PathoPhenoDB, linking human pathogens to their phenotypes in support of infectious disease research.

Understanding the relationship between the pathophysiology of infectious disease, the biology of the causative agent and the development of therapeutic and diagnostic approaches is dependent on the synthesis of a wide range of types of information. Provision of a comprehensive and integrated disease phenotype knowledgebase has the potential to provide novel and orthogonal sources of information for the understanding of infectious agent pathogenesis, and support for research on disease mechanisms. We have developed PathoPhenoDB, a database containing pathogen-to-phenotype associations. PathoPhenoDB relies on manual curation of pathogen-disease relations, on ontology-based text mining as well as manual curation to associate host disease phenotypes with infectious agents. Using Semantic Web technologies, PathoPhenoDB also links to knowledge about drug resistance mechanisms and drugs used in the treatment of infectious diseases. PathoPhenoDB is accessible at http://patho.phenomebrowser.net/ , and the data are freely available through a public SPARQL endpoint

Performance of PVP in variant prioritization in WGS data, separated by mode of inheritance of the disease.

<p>Performance of PVP in variant prioritization in WGS data, separated by mode of inheritance of the disease.</p

Performance of PVP in identifying causative variants in whole genome sequences using human phenotypes (PVP-Human), model organisms phenotypes (PVP-Model), and combined phenotypes (PVP), and comparison of PVP to CADD, DANN, GWAVA, and Genomiser.

<p>Performance of PVP in identifying causative variants in whole genome sequences using human phenotypes (PVP-Human), model organisms phenotypes (PVP-Model), and combined phenotypes (PVP), and comparison of PVP to CADD, DANN, GWAVA, and Genomiser.</p

Overview of the performance of PVP, CADD, DANN, GWAVA and Exomiser in prioritizing causative variants in WGS data.

<p>We prioritize all variants in a VCF file resulting from WGS using the same models. Analysis is separated reflecting the performance of the various tools identifying exonic and non-exonic variants. For CADD, DANN, and GWAVA, we report only analysis results for which a prediction score is returned; consequently, total numbers are less than the total of 11,251 causative variants.</p

Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy

Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1 alpha subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1 alpha phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome

Genome-scale comparison of expanded gene families in Plasmodium ovale wallikeri and Plasmodium ovale curtisi with Plasmodium malariae and with other Plasmodium species

Malaria in humans is caused by six species of Plasmodium parasites, of which the nuclear genome sequences for the two Plasmodium ovale spp., P. ovale curtisi and P. ovale wallikeri, and Plasmodium malariae have not yet been analyzed. Here we present an analysis of the nuclear genome sequences of these three parasites, and describe gene family expansions therein. Plasmodium ovale curtisi and P. ovale wallikeri are genetically distinct but morphologically indistinguishable and have sympatric ranges through the tropics of Africa, Asia and Oceania. Both P. ovale spp. show expansion of the surfin variant gene family, and an amplification of the Plasmodium interspersed repeat (pir) superfamily which results in an approximately 30% increase in genome size. For comparison, we have also analyzed the draft nuclear genome of P. malariae, a malaria parasite causing mild malaria symptoms with a quartan life cycle, long-term chronic infections, and wide geographic distribution. Plasmodium malariae shows only a moderate level of expansion of pir genes, and unique expansions of a highly diverged transmembrane protein family with over 550 members and the gamete P25/27 gene family. The observed diversity in the P. ovale wallikeri and P. ovale curtisi surface antigens, combined with their phylogenetic separation, supports consideration that the two parasites be given species status