Cosuppression, high gene copy number-triggered homology-dependent gene silencing, may have evolved in eukaryotes to control molecular parasites such as viruses and transposons. Tyl retrotransposons are dispersed gene repeats with a copy number around 30 per haploid in tab strains. Tyl elements are seemingly expressed in an undeterred fashion to a level as high as 10% of total mRNA. We discovered that genes with homology to Tyl retrotransposons are either all expressed or all shut off, without uncoordinated expression in any individual yeast cell. The requirement of a high Tyl copy number for the off-regulation of Tyl-related genes establishes the phenomenon as cosuppression and argues for a Tyl-related epigenetic factor being the underlying cause. The idea of inter-regulation of gene expression among Tyl-related genes is further supported by our recent observation of Tyl anti-cosuppression in which a Tyl insertion allele shows a dominant negative effect on Tyl cosuppression. Tyl cosuppression is transcriptional, as Tyl transcriptional repressors facilitate the onset of Tyl cosuppression and the native Tyl promoter is critical to Tyl cosuppression. Comparative studies indicate that the mechanism for transcriptional cosuppression may be conserved, and Tyl cosuppression could be a good model for transcriptional cosuppression. Our long-term goal is to elucidate the mechanism of Tyl cosuppression. We plan to use the methods of molecular genetics and genomics to answer the following questions. What is the molecule that initiates Tyl cosuppression? ls it a Tyl-specific RNA duplex as in other known forms of cosuppression? Can other yeast genes be transcriptionally cosuppressed? What yeast genes are required for Tyl cosuppression? Which molecular pathways or processes are involved in Tyl cosuppression? How are Tyl-related genes targeted by cosuppression?