Vaihtuvat epigeneettiset informaatioprofiilit johtavat virheisiin DNA:ssa

Olen jo usean vuoden ajan tiennyt, että evoluutiolle ei ole mekanismia. Rappeutumisen mekanismit ovat sen sijaan varsin hyvin tutkijoiden tiedossa. Vaihtuvat ja muutoksia kokevat epigeneetiset tekijät, erityisesti vaihtuvat metylaatioprofiilit aiheuttavat geneettisiä virheitä. Näitä olen tutkinut viime vuosina ja kokoamani lista on vakuuttava.

https://www.nature.com/articles/modpathol2009130
"Loss of expression of the O6-methylguanine DNA methyltransferase (MGMT) protein is a frequent occurrence in many types of cancer, including 30–46% of sporadic colorectal cancers.9, 10, 11, 12, 13 This is almost invariably associated with methylation of the MGMT promoter.9 MGMT is a ubiquitously expressed DNA repair protein that protects against mutagenesis by repairing mutagenic O6-methylguanines within DNA. By direct cleavage of the methyl adducts, the enzyme can restore the affected guanine nucleotides to normal.14 If this fails to occur, O6-methylguanines can pair erroneously with thymine during DNA replication, resulting in G:C>A:T transitions in the DNA, which can be important in neoplastic transformation."
"Recently, MGMT methylation was found to be closely associated with the C>T SNP (rs16906252) within the first exon of MGMT in colorectal cancer."

https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004585
"Surprisingly, hydroxymethylated sites are consistently associated with elevated C to G transversion rates at the level of segregating polymorphisms, fixed substitutions, and somatic mutations in tumors."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578878/
"DNA hypomethylation promotes genomic instability 4, in many cases leading to an increased mutational load and activation of proto-oncogenes."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930698/
"DNA methylation has been linked to mismatch repair (MMR) deficiency and genomic instability in multiple contexts, in both cell lines and in disease. In the HCT116 colorectal cancer cell line, ablation of catalytically active DNMT1 causes cell cycle arrest and apoptosis due to increased chromosomal instability. In mouse ES cells, loss of Dnmt1 also causes global hypomethylation and increased mutation rates."

https://www.ncbi.nlm.nih.gov/pubmed/20846930
"If we assume that CpHpG methylation also occurs in the germline, and that 5mC deamination can occur within a CpHpG context, then we might surmise that methylated CpHpG sites could also constitute mutation hotspots causing human genetic disease. To test this postulate, 54,625 missense and nonsense mutations from 2,113 genes causing inherited disease were retrieved from the Human Gene Mutation Database (http://www.hgmd.org). Some 18.2 per cent of these pathological lesions were found to be C > T and G > A transitions located in CpG dinucleotides (compatible with a model of methylation-mediated deamination of 5mC), an approximately ten-fold higher proportion than would have been expected by chance alone."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC33658/
"Altered DNA methylation and genome instability: A new pathway to cancer"

http://www.biochemist.org/bio/03905/0012/039050012.pdf
"This increased genome instability is characterized by increased occurrences of mutations, cells with incorrect chromosome number, loss of heterochromatin and mistakes in transcription."

https://www.intechopen.com/online-first/a-hypothesis-to-explain-how-the-dna-of-elderly-people-is-prone-to-damage-genome-wide-hypomethylation
"A reduction in DNA methylation leads to genomic instability, accumulation of endogenous DNA damage, and sensitivity to DNA-damaging agents."

https://jcs.biologists.org/content/112/24/4513
"CpG methylation reduces genomic instability."

https://pdfs.semanticscholar.org/d685/909cc287511ce7ab88368a72de1f09e988b8.pdf
"As well, DNA methylation is thought to be a major contributor of point mutations leading to human genetic disease, when it precedes deamination of 5-methylcytosine (m5C) present within CpG dinucleotides. CpG dinucleotides are hypothesized to be a hotspot for mutations in a variety of genes, where a substantial proportion of intragenic single base-pair mutations (35%) occur in CpG dinucleotides and are the result of C>T or G>A transitions. Consequently, the rate of transitions at CpGs is suggested to be 20-fold higher than transitions at non-CpG sites."

https://www.atdbio.com/content/56/Epigenetics#Role-of-base-flipping-in-DNA-methylation
"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, however, the product, thymine, is not repaired by DNA repair enzymes."

https://jb.asm.org/content/200/24/e00371-18
"I show that sites methylated by the Dcm enzyme exhibit an 8-fold increase in mutation rate in natural bacterial populations. I also show that modifications at other sites in various b