RECENT FINDINGS: USING THE DIVERGENCE OF L1 INSERTS TO DETERMINE THE MUTATION RATE - The neutral DNA mutation rate (i.e., the accumulation of base substitutions in the absence of natural selection) is a fundamental biological parameter. However, it varies considerably both within and between chromosomes, which, despite considerable study by others, remains largely unexplained. We found that the tens of thousands of non-functional, neutrally evolving L1 fossils interspersed throughout the genome are ideal monitors of mutation rates especially for investigating one of the most intriguing and inexplicable covariates of the mutation rate, namely its positive correlation with CpG content. Why is this so? CpGs are hypermutable &a major source of genetic diversity and genetic defects in humans. However, even after accounting for mutations at CpG sites, the correlation between CpG content and mutation rate persists. The prevailing view was that the non-CpG mutation rate and CpG content are likely joint manifestations of the chromosomal environment. However, we considered the alternative possibility that methylated CpGs per se, or mutations thereof, could directly affect the mutation of flanking non-CpG DNA. As L1 fossils are not under selection, mutations of CpGs to TpGs/CpAs occur over time. Thus, the CpG content of younger L1 families should be higher than older ones, and if our supposition is correct so should their mutation rate, regardless of chromosomal location. And this is precisely what we found. By extending these analyses over a wide range of CpG content we find that the change of the non-CpG mutation rate with CpG content fits a sigmoidal (dose response) curve. Thus, the effect of CpG content on non-CpG divergence not only requires a certain threshold to have an observable effect but also reaches saturation. Most provocatively we found that changes in the transition/transversion ratio parallel the overall non-CpG mutation rate. Thus, a CpG content sufficient to affect non-CpG divergence also affects the mutational environment, producing transition/transversion ratios that are reminiscent of the mutator phenotype of some tumors. Although methyl-CpG per se (by recruiting various chromatin modifying proteins) could alter the mutational environment of DNA, perhaps T:G mismatches resulting from the deamination of methyl-C might recruit repair mechanisms that introduce errors in flanking non-CpG DNA. We are now testing this latter idea experimentally.
| Chen, Jia; Furano, Anthony V (2015) Breaking bad: The mutagenic effect of DNA repair. DNA Repair (Amst) 32:43-51 |
| Chen, Jia; Miller, Brendan F; Furano, Anthony V (2014) Repair of naturally occurring mismatches can induce mutations in flanking DNA. Elife 3:e02001 |
| Walser, Jean-Claude; Furano, Anthony V (2010) The mutational spectrum of non-CpG DNA varies with CpG content. Genome Res 20:875-82 |
| Walser, Jean-Claude; Ponger, Loic; Furano, Anthony V (2008) CpG dinucleotides and the mutation rate of non-CpG DNA. Genome Res 18:1403-14 |
