Genome-scale metabolic modelling identifies reactions mediated by SNP-SNP interactions associated with yeast sporulation

Genome-scale metabolic models (GEMs) are powerful tools used to understand the functional effects of genetic variants. However, the impact of single nucleotide polymorphisms (SNPs) in transcription factors and their interactions on metabolic fluxes remains largely unexplored. Using gene expression data from a yeast allele replacement panel grown during sporulation, we constructed co-expression networks and SNP-specific GEMs. Analysis of co-expression networks revealed that during sporulation, SNP-SNP interactions impact the connectivity of metabolic regulators involved in glycolysis, steroid and histidine biosynthesis, and amino acid metabolism. Further, genome-scale differential flux analysis identified reactions within six major metabolic pathways associated with sporulation efficiency variation. Notably, autophagy was predicted to act as a pentose pathway-dependent compensatory mechanism supplying critical precursors like nucleotides and amino acids, enhancing sporulation. Our study highlights how transcription factor polymorphisms interact to shape metabolic pathways in yeast, offering insights into genetic variants associated with metabolic traits in genome-wide association studies.