Browsing by Subject "Computational Biology"

Now showing 1 - 9 of 9
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    Open Access
    Conserved recombination patterns across coronavirus subgenera
    (2022) de Klerk, Arne; Martin, Darrin Patrick
    Recombination contributes to the genetic diversity found in coronaviruses and is known to be a prominent mechanism whereby they evolve. It is apparent, both from controlled experiments and in genome sequences sampled from nature, that patterns of recombination in coronaviruses are nonrandom and that this is likely attributable to a combination of sequence features that favour the occurrence of recombination breakpoints at specific genomic sites, and selection disfavouring the survival of recombinants within which favourable intra-genome interactions have been disrupted. Here we leverage available whole-genome sequence data for six coronavirus subgenera to identify specific patterns of recombination that are conserved between multiple subgenera and then identify the likely factors that underlie these conserved patterns. Specifically, we confirm the non-randomness of recombination breakpoints across all six tested coronavirus subgenera, locate conserved recombination hot- and cold-spots, and determine that the locations of transcriptional regulatory sequences are likely major determinants of conserved recombination breakpoint hot-spot locations. We find that while the locations of recombination breakpoints are not uniformly associated with degrees of nucleotide sequence conservation, they display significant tendencies in multiple coronavirus subgenera to occur in low guanine-cytosine content genome regions, in non-coding regions, at the edges of genes, and at sites within the Spike gene that are predicted to be minimally disruptive of Spike protein folding. While it is apparent that sequence features such as transcriptional regulatory sequences are likely major determinants of where the template-switching events that yield recombination breakpoints most commonly occur, it is evident that selection against misfolded recombinant proteins also strongly impacts observable recombination breakpoint distributions in coronavirus genomes sampled from nature.
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    Data integration for the analysis of uncharacterized proteins in Mycobacterium tuberculosis
    (2010) Mazandu, Gaston Kuzamunu; Mulder, Nicola
    Mycobacterium tuberculosis is a bacterial pathogen that causes tuberculosis, a leading cause of human death worldwide from infectious diseases, especially in Africa. Despite enormous advances achieved in recent years in controlling the disease, tuberculosis remains a public health challenge. The contribution of existing drugs is of immense value, but the deadly synergy of the disease with Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS) and the emergence of drug resistant strains are threatening to compromise gains in tuberculosis control. In fact, the development of active tuberculosis is the outcome of the delicate balance between bacterial virulence and host resistance, which constitute two distinct and independent components. Significant progress has been made in understanding the evolution of the bacterial pathogen and its interaction with the host. The end point of these efforts is the identification of virulence factors and drug targets within the bacterium in order to develop new drugs and vaccines for the eradication of the disease.
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    Designing a course model for distance-based online bioinformatics training in Africa: The H3ABioNet experience
    (2017) Maslamoney, Suresh; Domelevo Entfellner, Jean-Baka; Guerfali, Fatma Z; Saunders, Colleen; Mansour Alzohairy, Ahmed; Cloete, Ruben; Mulder, Nicola
    Africa is not unique in its need for basic bioinformatics training for individuals from a diverse range of academic backgrounds. However, particular logistical challenges in Africa, most notably access to bioinformatics expertise and internet stability, must be addressed in order to meet this need on the continent. H3ABioNet (www.h3abionet.org), the Pan African Bioinformatics Network for H3Africa, has therefore developed an innovative, free-of-charge “Introduction to Bioinformatics” course, taking these challenges into account as part of its educational efforts to provide on-site training and develop local expertise inside its network. A multiple-delivery–mode learning model was selected for this 3-month course in order to increase access to (mostly) African, expert bioinformatics trainers. The content of the course was developed to include a range of fundamental bioinformatics topics at the introductory level. For the first iteration of the course (2016), classrooms with a total of 364 enrolled participants were hosted at 20 institutions across 10 African countries. To ensure that classroom success did not depend on stable internet, trainers pre-recorded their lectures, and classrooms downloaded and watched these locally during biweekly contact sessions. The trainers were available via video conferencing to take questions during contact sessions, as well as via online “question and discussion” forums outside of contact session time. This learning model, developed for a resource-limited setting, could easily be adapted to other settings.
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    Genetic dating and pattern of admixture in modern human evolution
    (2017) Defo, Joel; Mulder, Nicola; Rugamika, Emile Chimusa
    Genetic variation is shaped by admixture between populations in an evolutionary process. The mixture dynamic between groups of populations results in a mosaic of chromosomal segments inherited from multiple ancestral populations. The distribution of ancestral chromosomal segments and the recombination breakpoints in an admixed genome provide information about the time of admixture. Studying populations with particular ancestries has become a major interest in population genetics because of medical and evolutionary impacts of the patterns of single nucleotide polymorphisms. It provides a better understanding of the impact of population migrations and helps us uncover interactions between several populations. Most of the research on admixed population dating has focused on a single interaction between two populations using various approaches. Some have extended this to mixing of three populations based on assumptions and approaches which differ from one tool to another. However, the inference of distinct ancestral proportions along the genome of an admixed individual and plausible dates of admixture, still remain a challenge in the case of multi-way admixed populations. This dissertation consists of three research initiatives. First, provide a succinct review of current methods for dating the admixture events. We accomplish this by providing a comprehensive review and comparison of current methods pertinent to date admixture event. Second, we assess various admixture dating tools which estimate the time of admixture between two parental populations. We do so by performing various simulations assuming a particular number of generations and use these to evaluate the tools. Third, we apply the top three assessed methods to some admixed populations from the 1000 Genomes project. Despite MALDER shows improvement and produces reasonable date estimates over other current methods, the results from both simulation and real data suggest that dating ancient admixture events accounting for the effect of other admixtures remains a challenge. Our results suggest the need for developing a new approach to date ancient and complex admixture events in multi-way admixed populations.
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    H3ABioNet, a sustainable pan-African bioinformatics network for human heredity and health in Africa
    (2016) Mulder, Nicola J; Adebiyi, Ezekiel; Alami, Raouf; Benkahla, Alia; Brandful, James; Doumbia, Seydou; Everett, Dean; Fadlelmola, Faisal M; Gaboun, Fatima; Gaseitsiwe, Simani; Ghazal, Hassan; Hazelhurst, Scott; Hide, Winston; Ibrahimi, Azeddine; Jaufeerally Fakim, Yasmina; Jongeneel, C Victor; Joubert, Fourie; Kassim, Samar; Kayondo, Jonathan; Kumuthini, Judit; Lyantagaye, Sylvester; Makani, Julie; Mansour Alzohairy, Ahmed; Masiga, Daniel; Moussa, Ahmed; Nash, Oyekanmi; Ouwe Missi Oukem-Boyer, Odile; Owusu-Dabo, Ellis; Panji, Sumir; Patterton, Hugh; Radouani, Fouzia; Sadki, Khalid
    The application of genomics technologies to medicine and biomedical research is increasing in popularity, made possible by new high-throughput genotyping and sequencing technologies and improved data analysis capabilities. Some of the greatest genetic diversity among humans, animals, plants, and microbiota occurs in Africa, yet genomic research outputs from the continent are limited. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive the development of genomic research for human health in Africa, and through recognition of the critical role of bioinformatics in this process, spurred the establishment of H3ABioNet, a pan-African bioinformatics network for H3Africa. The limitations in bioinformatics capacity on the continent have been a major contributory factor to the lack of notable outputs in high-throughput biology research. Although pockets of high-quality bioinformatics teams have existed previously, the majority of research institutions lack experienced faculty who can train and supervise bioinformatics students. H3ABioNet aims to address this dire need, specifically in the area of human genetics and genomics, but knock-on effects are ensuring this extends to other areas of bioinformatics. Here, we describe the emergence of genomics research and the development of bioinformatics in Africa through H3ABioNet.
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    Identifying recombinants in human and primate immunodeficiency virus sequence alignments using quartet scanning
    (BioMed Central Ltd, 2009) Lemey, Philippe; Lott, Martin; Martin, Darren; Moulton, Vincent
    BACKGROUND:Recombination has a profound impact on the evolution of viruses, but characterizing recombination patterns in molecular sequences remains a challenging endeavor. Despite its importance in molecular evolutionary studies, identifying the sequences that exhibit such patterns has received comparatively less attention in the recombination detection framework. Here, we extend a quartet-mapping based recombination detection method to enable identification of recombinant sequences without prior specifications of either query and reference sequences. Through simulations we evaluate different recombinant identification statistics and significance tests. We compare the quartet approach with triplet-based methods that employ additional heuristic tests to identify parental and recombinant sequences. RESULTS: Analysis of phylogenetic simulations reveal that identifying the descendents of relatively old recombination events is a challenging task for all methods available, and that quartet scanning performs relatively well compared to the triplet based methods. The use of quartet scanning is further demonstrated by analyzing both well-established and putative HIV-1 recombinant strains. In agreement with recent findings, we provide evidence that the presumed circulating recombinant CRF02_AG is a 'pure' lineage, whereas the presumed parental lineage subtype G has a recombinant origin. We also demonstrate HIV-1 intrasubtype recombination, confirm the hybrid origin of SIV in chimpanzees and further disentangle the recombinant history of SIV lineages in a primate immunodeficiency virus data set. CONCLUSION: Quartet scanning makes a valuable addition to triplet-based methods for identifying recombinant sequences without prior specifications of either query and reference sequences. The new method is available in the VisRD v.3.0 package http://www.cmp.uea.ac.uk/~vlm/visrd.
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    Mapping genes underlying ethnic differences in tuberculosis risk by linkage disequilibrium in the South African coloured population of the Western Cape
    (2013) Rugamika, Emile Chimusa; Mulder, Nicola; Price, Alkes; Van Helden, Eileen Hoal
    The South Africa Coloured population of the Western Cape is the result of unions between Europeans, Africans (Bantu and Khoisan), and various other populations (Malaysian or Indonesian descent). The world-wide burden of tuberculosis remains an enormous problem, and is particularly severe in this population. In general, admixed populations that have arisen in historical times can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Despite numerous successful genome-wide association studies, detecting variants that have low disease risk still poses a challenge. Furthermore, admixture association studies for multi-way admixed populations pose constant challenges, including the choice of an accurate ancestral panel to infer ancestry and for imputing missing genotypes to identify possible genetic variants causing susceptibility to disease. This thesis addresses some of these challenges. We first developed PROXYANC, an approach to select the best proxy ancestral populations for admixed populations. From the simulation of a multi-way admixed population, we demonstrated the ability and accuracy of PROXYANC in selecting the best proxy ancestry and illustrated the importance of the choice of ancestries in both estimating admixture proportions and imputing missing genotypes. We applied this approach to the South African Coloured population, to refine both the choice of ancestral populations and their genetic contributions. We also demonstrated that the ancestral allele frequency differences correlated with increased linkage disequilibrium in the SAC, and that the increased LD originates from admixture events rather than population bottlenecks. Secondly, we conducted a study to determine whether ancestry-specific genetic contributions affect tuberculosis risk. We additionally conducted imputation genome-wide association studies and a meta-analysis incorporating previous genome-wide association studies of tuberculosis.
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    RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response
    (2016) Bergmann, Sven
    Abstract Background The transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood. Here we present an analysis of RNAseq profiles from heart tissue of 18 inbred mouse strains treated with the β-blocker atenolol (ATE) and the β-agonist isoproterenol (ISO). Results Differential expression analyses revealed a large set of genes responding to ISO (n = 1770 at FDR = 0.0001) and a comparatively small one responding to ATE (n = 23 at FDR = 0.0001). At a less stringent definition of differential expression, the transcriptional responses to these two antagonistic drugs are reciprocal for many genes, with an overall anti-correlation of r = −0.3. This trend is also observed at the level of most individual strains even though the power to detect differential expression is significantly reduced. The inversely expressed gene sets are enriched with genes annotated for heart-related functions. Modular analysis revealed gene sets that exhibit coherent transcription profiles across some strains and/or treatments. Correlations between these modules and a broad spectrum of cardiovascular traits are stronger than expected by chance. This provides evidence for the overall importance of transcriptional regulation for these organismal responses and explicits links between co-expressed genes and the traits they are associated with. Gene set enrichment analysis of differentially expressed groups of genes pointed to pathways related to heart development and functionality. Conclusions Our study provides new insights into the transcriptional response of the heart to perturbations of the β-adrenergic system, implicating several new genes that had not been associated to this system previously.
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    The Clinical and Economic Impact of Point-of-Care CD4 Testing in Mozambique and Other Resource-Limited Settings: A Cost-Effectiveness Analysis
    (2014) Hyle, Emily P; Jani, Ilesh V; Lehe, Jonathan; Su, Amanda E; Wood, Robin; Quevedo, Jorge; Losina, Elena; Bassett, Ingrid V; Pei, Pamela P; Paltiel, A David; Resch, Stephen; Freedberg, Kenneth A; Peter, Trevor; Walensky, Rochelle P
    Point-of-care CD4 tests at HIV diagnosis could improve linkage to care in resource-limited settings. Our objective is to evaluate the clinical and economic impact of point-of-care CD4 tests compared to laboratory-based tests in Mozambique.