Computational prediction of essential genes in an unculturable endosymbiotic bacterium, Wolbachia of Brugia malayi

<p>Abstract</p> <p>Background</p> <p><it>Wolbachia </it>(<it>w</it>Bm) is an obligate endosymbiotic bacterium of <it>Brugia malayi</it>, a parasitic filarial nematode of humans and one of the causative agents of lymphatic filariasis. There is a pressing need for new drugs against filarial parasites, such as <it>B. malayi</it>. As <it>w</it>Bm is required for <it>B. malayi </it>development and fertility, targeting <it>w</it>Bm is a promising approach. However, the lifecycle of neither <it>B. malayi </it>nor <it>w</it>Bm can be maintained <it>in vitro</it>. To facilitate selection of potential drug targets we computationally ranked the <it>w</it>Bm genome based on confidence that a particular gene is essential for the survival of the bacterium.</p> <p>Results</p> <p><it>w</it>Bm protein sequences were aligned using BLAST to the Database of Essential Genes (DEG) version 5.2, a collection of 5,260 experimentally identified essential genes in 15 bacterial strains. A confidence score, the Multiple Hit Score (MHS), was developed to predict each <it>w</it>Bm gene's essentiality based on the top alignments to essential genes in each bacterial strain. This method was validated using a jackknife methodology to test the ability to recover known essential genes in a control genome. A second estimation of essentiality, the Gene Conservation Score (GCS), was calculated on the basis of phyletic conservation of genes across <it>Wolbachia's </it>parent order <it>Rickettsiales</it>. Clusters of orthologous genes were predicted within the 27 currently available complete genomes. Druggability of <it>w</it>Bm proteins was predicted by alignment to a database of protein targets of known compounds.</p> <p>Conclusion</p> <p>Ranking <it>w</it>Bm genes by either MHS or GCS predicts and prioritizes potentially essential genes. Comparison of the MHS to GCS produces quadrants representing four types of predictions: those with high confidence of essentiality by both methods (245 genes), those highly conserved across <it>Rickettsiales </it>(299 genes), those similar to distant essential genes (8 genes), and those with low confidence of essentiality (253 genes). These data facilitate selection of <it>w</it>Bm genes for entry into drug design pipelines.</p>

Abstract licence: CC BY-NC-ND

• DEG 10, an update of the database of essential genes that includes both protein-coding genes and noncoding genomic elements: Table 1. · 2013

• New Insights into the Evolution of Wolbachia Infections in Filarial Nematodes Inferred from a Large Range of Screened Species · 2011

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