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Coding Constraints Modulate Chemically Spontaneous Mutational Replication Gradients in Mitochondrial Genomes

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Coding Constraints Modulate Chemically Spontaneous Mutational Replication Gradients in Mitochondrial Genomes Current Genomics, 2012, 13, 37-54 37 Coding Constraints Modulate Chemically Spontaneous Mutational Replication Gradients in Mitochondrial Genomes Hervé Seligmann* National Collections of Natural History at the Hebrew University of Jerusalem, Jerusalem 91404; Department of Life Sciences, Ben Gurion University, 84105 Beer Sheva, Israel 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. Received on: June 30, 2011 - Revised on: September 07, 2011 - Accepted on: September 20, 2011 Keywords: Frameshift, overlapping genetic code, protein synthesis, secondary structure formation, RNA synthesis, tRNA, transcription, translation. INTRODUCTION references in [18]). In vertebrate mitochondria, the unidirectional replication of the heavy strand (hs) DNA is The study of replicational gradients, gradual changes in initiated at the origin of heavy strand replication (ORIh) frequencies of specific types of mutational substitutions and [19]. Times spent single stranded by the heavy strand during the resulting nucleotide contents along genomes [1-2], replication are also determined by the distance of DNA sites presents the advantage that evidence originating from bioinformatic comparative genome analyses can be from the light strand (ls) replication origin (ORIl), which considered as compelling for a mutational gradient and determines when the hs DNA hybridizes with the freshly existence of the associated replication origin [3-8]. Gradients synthesized complementary light strand DNA, the double result from the fact that different regions of the genome stranded state protecting DNA against mutations [20, 21]. remain singlestranded during different durations, and that Association of deamination gradients in mitochondria with DNA is particularly sensitive to certain types of mutations replication origins is shown by exceptional genomes (mainly hydrolytic deaminations A->G and C->T) in the possessing strand inversions of the replication origin where singlestranded state [9-12]. DNA is single stranded during gradient directions are also inverted [22, 23]. Similarly, each RNA and DNA synthesis [13-15]. Gradients coincide in phylogenetic comparisons between different species enabled each case with distances from promoters of RNA synthesis to estimate mutational frequencies in different genes and and replication origins [11, 16-17]. The relative dominance show that these correspond with singlestrandedness during of each, transcriptional or replicational gradient, depends on mitochondrial replication [20, 24]. Results from specific properties of the organism (see discussion and phylogenetic reconstructions correspond to expectations based on chemical information: the chemically relatively fast C->T reaction associates with a high slope which saturates *Address correspondence to this author at the National Collections of quickly, as detected by phylogenetic analyses in the Natural History at the Hebrew University of Jerusalem, Jerusalem 91404, mutational gradient, while the slower A->G chemical Department of Life Sciences, Ben Gurion University, 84105 Beer Sheva, reaction corresponds to a slower linear gradient across the Israel; Tel: +972-2-6585874; Fax: +972-2-6584741; E-mail: [email protected] whole mitochondrial genome [20, 24]. 1389-2029/12 $58.00+.00 ©2012 Bentham Science Publishers 38 Current Genomics, 2012, Vol. 13, No. 1 Hervé Seligmann The study of mutational gradients in mitochondria 36]. The gradients are also themselves affected by coding contributed to the controversy that several heavy strand properties of genomes [37]: for example, while nucleotide DNA regions function as light strand replication origins contents follow fairly well predictions from replicational (mainly tDNA templating for tRNAs), not only the gradients in primate mitochondria at 3rd codon positions of recognized ORIl: strengths of gradients starting in the protein coding genes (transitions do not result in amino acid vicinity of tRNA genes are proportional to capacities of the replacements at the protein level at the 3rd codon position in corresponding heavy strand tDNA to form ORIl-like vertebrate mitochondria and are hence relatively free to secondary structures [21] and with hs sequences mutate), gradient strengths are weaker at the 1st, and weakest corresponding to the tRNA’s anticodon loop resembling the at the 2nd (most crucial codon position from a coding point loop of the regular ORIl in that species [25]. In addition, the of view) codon positions [21]. This means that functional stability of hs tDNA: ls tRNA hybridization, presumably constraints related to protein coding and synthesis affect competing with ORIl formation by self-hybridization of the mutational gradients. Several additional factors, beyond hs tDNA, decreases the strength of the corresponding codon position, and potentially modulating deamination gradient [26]. Comparative analyses of gradients in different gradients, are explored here: replication versus transcription, primates show that some tRNA genes function as replication codon-family specific effects on gradients, effects of origins, while others usually do not [21]. Analyses of human transitions at 3rd codon positions on codon-anticodon polymorphisms in tRNA genes show that in tRNAs that are mismatches and protein synthesis accuracy [38, 39], off not predicted to function as ORIl in the regular physiology, frame stop codons terminating early frameshifted nonsense pathogenic mutations tend to increase formation of ORIl-like protein synthesis after accidental ribosomal slippage [40, secondary structures by the hs tDNA, as compared to non- 41], and additional coding by overlapping genes [42]. pathogenic polymorphisms: pathogenicity in this case is Analyses here are effectuated, when technically possible, on promoted by increased abnormal ORIl activity, presumably 3rd codon position nucleotide contents of human causing deamination gradients such as to promote mutations mitochondrial protein coding genes and on mitochondrial in genes maladapted to be at the higher end of the synonymous mutations observed within human populations deamination gradient. For tRNA genes that comparative at 3rd codon positions. analyses suggest to function as ORIl in regular circumstances, the opposite is observed: pathogenic TRANSCRIPTIONAL VERSUS REPLICATIONAL mutations decrease formation of ORIl-like secondary GRADIENTS: NUCLEOTIDE CONTENTS structures, as compared to non-pathogenic polymorphisms Asymmetry in substitutions associated with time spent [27], meaning that decreased ORIl activity is pathogenic in single stranded and favouring deaminations results in greater these cases, perhaps because decreasing rates of replication A->G and C->T substitutions on the heavy strand, initiation. Patterns of associations between pathogenicity and proportionally to time spent singlestranded. Replicational hs tDNA: ls tRNA hybridization stabilities also follow these time spent single stranded (Dsshr) is a function of the predictions [26]. These analyses indicate that tRNA genes distance of a given site from the ORIh and the ORIl. It is function as ORIl, and contribute to the controversy that Dsshr = 2x(b-ORIl)/N for all genes besides ND1 and ND2, multiple light strand replication origins may function in and Dsshr = 2x b/N, where b is the position of the site along mitochondria [28-30], but the issue is still far from solved the genome numbering from the ORIh, ORIl is the position and probably more complex than believed, with a number of of the light strand origin of replication according
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