Evaluation of genome designs for oxidation resistance: guanine minimization and scavenger guanine
Friedman, Keith Albert
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The genome's environment contains strong oxidizers, some of which selectively attack guanine, the most readily oxidized nucleotide. The ranking of guanine oxidation rates is central G in GGG (GGG) ≥ 5' G in GG (GG) > isolated or 3' G. Vulnerability to selective oxidants puts mutation pressure on guanine. This is apparent in the differences between observed levels of GGG and levels predicted by probability from total G. GGG is below probability predictions in the genomes of D. melanogaster, C. elegans, A. thaliana, S. cerevisiae and S. pombe. GGG is statistically under-represented in H. sapiens exons, but over-represented in H. sapiens introns and intergenic domains. It is not under-represented in E. cuniculi. It is over-represented P. falciparum chromosomes 2 and 3, but this organism's total G levels are extremely low. GG generally is not underrepresented in these genomes. Beyond enzymatic elimination of the oxidizing agents and their precursors, and excision and repair of oxidative lesions, we propose that genomes are built to mitigate damage to essential domains. Resistance to oxidation could be enhanced by making genomes more “noble” by reducing the fractions of total G, GG and particularly GGG. Alternately, if the duplex conducts electron vacancies (holes) over ∼100 bp, oxidation could be shifted from essential domains to sacrificially oxidizable GGG and GG in nonessential domains. The distribution of GGG and GG in exons, introns and intergenic domains of eight model genomes suggests ennoblement in six, protection by sacrificial anodes in one, and no guanine-based protection in one (E. cuniculi). GGG triads are excluded or are statistically underrepresented in exons and short splicing-controlling introns of D. melanogaster, C. elegans, A. thaliana, S. cerevisiae, S. pombe and P. falciparum chromosomes 2 and 3. The introns of H. sapiens, which are about twenty times longer than those of the other organisms, are rich in sacrificially oxidizable GGG triads that are 50-100 bp from the exons. Their frequency correlates with the presence of protection-requiring GGG triads in the exons.