Proteins containing regions of amino acid bias are often found in eukaryotes and are associated with particular functional groups. We have carried out a genomic analysis of yeast proteins containing regions with a significant bias of Ser and Thr residues. Our findings reveal that a high number are cell surface proteins or regulatory proteins involved in many aspects of cell differentiation. Furthermore, in Saccharomyces-related species, a highly significant correlation exists between the frequency of Ser-rich regions and DNA repeats, indicating that their generation may rely on similar factors. Cluster analysis shows that Ser/Thr-rich regions, located within the tandem repeats of cell surface proteins, are encoded to an increased frequency by UCU (Ser) and ACU/ACC (Thr), implying that mutational events that generate iterations could involve these codons. Replication slippage is proposed to be a contributing factor, as mounting evidence suggests that repeat generation in cell surface proteins can occur independently of meiosis. To reinforce this argument, we have discovered a premeiotic association between Mre11p, a nuclease involved in DNA repair, and ORFs encoding Ser/Thr-rich regions. Several macromolecules involved in the glycosylation and phosphorylation of proteins require Ser and Thr residues as binding sites. Ser/Thr-rich regions, through polymorphisms, are associated with the evolution of functional sites, particularly in providing motifs for glycosylation and phosphorylation. These results point to a Ser/Thr-biased somatic mutation mechanism that contributes to rapid evolution in yeast.