Identification of bacterial pathogenic gene classes subject to diversifying selection

Philosophiae Doctor - PhD (Biotechnology)Availability of genome sequences for numerous bacterial species comprising of different bacterial strains allows elucidation of species and strain specific adaptations that facilitate their survival in widely fluctuating micro-environments and enhance their pathogenic potential. Different bacterial species use different strategies in their pathogenesis and the pathogenic potential of a bacterial species is dependent on its genomic complement of virulence factors. A bacterial virulence factor, within the context of this study, is defined as any endogenous protein product encoded by a gene that aids in the adhesion, invasion, colonization, persistence and pathogenesis of a bacterium within a host. Anecdotal evidence suggests that bacterial virulence genes are undergoing diversifying evolution to counteract the rapid adaptability of its host’s immune defences. Genome sequences of pathogenic bacterial species and strains provide unique opportunities to study the action of diversifying selection operating on different classes of bacterial genes.South Afric

Taste and odorant receptors of the coelecanth- a gene repertoire in transition

G-protein coupled chemosensory receptors (GPCR-CRs) aid in the perception of odors and tastes in vertebrates. So far, six GPCR-CR families have been identified that are conserved in most vertebrate species. Phylogenetic analyses indicate differing evolutionary dynamics between teleost fish and tetrapods. The coelacanth Latimeria chalumnae belongs to the lobe-finned fishes, which represent a phylogenetic link between these two groups. We searched the genome of L. chalumnae for GPCR-CRs and found that coelacanth taste receptors are more similar to those in tetrapods than in teleost fish: two coelacanth T1R2s co-segregate with the tetrapod T1R2s that recognize sweet substances, and our phylogenetic analyses indicate that the teleost T1R2s are closer related to T1R1s (umami taste receptors) than to tetrapod T1R2s. Furthermore, coelacanths are the first fish with a large repertoire of bitter taste receptors (58 T2Rs). Considering current knowledge on feeding habits of coelacanths the question arises if perception of bitter taste is the only function of these receptors. Similar to teleost fish, coelacanths have a variety of olfactory receptors (ORs) necessary for perception of water-soluble substances. However, they also have seven genes in the two tetrapod OR subfamilies predicted to recognize airborne molecules. The two coelacanth vomeronasal receptor families are larger than those in teleost fish, and similar to tetrapods, form V1R and V2R monophyletic clades. This may point to an advanced development of the vomeronasal organ as reported for lungfish. Our results show that the intermediate position of Latimeria in the phylogeny is reflected in its GPCR-CR repertoire.The South African Research Chairs Initiative of the Department of Science and Technology and the National Research Foundation: Grant 64751.Web of Scienc

The African Coelecanth genome provides insights into tetrapod evolution

The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.Web of Scienc

Building Infrastructure for African Human Genomic Data Management

Human genomic data are large and complex, and require adequate infrastructure for secure storage and transfer. The NIH and The Wellcome Trust have funded multiple projects on genomic research, including the Human Heredity and Health in Africa (H3Africa) initiative, and data are required to be deposited into the public domain. The European Genome-phenome Archive (EGA) is a repository for sequence and genotype data where the data access is controlled by access committees. Access is determined by a formal application procedure for the purpose of secure storage and distribution, and must be in line with the informed consent of the study participants. H3Africa researchers based in Africa and generating their own data can benefit tremendously from the data sharing capabilities of the internet by using the appropriate technologies. The H3Africa Data Archive is an effort between the H3Africa data generating projects, H3ABioNet and the EGA to store and submit genomic data to public repositories. H3ABioNet maintains the security of the H3Africa Data Archive, ensures ethical security compliance, supports users with data submission and facilitates the data transfer. The goal is to ensure efficient data flow between researchers, the archive and the EGA or other public repositories. To comply with the H3Africa data sharing and release policy, nine months after the data is in secure storage, H3ABioNet converts the data into an XML format ready for submission to EGA. This article describes the infrastructure that has been developed for African human genomic data management

Hackathons as a means of accelerating scientific discoveries and knowledge transfer

Scientific research plays a key role in the advancement of human knowledge and pursuit of solutions to important societal challenges. Typically, research occurs within specific institutions where data are generated and subsequently analyzed. Although collaborative science bringing together multiple institutions is now common, in such collaborations the analytical processing of the data is often performed by individual researchers within the team, with only limited internal oversight and critical analysis of the workflow prior to publication. Here, we show how hackathons can be a means of enhancing collaborative science by enabling peer review before results of analyses are published by cross-validating the design of studies or underlying data sets and by driving reproducibility of scientific analyses. Traditionally, in data analysis processes, data generators and bioinformaticians are divided and do not collaborate on analyzing the data. Hackathons are a good strategy to build bridges over the traditional divide and are potentially a great agile extension to the more structured collaborations between multiple investigators and institutions.SCOPU

Rapid evolution of cancer/testis genes on the X chromosome

BACKGROUND: Cancer/testis (CT) genes are normally expressed only in germ cells, but can be activated in the cancer state. This unusual property, together with the finding that many CT proteins elicit an antigenic response in cancer patients, has established a role for this class of genes as targets in immunotherapy regimes. Many families of CT genes have been identified in the human genome, but their biological function for the most part remains unclear. While it has been shown that some CT genes are under diversifying selection, this question has not been addressed before for the class as a whole. RESULTS: To shed more light on this interesting group of genes, we exploited the generation of a draft chimpanzee (Pan troglodytes) genomic sequence to examine CT genes in an organism that is closely related to human, and generated a high-quality, manually curated set of human:chimpanzee CT gene alignments. We find that the chimpanzee genome contains homologues to most of the human CT families, and that the genes are located on the same chromosome and at a similar copy number to those in human. Comparison of putative human:chimpanzee orthologues indicates that CT genes located on chromosome X are diverging faster and are undergoing stronger diversifying selection than those on the autosomes or than a set of control genes on either chromosome X or autosomes. CONCLUSION: Given their high level of diversifying selection, we suggest that CT genes are primarily responsible for the observed rapid evolution of protein-coding genes on the X chromosome

Hackathons as a means of accelerating scientific discoveries and knowledge transfer

International audienceScientific research plays a key role in the advancement of human knowledge and pursuit of solutions to important societal challenges. Typically, research occurs within specific institutions where data are generated and subsequently analyzed. Although collaborative science bringing together multiple institutions is now common, in such collaborations the analytical processing of the data is often performed by individual researchers within the team, with only limited internal oversight and critical analysis of the workflow prior to publication. Here, we show how hackathons can be a means of enhancing collab-orative science by enabling peer review before results of analyses are published by cross-validating the design of studies or underlying data sets and by driving reproducibility of scientific analyses. Traditionally, in data analysis processes, data generators and bioinformaticians are divided and do not collaborate on analyzing the data. Hackathons are a good strategy to build bridges over the traditional divide and are potentially a great agile extension to the more structured collaborations between multiple investigators and institutions

Polygenic risk scores for disease risk prediction in Africa

Early identification of genetic risk factors for complex diseases can enable timely interventions and prevent serious outcomes, including mortality. While the genetics underlying many Mendelian diseases have been elucidated, it is harder to predict risk for complex diseases arising from the combined effects of many genetic variants with smaller individual effects on disease aetiology. Polygenic risk scores (PRS), which combine multiple contributing variants to predict disease risk, have the potential to influence the implementation for precision medicine. However, the majority of existing PRS were developed from European data with limited transferability to African populations. Notably, African populations have diverse genetic backgrounds, and a genomic architecture with smaller haplotype blocks compared to European genomes. Subsequently, growing evidence shows that using large-scale African ancestry cohorts as discovery for PRS development may generate more generalizable findings. Here, we (1) discuss the factors contributing to the poor transferability of PRS in African populations, (2) showcase the novel Africa genomic datasets for PRS development, (3) explore the potential clinical utility of PRS in African populations, and (4) provide insight into the future of PRS in Africa

The H3ABioNet helpdesk: an online bioinformatics resource, enhancing Africa’s capacity for genomics research

Abstract Background Currently, formal mechanisms for bioinformatics support are limited. The H3Africa Bioinformatics Network has implemented a public and freely available Helpdesk (HD), which provides generic bioinformatics support to researchers through an online ticketing platform. The following article reports on the H3ABioNet HD (H3A-HD)‘s development, outlining its design, management, usage and evaluation framework, as well as the lessons learned through implementation. Results The H3A-HD evaluated using automatically generated usage logs, user feedback and qualitative ticket evaluation. Evaluation revealed that communication methods, ticketing strategies and the technical platforms used are some of the primary factors which may influence the effectivity of HD. Conclusion To continuously improve the H3A-HD services, the resource should be regularly monitored and evaluated. The H3A-HD design, implementation and evaluation framework could be easily adapted for use by interested stakeholders within the Bioinformatics community and beyond

Using a multiple-delivery-mode training approach to develop local capacity and infrastructure for advanced bioinformatics in Africa

With more microbiome studies being conducted by African-based research groups, there is an increasing demand for knowledge and skills in the design and analysis of microbiome studies and data. However, high-quality bioinformatics courses are often impeded by differences in computational environments, complicated software stacks, numerous dependencies, and versions of bioinformatics tools along with a lack of local computational infrastructure and expertise. To address this, H3ABioNet developed a 16S rRNA Microbiome Intermediate Bioinformatics Training course, extending its remote classroom model. The course was developed alongside experienced microbiome researchers, bioinformaticians, and systems administrators, who identified key topics to address. Development of containerised workflows has previously been undertaken by H3ABioNet, and Singularity containers were used here to enable the deployment of a standard replicable software stack across different hosting sites. The pilot ran successfully in 2019 across 23 sites registered in 11 African countries, with more than 200 participants formally enrolled and 106 volunteer staff for onsite support