A New Piece of the Eukaryotic Puzzle Alejandro Sanchez-Flores

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GENOME WATCH A new piece of the eukaryotic puzzle Alejandro Sanchez-Flores

This month’s Genome Watch discusses The N. gruberi genome revealed several pathogenic species responsible for primary the genome of the free-living interesting cellular features2,3. For example, amoebic meningoencephalitis in humans. The amoeboflagellate protist Naegleria gruberi. there is no cytological evidence of a Golgi authors propose that some potential N. fowleri complex in this species, but genes relevant drug targets can be elucidated from the N. gru- In the eukaryotic tree, the free-living pro- for membrane trafficking in the Golgi com- beri genome4, including the enzymes involved tist Naegleria gruberi belongs to the class plex were detected. The genome also contains in the hydroxymethylglutaryl CoA (HMG- Heterolobosea, which is a major eukaryotic a large superfamily of tubulin genes span- CoA) pathway, a bacterial-like mitochondrial lineage and part of the ancient JEH (Jakobida– ning almost all known tubulin subfamilies. nitroreductase (NTR1) and the alternative oxi- Euglenoza–Heterolobosea) clade. This clade This includes a group of divergent α-tubulin dase (AOX). The HMG-CoA pathway gener- was not resolved until the N. gruberi genome proteins that are probably involved in the ates the precursor for isoprenoids and sterols, became available, and its resolution con- assembly of the atypical mitotic spindle in which are components of the plasma mem- tributed to the re-rooting of the eukaryotic N. gruberi. The mitochondrial genome is brane. Current treatment5 for primary amoebic tree with all six major eukaryotic groups — contained in a single circular chromosome3 meningoencephalitis includes amphotericin B, Opisthokonta, Ameobozoa, Viridiplantae, instead of many circular DNA molecules, thus which associates with ergosterol and disrupts Alveolata, POD (Parabasalia–Oxymonadida– resembling a bacterial genome. In contrast the membrane. Shutting down the HMG-CoA Diplomonadida) and JEH. This provided a to the mammalian mitochondrial genome, pathway would generate the same effect. NTR1 wider window on early eukaryotic evolution1. which encodes only 13 proteins and a few has been detected only in trypanosomatids, in The genome of N. gruberi comprises RNA-coding genes, the N. gruberi mitochon- which it activates drugs into parasiticidal meta 41 million bp, distributed across 12 chromo- drial genome encodes 69 genes, including bolites. AOX is absent in humans but is a key somes. In addition, a 14 kb extrachromosomal 43 that are protein coding. A complete set metabolic enzyme for N. fowleri proliferation in plasmid and a 50 kb mitochondrial genome of tRNAs is present, suggesting independ- the human brain. were sequenced2. The nuclear genome has ent mitochondrial-gene translation. Some The knowledge base provided by the 15,727 protein-coding genes (57.8% of the of the protein-coding genes correspond to N. gruberi genome not only reveals ancestral total), so it is compact but gene rich. The cytochrome units that are lost in other JEH eukaryotic features and the diversity of the authors compared these proteins with 17 organisms, and their presence results in a flex- eukaryotes but also provides a comparative proteomes from across the six major eukary- ible metabolism in both aerobic and anaero- model to study the rare fulminant pathogen otic groups. They constructed 4,133 protein bic conditions. Genomic information on N. fowleri. groups containing a minimum of one N. gru- the metabolism of N. gruberi 4 is important, Alejandro Sanchez-Flores is at the Sanger Institute, beri protein and two orthologues, requir- as experimental data are scarce. In addition Wellcome Trust Genome Campus, ing at least one of the orthologues to be from to mitochondrial metabolism, important Hinxton, Cambridge CB10 1SA, UK. another major eukaryotic group. These pro- anaerobic traits were predicted. For example, e-mail: [email protected] teins are inferred to have been present in the from the carbohydrate metabolic pathway doi:10.1038/nrmicro2680 1. Rodriguez-Ezpeleta, N. et al. Toward resolving the common ancestor of all extant eukaryotes, an it can be inferred that the final products of eukaryotic tree: the phylogenetic positions of Jakobids assumption supported by the fact that 92% aerobic metabolism are carbon dioxide and and Cercozoans. Curr. Biol. 17, 1420–1425 (2007). 2. Fritz-Laylin, L. K. et al. The genome of Naegleria gruberi and ~50% are present in three and five major water. In anaerobic conditions, metabolites illuminates early eukaryotic versatility. Cell 140, eukaryotic groups, respectively. Of the 4,133 such as succinate, acetate and probably also 631–642 (2010). 4 3. Fritz-Laylin, L. K., Ginger, M. L., Walsh, C., Dawson, S. C. proteins, 40% belong exclusively to eukary- ethanol and d‑lactate can be produced . & Fulton, C. The Naegleria genome: a free-living microbial otes, and most are hypothetical proteins Analysis of the N. gruberi genome eukaryote lends unique insights into core eukaryotic cell biology. Res. Microbiol. 162, 607–618 (2011). of unknown function. In addition, ~1% indicates ancestral features 4. Opperdoes, F. R., De Jonckheere, J. F. & Tielens, A. G. of the proteins in N. gruberi with no that are indicative of the M. Naegleria gruberi metabolism. Int. J. Parasitol. 41, 915–924 (2011). eukaryotic homologues are simi- eukaryotic common 5. Vargas-Zepeda, J. et al. Successful treatment of lar to bacterial or archaeal proteins. ancestor. N. gruberi is Naegleria fowleri meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin. Phylogenetic analysis suggests that also important as a com- Arch. Med. Res. 36, 83–86 (2005). these genes were acquired by parative model for Naegleria Competing interests statement lateral gene transfer2. fowleri, a closely related The author declares no competing financial interests.