Question

Spontaneous mutational "hotspots" occur at CG sequences in mammals where the C is methylated. The best explanation for the high number of mutations occurring at these sites is that:

A. The methylated cytosine deaminates to thymine.
B. These CG sequences are prone to undergo unequal crossing over.
C. Deletions occur at a high frequency at these sites.
D. The methylated cytosine mispairs with thymine often.
E. None of the above explanations is correct.

Answer 1

The most plausible explanation for the high mutation rate at methylated CG sequences is that the methylated cytosine deaminates to thymine, causing a C-G to T-A transition mutation. This happens because of the increased likelihood of cytosine deamination when methylated, and the cellular DNA repair mechanisms occasionally recognizing the resultant uracil as thymine.

Step-by-step explanation:

Spontaneous mutational "hotspots" occur at CG sequences in mammals where the C is methylated. The best explanation for the high number of mutations occurring at these sites is that the methylated cytosine deaminates to thymine. Methylation of cytosine can indeed lead to a higher mutational rate due to spontaneous deamination, a process where the amino group of cytosine is replaced with a keto group, transforming the cytosine into uracil. Since uracil closely resembles thymine, the cell's DNA repair mechanisms might mistakenly repair the uracil as if it was thymine, leading to a C-G to T-A transition mutation upon DNA replication.

DNA methyltransferases, which add methyl groups to cytosine, are often associated with these mutation hotspots because the methylated cytosine is more prone to undergo spontaneous deamination than unmethylated cytosine. The DNA repair mechanisms sometimes fail to correct this error, leading to a permanent mutation when the DNA is replicated, as the uracil is read as thymine, which pairs with adenine instead of guanine.