on the Neolithic Transition in Europe: Clues from Ancient and Modern Genetic Data
Get PDFThe arrival of agriculture into Europe during the Neolithic transition brought a significant shift in human lifestyle and subsistence. However, the conditions under which the spread of the new culture and technologies occurred are still debated. Similarly, the roles played by women and men during the Neolithic transition are not well understood, probably due to the fact that mitochondrial DNA (mtDNA) and Y chromosome (NRY) data are usually studied independently rather than within the same statistical framework. Here, we applied an integrative approach, using different model-based inferential techniques, to analyse published datasets from contemporary and ancient European populations. By integrating mtDNA and NRY data into the same admixture approach, we show that both males and females underwent the same admixture history and both support the demic diffusion model of Ammerman and Cavalli-Sforza. Similarly, the patterns of genetic diversity found in extant and ancient populations demonstrate that both modern and ancient mtDNA support the demic diffusion model. They also show that population structure and differential growth between farmers and hunter-gatherers are necessary to explain both types of data. However, we also found some differences between male and female markers, suggesting that the female effective population size was larger than that of the males, probably due to different demographic histories. We argue that these differences are most probably related to the various shifts in cultural practices and lifestyles that followed the Neolithic Transition, such as sedentism, the shift from polygyny to monogamy or the increase of patrilocality.FCT grant: (SFRH/BD/30821/2006), CNRS (Centre National de la Recherche Scientifique, France), Laboratoire d’Excellence LABEX TULIP (ANR-10-LABX-41), CALMIP, Toulouse grants: (2010-P1038, 2012-P1244)
Reductionism at the vertebrate kinetochore
Get PDFThe kinetochore forms the site of attachment for mitotic spindle microtubules driving chromosome segregation. The interdependent protein interactions in this large structure have made it difficult to dissect the function of its components. In this issue, Hori et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201210106) present a novel and powerful methodology to address the sufficiency of individual proteins for the creation of a functional de novo centromere.Não possuí patrocionadores
Co-option of a coordinate system defined by the EGFr and Dpp pathways in the evolution of a morphological novelty
Get PDFMorphological innovation is an elusive and fascinating concept in evolutionary biology. A novel structure may open up an array of possibilities for adaptation, and thus is fundamental to the evolution of complex multicellular life. We use the respiratory appendages on the dorsal-anterior side of the Drosophila eggshell as a model system for morphological novelty. To study the co-option of genetic pathways in the evolution of this novelty we have compared oogenesis and eggshell patterning in Drosophila melanogaster with Ceratitis capitata, a dipteran whose eggs do not bear dorsal appendages.FCT fellowship: (SFRH/BD/33216/2007), Collaborative Research Centre 680 ‘Molecular Basis of Evolutionary Innovations (DFG grant), Fundação Calouste Gulbenkian, Instituto Gulbenkian de Ciência
Niflumic acid disrupts marine spermatozoan chemotaxis without impairing the spatiotemporal detection of chemoattractant gradients
Get PDFIn many broadcast-spawning marine organisms, oocytes release chemicals that guide conspecific spermatozoa towards them through chemotaxis. In the sea urchin Lytechinus pictus, the chemoattractant peptide speract triggers a train of fluctuations of intracellular Ca(2+) concentration in the sperm flagella. Each transient Ca(2+) elevation leads to a momentary increase in flagellar bending asymmetry, known as a chemotactic turn. Furthermore, chemotaxis requires a precise spatiotemporal coordination between the Ca(2+)-dependent turns and the form of chemoattractant gradient. Spermatozoa that perform Ca(2+)-dependent turns while swimming down the chemoattractant gradient, and conversely suppress turning events while swimming up the gradient, successfully approach the center of the gradient. Previous experiments in Strongylocentrotus purpuratus sea urchin spermatozoa showed that niflumic acid (NFA), an inhibitor of several ion channels, drastically altered the speract-induced Ca(2+) fluctuations and swimming patterns. In this study, mathematical modeling of the speract-dependent Ca(2+) signaling pathway suggests that NFA, by potentially affecting hyperpolarization-activated and cyclic nucleotide-gated channels, Ca(2+)-regulated Cl(-) channels and/or Ca(2+)-regulated K(+) channels, may alter the temporal organization of Ca(2+) fluctuations, and therefore disrupt chemotaxis. We used a novel automated method for analyzing sperm behavior and we identified that NFA does indeed disrupt chemotactic responses of L. pictus spermatozoa, although the temporal coordination between the Ca(2+)-dependent turns and the form of chemoattractant gradient is unaltered. Instead, NFA disrupts sperm chemotaxis by altering the arc length traveled during each chemotactic turning event. This alteration in the chemotactic turn trajectory disorientates spermatozoa at the termination of the turning event. We conclude that NFA disrupts chemotaxis without affecting how the spermatozoa decode environmental cues.Consejo Nacional de Ciencia y Tecnología grants: (49113, 128566, 132478); Programa de Apoyo a Proyectos de Investigación e Innovación Technológica grant: (IN211809, DGAPA/IXTLI IX200910, IN223810, IN109210-F)
On the physiological significance of alternative splicing events in higher plants
Get PDFAlternative splicing, which generates multiple transcripts from the same gene and potentially different protein isoforms, is a key posttranscriptional regulatory mechanism for expanding proteomic diversity and functional complexity in higher eukaryotes. The most recent estimates, based on whole transcriptome sequencing, indicate that about 95 % of human and 60 % of Arabidopsis multi-exon genes undergo alternative splicing, suggesting important roles for this mechanism in biological processes. However, while the misregulation of alternative splicing has been associated with many human diseases, its biological relevance in plant systems is just beginning to unfold. We review here the few plant genes for which the production of multiple splice isoforms has been reported to have a clear in vivo functional impact. These case studies implicate alternative splicing in the control of a wide range of physiological and developmental processes, including photosynthetic and starch metabolism, hormone signaling, seed germination, root growth and flowering, as well as in biotic and abiotic stress responses. Future functional characterization of alternative splicing events and identification of the transcripts targeted by major regulators of this versatile means of modulating gene expression should uncover the breadth of its physiological significance in higher plants.FCT fellowship: (SFRH/BPD/80073/2011); Programa Ciência (QREN/MCTES)