C>T mutation bias leading to inevitable genetic entropy now explained
Epigenetic modifications elevate the risk of cytosine-to-thymine mutations. Methylated cytosines (5mC) are prone to turn to thymines in deamination caused by i.e. oxidative stress. After my previous articles, atheists have attacked them claiming that I don't understand these mechanisms or that I'm lying. So, now it's better to explain fundamentally, why these C>T mutations happen and why they result in inevitable genetic entropy.
Most C>T mutations are associated with epigenetic modifications
Excerpt: "Links between epigenetic marks and mutation rates are best documented for DNA methylation patterns, which were first demonstrated to be mutagenic in E. coli in 1978 (Coulondre et al., 1978; Duncan & Miller, 1980). Overall at the molecular level, as the rate of deamination of 5-methylcytosine into thymine is about 3.5 times higher than that of unmethylated cytosine into uracil (Jones et al., 1992), and as mismatched uracils are excised up to 6000 times more efficiently than mismatched thymines (Schmutte et al., 1995), the mutation rate of 5-methylcytosine appears about 20000 times higher than that of unmethylated cytosines (Gorelick, 2003). As a consequence, methylated cytosines are suspected to cause 30–40% of germline point mutations in humans (Jones et al., 1992). This very large difference in genomic stability results from the cumulative effects of natural cytosine and 5-methylcytosine deamination, plus the differential efficiency of mismatch repair and maintenance methylation, plus natural tautomeric shift processes (Gorelick, 2003). It has also been suggested that this difference in mutability may result from the joint action of various types of covarying epigenetic marks or their interactions (review in Makova & Hardison, 2015)."
DNA repair enzymes will not repair methylated-cytosine-to-thymine mutations
"When cytosine is mutated to uracil by spontaneous deamination, the DNA glycosylase enzyme UDG (uracil DNA glycosylase) reverses the damage, in a base excision repair mechanism. When the equivalent deamination reaction occurs on 5-methylcytosine (5mC), however, the product, thymine, is not repaired by DNA repair enzymes."
My comment: As we see, there is no specific repair mechanism for 5mC > T mutations.
My comment: As we see, there is no specific repair mechanism for 5mC > T mutations.
Excerpt: "Deamination of unmethylated cytosine produces uracil (U), which can be removed by uracil glycosylase (Lindahl 1974; Lindahl, Karran, and Wood 1997), but 5mC deamination generates thymine (T), which cannot be processed by this enzyme. The consequence in humans is that the mutation rate from 5mC to T is 10-fold to 50-fold higher than other transitions (Duncan and Miller 1980; Bulmer 1986; Britten et al. 1988; Sved and Bird 1990). More than one-third of the germline point mutations that cause human genetic diseases (Cooper and Youssoufian 1988; Cooper and Krawczak 1993), and many of the somatic mutations leading to cancer (Jones et al. 1992; Hollstein et al. 1994) are caused by CpG hypermutability. The evolutionary consequence in humans is that the CpG dinucleotide is statistically underrepresented (Bird 1980) throughout almost the entire human genome (Lander et al. 2001). The extent of CpG underrepresentation is inversely correlated with GC content (Adams and Eason 1984; Bernardi et al. 1985; Bernardi 1995)."
5mC > T mutations can be observed as G-T mismatch pairs in the genome
G-T pair is a mismatched pair in regards to DNA grammar. When DNA replicates, the so-called DNA mismatch repair mechanism (MMR) often recognizes most of these mismatched pairs. However, a significant proportion of them are escaped from the repair mechanism:
https://news.osu.edu/study-reveals-how-the-most-common-dna-mutation-happens/
https://news.osu.edu/study-reveals-how-the-most-common-dna-mutation-happens/
The mutation’s survival is a real feat, since it has to overcome a good bit of basic physics. Bases pair in a certain way because of how the protons and electrons in their atoms are arranged. Base pairing requires some amount of energy, and the easiest, most energy-efficient pairs to form are the “right” ones—A-T and C-G.
In effect, the G-T pair has to overcome an energy barrier to form and maintain itself. It turns out that when the G and T bases change shape, they make themselves more energy efficient—still less efficient than a normal base pair, but efficient enough."
https://biobeat.nigms.nih.gov/2017/04/six-things-to-know-about-dna-and-dna-repair/
"Although scientists have not yet determined the full details of the human mismatch repair system, they estimate the process catches all but one out of every 1,000 or so mismatch errors."
https://www.sciencedirect.com/science/article/abs/pii/S1383574299000654
Excerpt: "The likely intermediate in the conversion of a 5-methylcytosine (5meC)⋅G bp to T:A is a 5meC⋅A or a T⋅G mismatch. The former mismatch could be produced through misreplication of 5meC, but there is no support for the possibility that DNA polymerases copy a cytosine incorrectly when it is methylated [15]. In contrast, a process called hydrolytic deamination is known to convert 5meC to T 16, 17 and is analogous to the deamination process that converts C to U [18]. For this reason, a T⋅G mismatch is the expected intermediate in the conversion of 5meC⋅G to T⋅A."
My comment: One out of every 1,000 G-T mismatch pairs are left without a repair. In DNA replication, these mismatched pairs are turned into A-T pairs due to energy-efficiency reasons. This is why C>T mutation bias is a biological fact. This is why GC content gradually turns into AT content. GC content is often elevated during meiotic recombination but the price will be loss of genes, loss of transcripts, loss of CpG islands, loss of mRNAs, and loss of non-coding RNAs.
