Genetical Genomics Analysis of a Yeast Segregant Population for Transcription Network Inference

Genetic analysis of gene expression in a segregating population, which is expression profiled and genotyped at DNA markers throughout the genome, can reveal regulatory networks of polymorphic genes. We propose an analysis strategy with several steps: (1) genome-wide QTL analysis of all expression profiles to identify eQTL confidence regions, followed by fine mapping of identified eQTL; (2) identification of regulatory candidate genes in each eQTL region; (3) correlation analysis of the expression profiles of the candidates in any eQTL region with the gene affected by the eQTL to reduce the number of candidates; (4) drawing directional links from retained regulatory candidate genes to genes affected by the eQTL and joining links to form networks; and (5) statistical validation and refinement of the inferred network structure. Here, we apply an initial implementation of this strategy to a segregating yeast population. In 65, 7, and 28% of the identified eQTL regions, a single candidate regulatory gene, no gene, or more than one gene was retained in step 3, respectively. Overall, 768 putative regulatory links were retained, 331 of which are the strongest candidate links, as they were retained in the expression correlation analysis and were located within or near an eQTL subregion identified by a multimarker analysis separating multiple linked QTL. One or several biological processes were statistically significantly overrepresented in independent network structures or in highly interconnected subnetworks. Most of the transcription factors found in the inferred network had a putative regulatory link to only one other gene or exhibited cis-regulation.