Coding Constraints Modulate Chemically Spontaneous Mutational Replication Gradients in Mitochondrial Genomes

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.

Evolution of Nucleotide Punctuation Marks: From Structural to Linear Signals

“…In some cases, translational termination combines secondary and primary structures, as shown in Figure 1B for polymerization signals. This principle is in line with an otherwise unexplained observation of the architecture of the genetic code: codon assignments maximize potential for hairpin formation (Itzkovitz and Alon, 2007), and in parallel maximize numbers of off frame stops, which prevent translation after ribosomal frameshifts (Seligmann and Pollock, 2004; Seligmann, 2007, 2010b, 2012a; Tse et al, 2010; Krizek and Krizek, 2012). This link between translation termination and hairpin formation might reflect that current termination codons replaced hairpins.…”

A binary representation of the genetic code

“…The system presented here accords with the theory that the genetic code has been shaped by natural selection [12] [13] [14], and that its evolution [15] [16] alongside the DNA mutation repair system [17] [18] and tRNA translation mechanism [19] has produced a table with the adaptive benefit [20] [21] that single-nucleotide mutations [22] most likely to cause a loss of protein function are also the most likely to be avoided [23] or fixed. Frameshifted "hidden" stop codons [24] can also quickly terminate protein synthesis upon ribosomal slippage. The protein translation machinery provides further robustness to error, in that non-cognate amino acids most likely to be misloaded by a tRNA molecule tend to have codons with the largest probability of being mismatched by the anticodon in the first place.…”

The most primitive extant ancestor of organisms and discovery of definitive evolutionary equations

“…In particular, replication of the lagging strand increases the probability of mutations as a result of the deamination of cytosine, and the inversion of nucleotide content differences reflects biological divergence. Similar phenomena are observed in mitochondria, which consist of heavy (H) and light (L) chains [30-32]. Plotting the GC skew vs. G content was used to classify animal mitochondria into two groups: high and low C/G 11 .…”