A systematic strategy for large-scale analysis of genotype–phenotype correlations: identification of candidate genes involved in African trypanosomiasis

Fisher, Paul; Hedeler, Cornelia; Wolstencroft, Katy; Hulme, Helen; Noyes, Harry; Kemp, Stephen J.; Stevens, Robert; Brass, Andy

doi:10.1093/nar/gkm623

Cited by 51 publications

(53 citation statements)

References 38 publications

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“…This methodology has been effective in the past and allows for the identification of genes responsible for infectious diseases or immune systemrelated phenotypes (16,27). One of the three candidate genes on Qivr2, Hc, was previously shown to be involved in both the innate and adaptive immune responses to infectious agents including low-pathogenic mouse-adapted influenza viruses (20).…”

Section: Discussionmentioning

confidence: 99%

Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

Boon

DeBeauchamp

Hollmann

et al. 2009

J Virol

157

175

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Despite the prevalence of H5N1 influenza viruses in global avian populations, comparatively few cases have been diagnosed in humans. Although viral factors almost certainly play a role in limiting human infection and disease, host genetics most likely contribute substantially. To model host factors in the context of influenza virus infection, we determined the lethal dose of a highly pathogenic H5N1 virus (A/Hong Kong/213/03) in C57BL/6J and DBA/2J mice and identified genetic elements associated with survival after infection. The lethal dose in these hosts varied by 4 logs and was associated with differences in replication kinetics and increased production of proinflammatory cytokines CCL2 and tumor necrosis factor alpha in susceptible DBA/2J mice. Gene mapping with recombinant inbred BXD strains revealed five loci or Qivr (quantitative trait loci for influenza virus resistance) located on chromosomes 2, 7, 11, 15, and 17 associated with resistance to H5N1 virus. In conjunction with gene expression profiling, we identified a number of candidate susceptibility genes. One of the validated genes, the hemolytic complement gene, affected virus titer 7 days after infection. We conclude that H5N1 influenza virus-induced pathology is affected by a complex and multigenic host component.

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Section: Discussionmentioning

confidence: 99%

Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

Boon

DeBeauchamp

Hollmann

et al. 2009

J Virol

157

175

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“…A Taverna workflow (12)(13)(14) was used to identify KEGG pathways that responded to infection and contained genes in QTL regions as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

“…To identify candidate genes in each QTL we used a Taverna workflow to obtain a list of all genes that were in the KEGG pathways that contained an excess of genes (P < 0.05) that either changed over time in response to infection or were differentially expressed between breeds. The workflow then obtained a list of all genes within the QTL region from Ensembl (Assembly Btau3) irrespective of whether they were differentially expressed (12)(13)(14). These two lists were then scanned for genes that were in a responding pathway and in a QTL region; such genes were considered as candidate QTG.…”

Section: Response Of the Transcriptomes Of N'dama And Boran To Infectmentioning

confidence: 99%

Genetic and expression analysis of cattle identifies candidate genes in pathways responding to Trypanosoma congolense infection

Noyes

Brass

Obara

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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African bovine trypanosomiasis caused by Trypanosoma sp., is a major constraint on cattle productivity in sub-Saharan Africa. Some African Bos taurus breeds are highly tolerant of infection, but the potentially more productive Bos indicus zebu breeds are much more susceptible. Zebu cattle are well adapted for plowing and haulage, and increasing their tolerance of trypanosomiasis could have a major impact on crop cultivation as well as dairy and beef production. We used three strategies to obtain short lists of candidate genes within QTL that were previously shown to regulate response to infection. We analyzed the transcriptomes of trypanotolerant N'Dama and susceptible Boran cattle after infection with Trypanosoma congolense. We sequenced EST libraries from these two breeds to identify polymorphisms that might underlie previously identified quantitative trait loci (QTL), and we assessed QTL regions and candidate loci for evidence of selective sweeps. The scan of the EST sequences identified a previously undescribed polymorphism in ARHGAP15 in the Bta2 trypanotolerance QTL. The polymorphism affects gene function in vitro and could contribute to the observed differences in expression of the MAPK pathway in vivo. The expression data showed that TLR and MAPK pathways responded to infection, and the former contained TICAM1, which is within a QTL on Bta7. Genetic analyses showed that selective sweeps had occurred at TICAM1 and ARHGAP15 loci in African taurine cattle, making them strong candidates for the genes underlying the QTL. Candidate QTL genes were identified in other QTL by their expression profile and the pathways in which they participate. nagana | positional cloning | sustainable agriculture | trypanosomosis

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“…For example, Paul Fisher and colleagues have reported on the benefits of being able to "systematically analyse any results we obtain without the need to prematurely filter the data for human convenience" [2] -which enabled them to identify a candidate gene that had previously been missed. Workflows are systematic and unbiased, and they capture data analysis methodologies explicitly.…”

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confidence: 99%

Software Design for Empowering Scientists

Roure

Goble

2009

IEEE Softw.

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Scientific research is increasingly digital. Some activities, like data analysis, search and simulation, can be accelerated by enabling scientists to write workflows and scripts that automate routine activities. These capture pieces of scientific method that can be shared with others. The Taverna Workbench, a widely deployed scientific workflow management system, together with the myExperiment social web site for the sharing of scientific experiments, have been devised according to six principles of designing software for adoption by scientists and six principles of user engagement.Science is becoming increasingly digital, and the scientist's tools are not just the experimental apparatus of the laboratory but also the software apparatus which they use to conduct their researchto analyse data, to search databases, to run simulations and to record their scientific process. New experimental methods -from DNA microarrays to sensor networks in the environment -are generating volumes of data that, without software assistance, just wouldn't get processed.Watch a researcher at work and we see lots of activity at the computer, using applications, services and data that might be local to the laboratory, the enterprise, or out on the Web. These new research tools and methods are evident across a very broad spectrum of disciplines. Some, like bioinformaticians working with protein sequences, might conduct some of their research entirely in silico. Meanwhile, chemists in the laboratory are looking up procedures, designing their experiments, conducting and recording their work, and running simulations, searches and analyses. Climate change researchers are capturing the latest data from radar images and sensor networks, and running and testing their models. Musicologists are extracting features from recorded music as part of musical analysis. Archaeologists are exploring 3D visualisations of their digs.Some of the processing is highly repetitive -repeating processes with new data, varying parameters, and making small changes to the process. It clearly helps speed things up and makes them more repeatable if some of this scientific activity at the computer can be automated. This in turn lets scientists concentrate on the science rather than the repetitive handling of data through multiple tools and applications. So, increasingly, we see these scientific activities at the computer being 'programmed'. Some disciplines have created scripting solutions, perhaps adopting their favourite scripting languages and creating libraries to handle their discipline-specific data, while others adopt workflow systems which automate the processing of data through a series of processing stages.Taverna is one of many scientific workflow management systems (see Workflow Management Systems on page 2) and supports what we might describe as 'application-level workflows', as opposed to some other systems which focus on scheduling tasks across computing resources [1]. Emerging from the UK's e-Science programme, Taverna is used extensively by scientists a...

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A systematic strategy for large-scale analysis of genotype–phenotype correlations: identification of candidate genes involved in African trypanosomiasis

Cited by 51 publications

References 38 publications

Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

Genetic and expression analysis of cattle identifies candidate genes in pathways responding to Trypanosoma congolense infection

Software Design for Empowering Scientists

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