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Wednesday, April 11, 2012

Genetic dissection of a model complex trait using the Drosophila Synthetic Population Resource

Genetic dissection of complex, polygenic trait variation is a key goal of medical and evolutionary genetics. Attempts to identify genetic variants underlying complex traits have been plagued by low mapping resolution in traditional linkage studies, and an inability to identify variants that cumulatively explain the bulk of standing genetic
variation in genome-wide association studies (GWAS). Thus, much of the heritability remains unexplained for most complex traits.

Here we describe a novel, freely-available
resource for the Drosophila community consisting of two sets of recombinant inbred lines (RILs), each derived from an advanced generation cross between a different set of eight highly-inbred, completely resequenced founders.

The Drosophila Synthetic
Population Resource (DSPR) has been designed to combine the high mapping resolution offered by multiple generations of recombination, with the high statistical power afforded by a linkage-based design.

Here, we detail the properties of the
mapping panel of >1,600 genotyped RILs, and provide an empirical demonstration of the utility of the approach by genetically dissecting alcohol dehydrogenase (ADH) enzyme activity.

We confirm that a large fraction of the variation in this classic
quantitative trait is due to allelic variation at the Adh locus, and additionally identify
several previously unknown modest-effect trans-acting QTL (quantitative trait loci). Using a unique property of multiparental linkage mapping designs, for each QTL we highlight a relatively small set of candidate causative variants for follow-up work.

DSPR represents an important step toward the ultimate goal of a complete understanding of the genetics of complex traits in the Drosophila model system.

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