Dysregulations of Expression of Genes of the Ubiquitin/SUMO Pathways in an In Vitro Model of Amyotrophic Lateral Sclerosis Combining Oxidative Stress and SOD1 Gene Mutation.

Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations.

Genes containing hexanucleotide repeats resembling C9ORF72 and expressed in the central nervous system are frequent in the human genome.

More than 40 human diseases, mainly diseases affecting the central nervous system, are caused by the expansion of unstable nucleotide repeats. Repeats of sequences like (CAG)n present in different genes can be responsible for various diseases of the central nervous system. An expanded hexanucleotide repeat (GGGGCC)n in the C9ORF72 gene has been characterized as the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar dementia. In this study, we performed a genome-wide analysis in the human genome and identified 74 genes containing this precise hexanucleotide repeat, with a preference for a location in exon 1 or intron 1, similar to the C9ORF72 gene. A total of 36 of these 74 genes may be of interest as candidates in neurodevelopmental or neurodegenerative diseases, based on their function.

Recurrent DNA virus domestication leading to different parasite virulence strategies.

Relics of ancient infections are abundant in eukaryote genomes, but little is known about how they evolve when they confer a functional benefit on their host. We show here, for the first time, that the virus-like particles shown to protect Venturia canescens eggs against host immunity are derived from a nudivirus genome incorporated by the parasitic wasp into its own genetic material. Nudivirus hijacking was also at the origin of protective particles from braconid wasps. However, we show here that the viral genes produce "liposomes" that wrap and deliver V. canescens virulence proteins, whereas the particles are used as gene transfer agents in braconid wasps. Our findings indicate that virus domestication has occurred repeatedly during parasitic wasp evolution but with different evolutionary trajectories after endogenization, resulting in different virulence molecule delivery strategies.

Variation of gene expression associated with colonisation of an anthropized environment: comparison between African and European populations of Drosophila simulans.

The comparison of transcriptome profiles among populations is a powerful tool for investigating the role of gene expression change in adaptation to new environments. In this study, we use massively parallel sequencing of 3' cDNAs obtained from large samples of adult males, to compare a population of Drosophila simulans from a natural reserve within its ancestral range (eastern Africa) with a derived population collected in the strongly anthropized Rhône valley (France). The goal was to scan for adaptation linked to the invasion of new environments by the species. Among 15,090 genes retained for the analysis, 794 were found to be differentially expressed between the two populations. We observed an increase in expression of reproduction-related genes in eastern Africa, and an even stronger increase in expression of Cytochrome P450, Glutathione transferase and Glucuronosyl transferase genes in the derived population. These three gene families are involved in detoxification processes, which suggests that pesticides are a major environmental pressure for the species in this area. The survey of the Cyp6g1 upstream region revealed the insertion of a transposable element, Juan, in the regulatory sequence that is almost fixed in the Rhône Valley, but barely present in Mayotte. This shows that Cyp6g1 has undergone parallel evolution in derived populations of D. simulans as previously shown for D. melanogaster. The increasing amount of data produced by comparative population genomics and transcriptomics should permit the identification of additional genes associated with functional divergence among those differentially expressed.

Population transcriptomics: insights from Drosophila simulans, Drosophila sechellia and their hybrids.

Sequence differentiation has been widely studied between populations and species, whereas interest in expression divergence is relatively recent. Using microarrays, we compared four geographically distinct populations of Drosophila simulans and a population of Drosophila sechellia, and interspecific hybrids. We observed few differences between populations, suggesting a slight population structure in D. simulans. This structure was observed in direct population comparisons, as well as in interspecific comparisons (hybrids vs. parents, D. sechellia vs. D. simulans). Expression variance is higher in the French and Zimbabwean populations than in the populations from the ancestral range of D. simulans (Kenya and Seychelles). This suggests a large scale phenomenon of decanalization following the invasion of a new environment. Comparing D. simulans and D. sechellia, we revealed 304 consistently differentially expressed genes, with striking overrepresentation of genes of the cytochrome P450 family, which could be related to their role in detoxification as well as in hormone regulation. We also revealed differences in genes involved in Juvenile hormone and Dopamine differentiation. We finally observed very few differentially expressed genes between hybrids and parental populations, with an overrepresentation of X-linked genes.

Genetic diversity in the Paramecium aurelia species complex.

Current understanding of the population genetics of free-living unicellular eukaryotes is limited, and the amount of genetic variability in these organisms is still a matter of debate. We characterized-reproductively and genetically-worldwide samples of multiple Paramecium species belonging to a cryptic species complex, Paramecium aurelia, whose species have been shown to be reproductively isolated. We found that levels of genetic diversity both in the nucleus and in the mitochondrion are substantial within groups of reproductively compatible P. aurelia strains but drop considerably when strains are partitioned according to their phylogenetic groupings. Our study reveals the existence of discrepancies between the mating behavior of a number of P. aurelia strains and their multilocus genetic profile, a controversial finding that has major consequences for both the current methods of species assignment and the species problem in the P. aurelia complex.

Ischemia is not required for arteriogenesis in zebrafish embryos.

OBJECTIVE: The role of ischemia in collateral vessel development (arteriogenesis) is a contentious issue that cannot be addressed using mammalian models. To investigate this, we developed models of arteriogenesis using the zebrafish embryo, which gains sufficient oxygenation via diffusion to prevent ischemia in response to arterial occlusion. METHODS AND RESULTS: We studied gridlock mutant embryos that suffer a permanently occluded aorta and show that these restore aortic blood flow by collateral vessels. We phenocopied gridlock mutants by laser-induced proximal aortic occlusion in transgenic Fli1:eGFP/GATA1:dsRED embryos. Serial imaging showed these restore aortic blood flow via collateral vessels by recruitment of preexisting endothelium in a manner similar to gridlocks. Collateral aortic blood flow in gridlock mutants was dependent on both nitric oxide and myeloid cells. Confocal microscopy of transgenic gridlock/Fli1:eGFP mutants demonstrated no aberrant angiogenic response to the aortic occlusion. qPCR of HIF1alpha expression confirmed the absence of hypoxia in this model system. CONCLUSIONS: We conclude that NO and myeloid cell-dependent collateral vessel development is an evolutionarily ancient response to arterial occlusion and is able to proceed in the absence of ischemia.