STRAND BIAS IN MUTATION INVOLVING 5-METHYLCYTOSINE DEAMINATION IN THE HUMAN HPRT GENE

Despite being generally under-represented in the genome, CpG sequences represent a disproportionately high fraction of sites involved in mutational events leading to human genetic disease. Cytosine within CpG dinucleotides is often modified to 5-methylcytosine. Deamination of 5-methylcytosine in situ yields a thymine, which being mispaired with guanine, is potentially mutagenic. Previous reports have indicated that most mutations recovered at these sites appear to originate on the non-transcribed strand as C - T transitions. This trend may however, reflect the lack of detectable mutant phenotypes resulting from this transition at the complementary positions on the transcribed strand. To date, there has not been a good model system in which mutations can be recovered on both strands at the same CpG site. The human hprt gene has MeCpG sites contained within arginine codons for which mutations have been recovered on both strands. From an analysis of a database of hprt mutations, a statistically significant strand bias is observed in mutations recovered at CpG sites. We describe some models for the bias of mutation distribution observed at MeCpG sites in light of this and previous work are described.