About Jeff Buzby Expertise I am a Research Scientist in Molecular Immunology with a PhD in Biochemistry, and have studied gene expression in cyanobacteria, plants, and humans. I also work as a Biotechnology consultant.
Molecular Biology - cytosine - the most mutable base in the human genome
Expert: Jeff Buzby - 6/20/2003
Question Good day
Jeff
I recently read a paper where the authors found a high frequency of C to T transitions in an exon;
their explanation was that C residues are the most mutable base in the human genome in the context of CpG dinucleotides.
How often are C residues methylated when they occur in exons and outside of CpG islands? Can you find CpG islands inside exons when they occur at the end of a gene? (in this case the gene was 25 kb, consisting of 12 exons; the mutation occured in exon 11).
I suppose even if the chance of a C being methylated were quite small as long as it were more than 1% it would still make Cs more mutable than any other base. So if the chance of any C being methylated was more than 1% it would make C-T transitions more likely than A - G, G - A, and T - C transitions. Methylation aside, are the four possible kinds of transitions all of equal likelihood? And are pyrimidine transitions more common than purine transitions? Are the other bases also amenable to methylation? and if so. What happens to them -if anything- when they deaminate?
I know this is quite a long, multicomponent question, so please take your time if you need it.
Much obliged
Philip Haycock
Answer
Dear Philip:
As described in the section on DNA Methylation from the online textbook, The Cell: A Molecular Approach, vertebrate "DNA is methylated specifically at the C's that precede G's in the DNA chain (CpG dinucleotides)" ( http://www.ncbi.nlm.nih.gov/books/bv.fcgi?tool=bookshelf&call=bv.View..ShowSecti... ). The section on Spontaneous Mutations from the online textbook, An Introduction to Genetic Analysis, provides more details about how the deamination of the resulting 5-methylcytosines ultimately generates an "underrepresentation of CpG dinucleotides in higher cells, because this sequence is methylated to give 5-methyl-CpG, which is gradually converted into TpG" ( http://www.ncbi.nlm.nih.gov/books/bv.fcgi?tool=bookshelf&call=bv.View..ShowSecti... ).
The section on DNA Repair from the online textbook, Molecular Biology of the Cell, provides some more info. on the relative mutability of cytosine. It would appear to be the most common base transition mechanism, since "about 5000 purine bases (adenine and guanine) are lost per day from the DNA of each human cell because of the thermal disruption of their N-glycosyl linkages to deoxyribose (depurination)...[, whereas]...spontaneous deamination of cytosine to uracil in DNA is estimated to occur at a rate of 100 bases per genome per day" ( http://www.ncbi.nlm.nih.gov/books/bv.fcgi?tool=bookshelf&call=bv.View..ShowSecti... ). Obviously these values do not represent the actual mutation rates, which are reduced by accurate DNA repair processes, but the likelyhood of C-T transitions is certainly increased by the tendency for cytosine deamination. In comparison to the other transitions, I ran across an interesting observation that a C-T transition is actually accompanied by a G-A transition on the opposite strand, so both of these transitions together probably share the title of "most likely to occur" due to cytosine deamination.
All of the above online textbooks are freely available courtesy of the NCBI Bookshelf program, sponsored by the Nat'l. Institutes of Health:
If you are interested in some more thought-provoking commentary on the potential evolutionary consequences of cytosine deamination, I ran across a series of non-technical essays that the author considers to represent the topic of "Biotic Reality" ( http://www.idthink.net/biot/index.html ) from his website entitled, "TeleoLogic" ( http://www.idthink.net/ ). The credentials of the author, Mike Gene, are not evident, but he does present several interesting arguments, along with some published scientific support, regarding potential evolutionary advantages for cytosine mutability in a series of essays entitled, "Designing Evolution Through Deamination":
Sorry to keep you waiting so long for your answers, but I hope that these resources help you to gain some more insight into this most interesting topic. Thanks for the great questions,
Jeff Buzby, Ph.D.
CHOC Research Institute
AllExperts Molecular Biology
