Abstract
Distances from heavy and light strand replication origins determine duration mitochondrial DNA remains singlestranded during replication. Hydrolytic deaminations from A->G and C->T occur more on single- than doublestranded DNA. Corresponding replicational nucleotide gradients exist across mitochondrial genomes, most at 3rd, least 2nd codon positions. DNA singlestrandedness during RNA transcription causes gradients mainly in long-lived species with relatively slow metabolism (high transcription/replication ratios). Third codon nucleotide contents, evolutionary results of mutation cumulation, follow replicational, not transcriptional gradients in Homo; observed human mutations follow transcriptional gradients. Synonymous third codon position transitions potentially alter adaptive off frame information. No mutational gradients occur at synonymous positions forming off frame stops (these adaptively stop early accidental frameshifted protein synthesis), nor in regions coding for putative overlapping genes according to an overlapping genetic code reassigning stop codons to amino acids. Deviation of 3rd codon nucleotide contents from deamination gradients increases with coding importance of main frame 3rd codon positions in overlapping genes (greatest if these are 2nd position in overlapping genes). Third codon position deamination gradients calculated separately for each codon family are strongest where synonymous transitions are rarely pathogenic; weakest where transitions are frequently pathogenic. Synonymous mutations affect translational accuracy, such as error compensation of misloaded tRNAs by codon-anticodon mismatches (prevents amino acid misinsertion despite tRNA misacylation), a potential cause of pathogenic mutations at synonymous codon positions. Indeed, codon-family-specific gradients are inversely proportional to error compensation associated with gradient-promoted transitions. Deamination gradients reflect spontaneous chemical reactions in singlestranded DNA, but functional coding constraints modulate gradients.
Highlights
The study of replicational gradients, gradual changes in frequencies of specific types of mutational substitutions and the resulting nucleotide contents along genomes [1,2], presents the advantage that evidence originating from bioinformatic comparative genome analyses can be considered as compelling for a mutational gradient and existence of the associated replication origin [3,4,5,6,7,8]
The study of mutational gradients in mitochondria contributed to the controversy that several heavy strand DNA regions function as light strand replication origins, the recognized ORIl: strengths of gradients starting in the vicinity of tRNA genes are proportional to capacities of the corresponding heavy strand tDNA to form ORIl-like secondary structures [21] and with hs sequences corresponding to the tRNA’s anticodon loop resembling the loop of the regular ORIl in that species [25]
Analyses of human polymorphisms in tRNA genes show that in tRNAs that are not predicted to function as ORIl in the regular physiology, pathogenic mutations tend to increase formation of ORIl-like secondary structures by the hs tDNA, as compared to nonpathogenic polymorphisms: pathogenicity in this case is promoted by increased abnormal ORIl activity, presumably causing deamination gradients such as to promote mutations in genes maladapted to be at the higher end of the deamination gradient
Summary
The study of replicational gradients, gradual changes in frequencies of specific types of mutational substitutions and the resulting nucleotide contents along genomes [1,2], presents the advantage that evidence originating from bioinformatic comparative genome analyses can be considered as compelling for a mutational gradient and existence of the associated replication origin [3,4,5,6,7,8]. Patterns of associations between pathogenicity and hs tDNA: ls tRNA hybridization stabilities follow these predictions [26] These analyses indicate that tRNA genes function as ORIl, and contribute to the controversy that multiple light strand replication origins may function in mitochondria [28,29,30], but the issue is still far from solved and probably more complex than believed, with a number of types of replication processes occurring each at different instances [31, 32]. ORIl function of hs tDNA distant from the regular ORIl increases the similarity between the replicational and the transcriptional gradient in vertebrate mitochondria This convergence decreases numbers of genes undergoing high mutational rates according to at least one of these two gradients [18]. Gradients result from spontaneous chemical processes, and are strong enough to affect coding properties of genes, as shown by different base and codon usages of genes on leading and lagging strands, which are affected by different mutational pressures due to the deamination gradients [34-
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