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

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Abstract

It is increasingly common to combine Microarray and Quantitative Trait Loci data to aid the search for candidate genes responsible for phenotypic variation. Workflows provide a means of systematically processing these large datasets and also represent a framework for the re-use and the explicit declaration of experimental methods. In this article, we highlight the issues facing the manual analysis of microarray and QTL data for the discovery of candidate genes underlying complex phenotypes. We show how automated approaches provide a systematic means to investigate genotype-phenotype correlations. This methodology was applied to a use case of resistance to African trypanosomiasis in the mouse. Pathways represented in the results identified Daxx as one of the candidate genes within the Tir1 QTL region. Subsequent re-sequencing in Daxx identified a deletion of an amino acid, identified in susceptible mouse strains, in the Daxx-p53 protein-binding region. This supports recent experimental evidence that apoptosis could be playing a role in the trypanosomiasis resistance phenotype. Workflows developed in this investigation, including a guide to loading and executing them with example data, are available at http://workflows. mygrid.org.uk/repository/myGrid/PaulFisher/.

Keyword(s)

APOPTOSIS; CELLS; COMPLEX TRAITS; CONGOLENSE; FUNCTIONAL GENOMICS; INFORMATION; MICE; QUANTITATIVE TRAIT LOCI; RESISTANCE; TRYPANOTOLERANCE

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