Drug target prediction and prioritization: using orthology to predict essentiality in parasite genomes

<p>Abstract</p> <p>Background</p> <p>New drug targets are urgently needed for parasites of socio-economic importance. Genes that are essential for parasite survival are highly desirable targets, but information on these genes is lacking, as gene knockouts or knockdowns are difficult to perform in many species of parasites. We examined the applicability of large-scale essentiality information from four model eukaryotes, <it>Caenorhabditis elegans, Drosophila melanogaster, Mus musculus </it>and <it>Saccharomyces cerevisiae</it>, to discover essential genes in each of their genomes. Parasite genes that lack orthologues in their host are desirable as selective targets, so we also examined prediction of essential genes within this subset.</p> <p>Results</p> <p>Cross-species analyses showed that the evolutionary conservation of genes and the presence of essential orthologues are each strong predictors of essentiality in eukaryotes. Absence of paralogues was also found to be a general predictor of increased relative essentiality. By combining several orthology and essentiality criteria one can select gene sets with up to a five-fold enrichment in essential genes compared with a random selection. We show how quantitative application of such criteria can be used to predict a ranked list of potential drug targets from <it>Ancylostoma caninum </it>and <it>Haemonchus contortus </it>- two blood-feeding strongylid nematodes, for which there are presently limited sequence data but no functional genomic tools.</p> <p>Conclusions</p> <p>The present study demonstrates the utility of using orthology information from multiple, diverse eukaryotes to predict essential genes. The data also emphasize the challenge of identifying essential genes among those in a parasite that are absent from its host.</p

Host-linked soil viral ecology along a permafrost thaw gradient

Climate change threatens to release abundant carbon that is sequestered at high latitudes, but the constraints on microbial metabolisms that mediate the release of methane and carbon dioxide are poorly understood1,2,3,4,5,6,7. The role of viruses, which are known to affect microbial dynamics, metabolism and biogeochemistry in the oceans8,9,10, remains largely unexplored in soil. Here, we aimed to investigate how viruses influence microbial ecology and carbon metabolism in peatland soils along a permafrost thaw gradient in Sweden. We recovered 1,907 viral populations (genomes and large genome fragments) from 197 bulk soil and size-fractionated metagenomes, 58% of which were detected in metatranscriptomes and presumed to be active. In silico predictions linked 35% of the viruses to microbial host populations, highlighting likely viral predators of key carbon-cycling microorganisms, including methanogens and methanotrophs. Lineage-specific virus/host ratios varied, suggesting that viral infection dynamics may differentially impact microbial responses to a changing climate. Virus-encoded glycoside hydrolases, including an endomannanase with confirmed functional activity, indicated that viruses influence complex carbon degradation and that viral abundances were significant predictors of methane dynamics. These findings suggest that viruses may impact ecosystem function in climate-critical, terrestrial habitats and identify multiple potential viral contributions to soil carbon cycling

Highlights from the Student Council Symposium 2011 at the International Conference on Intelligent Systems for Molecular Biology and European Conference on Computational Biology

The Student Council (SC) of the International Society for Computational Biology (ISCB) organized their annual symposium in conjunction with the Intelligent Systems for Molecular Biology (ISMB) conference

Diverse sediment microbiota shape methane emission temperature sensitivity in Arctic lakes

Northern post-glacial lakes are significant, increasing sources of atmospheric carbon through ebullition (bubbling) of microbially-produced methane (CH4) from sediments. Ebullitive CH4 flux correlates strongly with temperature, reflecting that solar radiation drives emissions. However, here we show that the slope of the temperature-CH4 flux relationship differs spatially across two post-glacial lakes in Sweden. We compared these CH4 emission patterns with sediment microbial (metagenomic and amplicon), isotopic, and geochemical data. The temperature-associated increase in CH4 emissions was greater in lake middles—where methanogens were more abundant—than edges, and sediment communities were distinct between edges and middles. Microbial abundances, including those of CH4-cycling microorganisms and syntrophs, were predictive of porewater CH4 concentrations. Results suggest that deeper lake regions, which currently emit less CH4 than shallower edges, could add substantially to CH4 emissions in a warmer Arctic and that CH4 emission predictions may be improved by accounting for spatial variations in sediment microbiota

Liver Enzymes Are Associated With Hepatic Insulin Resistance, Insulin Secretion, and Glucagon Concentration in Healthy Men and Women

International audienceOBJECTIVE: The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. RESEARCH DESIGN AND METHODS: We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. RESULTS: In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001). CONCLUSIONS: In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes

Biogem: an effective tool-based approach for scaling up open source software development in bioinformatics

Summary: Biogem provides a software development environment for the Ruby programming language, which encourages community-based software development for bioinformatics while lowering the barrier to entry and encouraging best practices

A genomic catalog of Earth’s microbiomes

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth’s continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes

The Worker Honeybee Fat Body Proteome Is Extensively Remodeled Preceding a Major Life-History Transition

Honeybee workers are essentially sterile female helpers that make up the majority of individuals in a colony. Workers display a marked change in physiology when they transition from in-nest tasks to foraging. Recent technological advances have made it possible to unravel the metabolic modifications associated with this transition. Previous studies have revealed extensive remodeling of brain, thorax, and hypopharyngeal gland biochemistry. However, data on changes in the abdomen is scarce. To narrow this gap we investigated the proteomic composition of abdominal tissue in the days typically preceding the onset of foraging in honeybee workers

Does the high gene density in the Sponge NK Homeobox gene cluster reflect limited regulatory capacity?

A huge discrepancy in morphological diversity exists between poriferans and eumetazoans. The disparate evolutionary outcomes of these two ancient metazoan lineages may be reflected in the composition, architecture, and regulation of genomes of modern representatives. As a case study, we compare the sizes of upstream intergenic regions of genes found within the NK homeobox cluster of the demosponge Amphimedon queenslandica with eumetazoan orthologs. This analysis includes NK genes as well as five structural genes interspersed in the cluster. The upstream intergenic regions of the homeobox genes are significantly smaller in Amphimedon than in eumetazoan orthologs, suggesting that the sponge genes house less cis-regulatory information. In contrast, the upstream intergenic regions of the structural genes are not significantly different. The simple developmental expression patterns of representative NK genes in Amphimedon lends support to the proposition that their regulatory apparatuses, unlike those of bilaterians, do not encode the information for dynamic, pleiotropic gene expression. On the basis of this example, we suggest that the size of the intergenic regions upstream of the transcription start site may act as a proxy for estimating regulatory complexity and reflect the limitations of the sponge genome to direct complex and varied morphogenetic processes

NUMTs in the sponge genome reveal conserved transposition mechanisms in metazoans

The transposition of parts of the mitochondrial (mt) genetic material into the nuclear genome (NUMTs) occurs in a wide range of eukaryotes. Here, we show that NUMTs exist for nearly all regions of the mt genome in the demosponge Amphimedon queenslandica, a representative of the oldest phyletic lineage of animals. Because the sponge NUMTs are small and noncoding, and transposed via a DNA intermediate, as in eumetazoans, we infer that the transpositonal processes underlying NUMT formation in contemporary animals existed in their most recent common ancestor. In contrast to most bilaterians, Amphimedon NUMTs are inserted into regions of high gene density. Given the common features of metazoan NUMTs, the reduction in animal mt genome sizes relative to other eukaryotes may be the product of the mt DNA transposition mechanisms that evolved along the metazoan stem