TreeDomViewer: a tool for the visualization of phylogeny and protein domain structure

Phylogenetic analysis and examination of protein domains allow accurate genome annotation and are invaluable to study proteins and protein complex evolution. However, two sequences can be homologous without sharing statistically significant amino acid or nucleotide identity, presenting a challenging bioinformatics problem. We present TreeDomViewer, a visualization tool available as a web-based interface that combines phylogenetic tree description, multiple sequence alignment and InterProScan data of sequences and generates a phylogenetic tree projecting the corresponding protein domain information onto the multiple sequence alignment. Thereby it makes use of existing domain prediction tools such as InterProScan. TreeDomViewer adopts an evolutionary perspective on how domain structure of two or more sequences can be aligned and compared, to subsequently infer the function of an unknown homolog. This provides insight into the function assignment of, in terms of amino acid substitution, very divergent but yet closely related family members. Our tool produces an interactive scalar vector graphics image that provides orthological relationship and domain content of proteins of interest at one glance. In addition, PDF, JPEG or PNG formatted output is also provided. These features make TreeDomViewer a valuable addition to the annotation pipeline of unknown genes or gene products. TreeDomViewer is available at

CoPub Mapper: mining MEDLINE based on search term co-publication

BACKGROUND: High throughput microarray analyses result in many differentially expressed genes that are potentially responsible for the biological process of interest. In order to identify biological similarities between genes, publications from MEDLINE were identified in which pairs of gene names and combinations of gene name with specific keywords were co-mentioned. RESULTS: MEDLINE search strings for 15,621 known genes and 3,731 keywords were generated and validated. PubMed IDs were retrieved from MEDLINE and relative probability of co-occurrences of all gene-gene and gene-keyword pairs determined. To assess gene clustering according to literature co-publication, 150 genes consisting of 8 sets with known connections (same pathway, same protein complex, or same cellular localization, etc.) were run through the program. Receiver operator characteristics (ROC) analyses showed that most gene sets were clustered much better than expected by random chance. To test grouping of genes from real microarray data, 221 differentially expressed genes from a microarray experiment were analyzed with CoPub Mapper, which resulted in several relevant clusters of genes with biological process and disease keywords. In addition, all genes versus keywords were hierarchical clustered to reveal a complete grouping of published genes based on co-occurrence. CONCLUSION: The CoPub Mapper program allows for quick and versatile querying of co-published genes and keywords and can be successfully used to cluster predefined groups of genes and microarray data

Plasmodium falciparum Heterochromatin Protein 1 Marks Genomic Loci Linked to Phenotypic Variation of Exported Virulence Factors

Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded by 60 var genes, to evade acquired immune responses. Antigenic variation of PfEMP1 occurs through in situ switches in mono-allelic var gene transcription, which is PfSIR2-dependent and associated with the presence of repressive H3K9me3 marks at silenced loci. Here, we show that P. falciparum heterochromatin protein 1 (PfHP1) binds specifically to H3K9me3 but not to other repressive histone methyl marks. Based on nuclear fractionation and detailed immuno-localization assays, PfHP1 constitutes a major component of heterochromatin in perinuclear chromosome end clusters. High-resolution genome-wide chromatin immuno-precipitation demonstrates the striking association of PfHP1 with virulence gene arrays in subtelomeric and chromosome-internal islands and a high correlation with previously mapped H3K9me3 marks. These include not only var genes, but also the majority of P. falciparum lineage-specific gene families coding for exported proteins involved in host–parasite interactions. In addition, we identified a number of PfHP1-bound genes that were not enriched in H3K9me3, many of which code for proteins expressed during invasion or at different life cycle stages. Interestingly, PfHP1 is absent from centromeric regions, implying important differences in centromere biology between P. falciparum and its human host. Over-expression of PfHP1 results in an enhancement of variegated expression and highlights the presence of well-defined heterochromatic boundaries. In summary, we identify PfHP1 as a major effector of virulence gene silencing and phenotypic variation. Our results are instrumental for our understanding of this widely used survival strategy in unicellular pathogens

The COMPARE Data Hubs

Data sharing enables research communities to exchange findings and build upon the knowledge that arises from their discoveries. Areas of public and animal health as well as food safety would benefit from rapid data sharing when it comes to emergencies. However, ethical, regulatory and institutional challenges, as well as lack of suitable platforms which provide an infrastructure for data sharing in structured formats, often lead to data not being shared or at most shared in form of supplementary materials in journal publications. Here, we describe an informatics platform that includes workflows for structured data storage, managing and pre-publication sharing of pathogen sequencing data and its analysis interpretations with relevant stakeholders

A Major Role for the Plasmodium falciparum ApiAP2 Protein PfSIP2 in Chromosome End Biology

The heterochromatic environment and physical clustering of chromosome ends at the nuclear periphery provide a functional and structural framework for antigenic variation and evolution of subtelomeric virulence gene families in the malaria parasite Plasmodium falciparum. While recent studies assigned important roles for reversible histone modifications, silent information regulator 2 and heterochromatin protein 1 (PfHP1) in epigenetic control of variegated expression, factors involved in the recruitment and organization of subtelomeric heterochromatin remain unknown. Here, we describe the purification and characterization of PfSIP2, a member of the ApiAP2 family of putative transcription factors, as the unknown nuclear factor interacting specifically with cis-acting SPE2 motif arrays in subtelomeric domains. Interestingly, SPE2 is not bound by the full-length protein but rather by a 60kDa N-terminal domain, PfSIP2-N, which is released during schizogony. Our experimental re-definition of the SPE2/PfSIP2-N interaction highlights the strict requirement of both adjacent AP2 domains and a conserved bipartite SPE2 consensus motif for high-affinity binding. Genome-wide in silico mapping identified 777 putative binding sites, 94% of which cluster in heterochromatic domains upstream of subtelomeric var genes and in telomere-associated repeat elements. Immunofluorescence and chromatin immunoprecipitation (ChIP) assays revealed co-localization of PfSIP2-N with PfHP1 at chromosome ends. Genome-wide ChIP demonstrated the exclusive binding of PfSIP2-N to subtelomeric SPE2 landmarks in vivo but not to single chromosome-internal sites. Consistent with this specialized distribution pattern, PfSIP2-N over-expression has no effect on global gene transcription. Hence, contrary to the previously proposed role for this factor in gene activation, our results provide strong evidence for the first time for the involvement of an ApiAP2 factor in heterochromatin formation and genome integrity. These findings are highly relevant for our understanding of chromosome end biology and variegated expression in P. falciparum and other eukaryotes, and for the future analysis of the role of ApiAP2-DNA interactions in parasite biology

Screening of global microbiomes implies ecological boundaries impacting the distribution and dissemination of clinically relevant antimicrobial resistance genes

Understanding the myriad pathways by which antimicrobial-resistance genes (ARGs) spread across biomes is necessary to counteract the global menace of antimicrobial resistance. We screened 17939 assembled metagenomic samples covering 21 biomes, differing in sequencing quality and depth, unevenly across 46 countries, 6 continents, and 14 years (2005-2019) for clinically crucial ARGs, mobile colistin resistance (mcr), carbapenem resistance (CR), and (extended-spectrum) beta-lactamase (ESBL and BL) genes. These ARGs were most frequent in human gut, oral and skin biomes, followed by anthropogenic (wastewater, bioreactor, compost, food), and natural biomes (freshwater, marine, sediment). Mcr-9 was the most prevalent mcr gene, spatially and temporally; bla(OXA-233) and bla(TEM-1) were the most prevalent CR and BL/ESBL genes, but bla(GES-2) and bla(TEM-116) showed the widest distribution. Redundancy analysis and Bayesian analysis showed ARG distribution was non-random and best-explained by potential host genera and biomes, followed by collection year, anthropogenic factors and collection countries. Preferential ARG occurrence, and potential transmission, between characteristically similar biomes indicate strong ecological boundaries. Our results provide a high-resolution global map of ARG distribution and importantly, identify checkpoint biomes wherein interventions aimed at disrupting ARGs dissemination are likely to be most effective in reducing dissemination and in the long term, the ARG global burden

Patterns of database citation in articles and patents indicate long-term scientific and industry value of biological data resources [version 1; referees: 2 approved]

Data from open access biomolecular data resources, such as the European Nucleotide Archive and the Protein Data Bank are extensively reused within life science research for comparative studies, method development and to derive new scientific insights. Indicators that estimate the extent and utility of such secondary use of research data need to reflect this complex and highly variable data usage. By linking open access scientific literature, via Europe PubMedCentral, to the metadata in biological data resources we separate data citations associated with a deposition statement from citations that capture the subsequent, long-term, reuse of data in academia and industry.  We extend this analysis to begin to investigate citations of biomolecular resources in patent documents. We find citations in more than 8,000 patents from 2014, demonstrating substantial use and an important role for data resources in defining biological concepts in granted patents to both academic and industrial innovators. Combined together our results indicate that the citation patterns in biomedical literature and patents vary, not only due to citation practice but also according to the data resource cited. The results guard against the use of simple metrics such as citation counts and show that indicators of data use must not only take into account citations within the biomedical literature but also include reuse of data in industry and other parts of society by including patents and other scientific and technical documents such as guidelines, reports and grant applications

Quantitative monitoring of nucleotide sequence data from genetic resources in context of their citation in the scientific literature

BACKGROUND: Linking nucleotide sequence data (NSD) to scientific publication citations can enhance understanding of NSD provenance, scientific use, and reuse in the community. By connecting publications with NSD records, NSD geographical provenance information, and author geographical information, it becomes possible to assess the contribution of NSD to infer trends in scientific knowledge gain at the global level. FINDINGS: We extracted and linked records from the European Nucleotide Archive to citations in open-access publications aggregated at Europe PubMed Central. A total of 8,464,292 ENA accessions with geographical provenance information were associated with publications. We conducted a data quality review to uncover potential issues in publication citation information extraction and author affiliation tagging and developed and implemented best-practice recommendations for citation extraction. We constructed flat data tables and a data warehouse with an interactive web application to enable ad hoc exploration of NSD use and summary statistics. CONCLUSIONS: The extraction and linking of NSD with associated publication citations enables transparency. The quality review contributes to enhanced text mining methods for identifier extraction and use. Furthermore, the global provision and use of NSD enable scientists worldwide to join literature and sequence databases in a multidimensional fashion. As a concrete use case, we visualized statistics of country clusters concerning NSD access in the context of discussions around digital sequence information under the United Nations Convention on Biological Diversity