First sequencing of the genome of a Eukaryote parasite

Paris, November 21, 2001

Several French teams associated with the CNRS* have collaborated to establish the genome sequence of the Encephalitozoon cuniculi microsporidia. This eukaryotic intracellular parasite infests various mammals, including humans, causing digestive and nervous disorders. This is the first success in the field of genome sequencing of non-bacterial parasitic organisms, and provides new insight on the exchanges between the parasite and its host. The results of this work are published in the November 22, 2001 issue of Nature.

Although many bacterial genomes have been fully sequenced since 1995, very few genomes of eukaryotes – organisms with a cellular nucleus – have been determined. Until today, no eukaryote parasite genome had been sequenced.

The researchers* selected a model parasite, the Encephalitozoon cuniculi microsporidia, whose genome size is less than three megabases (more than a thousand times smaller than the human genome), distributed over eleven chromosomes. Microsporidia are microparasites that have received attention, historically, through Louis Pasteur's research on silkworm disease. They form a group of 1,200 species that parasitize all animal groups, and humans in particular. They cause opportunistic infections in people with AIDS, but are increasingly found among immunocompetent people – those with an immune system capable of fighting a microbial attack. In the Western world, 38% of immunocompetent individuals have microsporidia antibodies. Microsporidioses are considered as emerging diseases.

Most intracellular parasites lose many of their functions in a host. Is this true for E. cuniculi? The analysis of its genome is essential, as it shows a "compaction" otherwise unknown in the eukaryote, that affects the structure of the genome and the genes. The number of predicted genes, after comparison with the genes identified in libraries, was estimated at two thousand – half the number found in the genomes of free bacteria and a third of the number of the beer yeast genome. This means than a certain number of genes have disappeared during the evolution of the host-parasite relationship. The genes that correspond to certain essential metabolisms are absent, and others have been shortened.

These results appear to indicate that the microsporidia must import a great many compounds from the host, to the detriment of the parasitized cells, through mechanisms similar to those observed in parasitic bacteria (for example, microsporidia and rickettsias have very similar transporters for importing energy or ATP).

But what is most surprising is the size of the genes themselves. They can be up to 20-30% smaller than homologous genes, whether they are eukaryotic or bacterial. This indicates the minimum size for protein functionality. Thus, by comparison with the other sequenced eukaryote organisms, one may hypothesize that the missing regions on the parasite's genes, which often correspond to an unknown function, are likely to be involved in the fine regulation of free organisms. The sequencing provides new information that suggests the existence of a residual organelle related to the mitochondria (the power sources of the cell) of the aerobic eukaryotes (those which need air to live).

Comparison with other organisms made it possible to identify potential therapeutic targets, i.e. proteins involved in metabolism that are not found in the host organism, and proteins that are sufficiently different. Similarly, identifying proteins specific to microsporidia will make it possible to obtain more reliable diagnostic tools. Phylogenic analyses confirm that microsporidia are close to the branch of fungi.

Researchers must now confirm that the identified sequences code for functional proteins. This is the aim of the protoemic study that involves analyzing all the proteins of an organism and must be combined with the study of interactions between proteins. Most importantly, the functions of the uncharacterized genes must be defined; as is true for other genomes, analysis only allows 55% of these genes to be predicted. The researchers expect that the forthcoming sequencing of the genomes of other intracellular microparasites, such as the agent of malaria and certain fungi, should make valuable comparisons possible, because, since they have a similar way of life, they may well share certain functions and regulations. Scientists may now consider identifying the genes shared by all intracellular microparasites so that common therapeutic targets can be found.

Reference:
Katinka, M.D. et al. - Genome sequence and gene compaction of the eukaryote parasite Encephalotozoon cuniculi. Nature 414, November 22, 2001.

Christian Vivarès, Program Director, "Unité de biologie comparée des protistes" (Comparative Biology of Protists Laboratory, CNRS — University of Clermont 2), Michaël Katinka and Jean Weissenbach, Génoscope (CNS — CNRS, Evry), Manolo Gouy, "Unité de biométrie et biologie évolutive" (Biometrics and Evolutionary Biology Laboratory, CNRS — University of Lyon I

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