A dominant modifier of transgene methylation is mapped by QTL analysis to mouse chromosome 13

The single-copy hepatitis B virus transgene in the E36 transgenic mouse str ain undergoes methylation changes in a parent-of-origin, tissue, and strain -specific fashion. In a C57BL/6 background, the paternally transmitted tran sgene is methylated in 30% of cells, whereas it is methylated in more than 80% of cells in (BALB/c x C57BL/6) F1 mice. We established previously that several genetic factors were likely to contribute to the transgene methylat ion profile, some with demethylating and some with de novo methylating acti vities. Using quantitative trait loci (QTL) mapping, we have now localized one major modifier locus on chromosome 13 (Mod13), which explains a 30% inc rease in the methylation level of this transgene with no effect on the flan king endogenous sequences. No other QTL could be identified, except for a d emethylating activity of low significance located on chromosome 12. Recombi nant inbred mice containing a BALB/c allele of Mod13 were then used to show that the presence of Mod13 is sufficient to induce de novo methylation. A segregation between de novo methylation and repression of transgene express ion was uncovered, suggesting that this genetic system is also useful for t he identification of factors that interpret methylation patterns in the gen ome.