Identification of novel therapeutics for complex diseases from genome-wide association data

Human genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data. In silico tools such as candidate gene prediction systems allow rapid identification of disease genes by identifying the most probable candidate genes linked to genetic markers of the disease or phenotype under investigation. Integration of drug-target data with candidate gene prediction systems can identify novel phenotypes which may benefit from current therapeutics. Such a drug repositioning tool can save valuable time and money spent on preclinical studies and phase I clinical trials.

Genome sequence of Ensifer medicae Di28; an effective N2-fixing microsymbiont of Medicago murex and M. polymorpha

Ensifer medicae Di28 is an aerobic, motile, Gram-negative, non-spore-forming rod that can exist as a soil saprophyte or as a legume microsymbiont of Medicago spp. Di28 was isolated in 1998 from a nodule recovered from the roots of M. polymorpha growing in the south east of Sardinia (Italy). Di28 is an effective microsymbiont of the annual forage legumes M. polymorpha and M. murex and is capable of establishing a partially effective symbiotic association with the perennial M. sativa. Here we describe the features of E. medicae Di28, together with genome sequence information and its annotation. The 6,553,624 bp standard draft genome is arranged into 104 scaffolds of 104 contigs containing 6,394 protein-coding genes and 75 RNA-only encoding genes. This rhizobial genome is one of 100 sequenced as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) project.

Genome sequence of the acid-tolerant Burkholderia sp. strain WSM2232 from Karijini National Park, Australia

Burkholderia sp. strain WSM2232 is an aerobic, motile, Gram-negative, non-spore-forming acid-tolerant rod that was trapped in 2001 from acidic soil collected from Karijini National Park (Australia) using Gastrolobium capitatum as a host. WSM2232 was effective in nitrogen fixation with G. capitatum but subsequently lost symbiotic competence during long-term storage. Here we describe the features of Burkholderia sp. strain WSM2232, together with genome sequence information and its annotation. The 7,208,311 bp standard-draft genome is arranged into 72 scaffolds of 72 contigs containing 6,322 protein-coding genes and 61 RNA-only encoding genes. The loss of symbiotic capability can now be attributed to the loss of nodulation and nitrogen fixation genes from the genome. This rhizobial genome is one of 100 sequenced as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) project.

Genome sequence of the dark pink pigmented Listia bainesii microsymbiont Methylobacterium sp. WSM2598

Strains of a pink-pigmented Methylobacterium sp. are effective nitrogen- (N2) fixing microsymbionts of species of the African crotalarioid genus Listia. Strain WSM2598 is an aerobic, motile, Gram-negative, non-spore-forming rod isolated in 2002 from a Listia bainesii root nodule collected at Estcourt Research Station in South Africa. Here we describe the features of Methylobacterium sp. WSM2598, together with information and annotation of a high-quality draft genome sequence. The 7,669,765 bp draft genome is arranged in 5 scaffolds of 83 contigs, contains 7,236 protein-coding genes and 18 RNA-only encoding genes. This rhizobial genome is one of 100 sequenced as part of the DOE Joint Genome Institute 2010 G enomic E ncyclopedia for B acteria and A rchaea- R oot N odule B acteria (GEBA-RNB) project.

Genome sequence of the Lotus corniculatus microsymbiont Mesorhizobium loti strain R88B

Mesorhizobium loti strain R88B was isolated in 1993 in the Rocklands range in Otago, New Zealand from a Lotus corniculatus root nodule. R88B is an aerobic, Gram-negative, non-spore-forming rod. This report reveals the genome of M. loti strain R88B contains a single scaffold of size 7,195,110 bp which encodes 6,950 protein-coding genes and 66 RNA-only encoding genes. This genome does not harbor any plasmids but contains the integrative and conjugative element ICEMlSym(R7A), also known as the R7A symbiosis island, acquired by horizontal gene transfer in the field environment from M. loti strain R7A. It also contains a mobilizable genetic element ICEMladh(R88B), that encodes a likely adhesin gene which has integrated downstream of ICEMlSym(R7A), and three acquired loci that together allow the utilization of the siderophore ferrichrome. This rhizobial genome is one of 100 sequenced as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) project.

Genome sequence of the Lotus spp. microsymbiont Mesorhizobium loti strain NZP2037

Mesorhizobium loti strain NZP2037 was isolated in 1961 in Palmerston North, New Zealand from a Lotus divaricatus root nodule. Compared to most other M. loti strains, it has a broad host range and is one of very few M. loti strains able to form effective nodules on the agriculturally important legume Lotus pedunculatus. NZP2037 is an aerobic, Gram negative, non-spore-forming rod. This report reveals that the genome of M. loti strain NZP2037 does not harbor any plasmids and contains a single scaffold of size 7,462,792 bp which encodes 7,318 protein-coding genes and 70 RNA-only encoding genes. This rhizobial genome is one of 100 sequenced as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) project.

Genome sequence of the Lotus spp. microsymbiont Mesorhizobium loti strain R7A

Mesorhizobium loti strain R7A was isolated in 1993 in Lammermoor, Otago, New Zealand from a Lotus corniculatus root nodule and is a reisolate of the inoculant strain ICMP3153 (NZP2238) used at the site. R7A is an aerobic, Gram-negative, non-spore-forming rod. The symbiotic genes in the strain are carried on a 502-kb integrative and conjugative element known as the symbiosis island or ICEMlSym(R7A). M. loti is the microsymbiont of the model legume Lotus japonicus and strain R7A has been used extensively in studies of the plant-microbe interaction. This report reveals that the genome of M. loti strain R7A does not harbor any plasmids and contains a single scaffold of size 6,529,530 bp which encodes 6,323 protein-coding genes and 75 RNA-only encoding genes. This rhizobial genome is one of 100 sequenced as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) project.

Advances in molecular genetic systems in malaria

Robust tools for analysing gene function in Plasmodium parasites, which are the causative agents of malaria, are being developed at an accelerating rate. Two decades after genetic technologies for use in Plasmodium spp. were first described, a range of genetic tools are now available. These include conditional systems that can regulate gene expression at the genome, transcriptional or protein level, as well as more sophisticated tools for gene editing that use piggyBac transposases, integrases, zinc-finger nucleases or the CRISPR-Cas9 system. In this Review, we discuss the molecular genetic systems that are currently available for use in Plasmodium falciparum and Plasmodium berghei, and evaluate the advantages and limitations of these tools. We examine the insights that have been gained into the function of genes that are important during the blood stages of the parasites, which may help to guide the development and improvement of drug therapies and vaccines.

Novel therapeutics for cononary artery disease from genome-wide association study data

Abstract
Background: Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene-centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD. Subsequent integration of drug-target data from drug databases with the predicted candidate genes can potentially identify novel therapeutics suitable for repositioning towards treatment of CAD.
Methods: Previously, we were able to predict 264 candidate genes and 104 potential therapeutic targets for CAD using Gentrepid (www.gentrepid.org), a candidate gene prediction platform with two bioinformatic modules to reanalyze Wellcome Trust Case-Control Consortium GWAS data. In an expanded study, using five bioinformatics modules on the same data, Gentrepid predicted 647 candidate genes and successfully replicated 55% of the candidate genes identified by the more powerful CARDIoGRAMplusC4D consortium meta-analysis. Hence, Gentrepid was capable of enhancing lower quality genotype-phenotype data, using an independent knowledgebase of existing biological data. Here, we used our methodology to integrate drug data from three drug databases: the Therapeutic Target Database, PharmGKB and Drug Bank, with the 647 candidate gene predictions from Gentrepid. We utilized known CAD targets, the scientific literature, existing drug data and the CARDIoGRAMplusC4D meta-analysis study as benchmarks to validate Gentrepid predictions for CAD.
Results: Our analysis identified a total of 184 predicted candidate genes as novel therapeutic targets for CAD, and 981 novel therapeutics feasible for repositioning in clinical trials towards treatment of CAD. The benchmarks based on known CAD targets and the scientific literature showed that our results were significant (p < 0.05).
Conclusions: We have demonstrated that available drugs may potentially be repositioned as novel therapeutics for the treatment of CAD. Drug repositioning can save valuable time and money spent on preclinical and phase I clinical studies.