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Highly conserved regimes of neighbor-base-dependent mutation generated the background primary-structural heterogeneities along vertebrate chromosomes.

Antezana MA, Jordan IK - PLoS ONE (2008)

Bottom Line: The best fit, however, is obtained with NBDM regimes lacking strand effects, which indicates that over the long term NBDM switches strands in the germline as one would expect for effects due to loosely contained background transcription.We conclude that the primary structure of vertebrate genic DNA at and below the trinucleotide level has been governed over the long term by highly conserved regimes of NBDM which should be under direct natural selection because they alter drastically missense-mutation rates and hence the somatic and the germline mutational loads.Therefore, the non-coding DNA of vertebrates may have been shaped by NBDM only epiphenomenally, with non-genic DNA being affected mainly when found in the proximity of genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Ecology and Evolution, University of Chicago, Chicago, Illinois, United States of America. marcos.antezana@gmail.com

ABSTRACT
The content of guanine+cytosine varies markedly along the chromosomes of homeotherms and great effort has been devoted to studying this heterogeneity and its biological implications. Already before the DNA-sequencing era, however, it was established that the dinucleotides in the DNA of mammals in particular, and of most organisms in general, show striking over- and under-representations that cannot be explained by the base composition. Here we show that in the coding regions of vertebrates both GC content and codon occurrences are strongly correlated with such "motif preferences" even though we quantify the latter using an index that is not affected by the base composition, codon usage, and protein-sequence encoding. These correlations are likely to be the result of the long-term shaping of the primary structure of genic and non-genic DNA by a regime of mutation of which central features have been maintained by natural selection. We find indeed that these preferences are conserved in vertebrates even more rigidly than codon occurrences and we show that the occurrence-preference correlations are stronger in intronic and non-genic DNA, with the R(2)s reaching 99% when GC content is approximately 0.5. The mutation regime appears to be characterized by rates that depend markedly on the bases present at the site preceding and at that following each mutating site, because when we estimate such rates of neighbor-base-dependent mutation (NBDM) from substitutions retrieved from alignments of coding, intronic, and non-genic mammalian DNA sorted and grouped by GC content, they suffice to simulate DNA sequences in which motif occurrences and preferences as well as the correlations of motif preferences with GC content and with motif occurrences, are very similar to the mammalian ones. The best fit, however, is obtained with NBDM regimes lacking strand effects, which indicates that over the long term NBDM switches strands in the germline as one would expect for effects due to loosely contained background transcription. Finally, we show that human coding regions are less mutable under the estimated NBDM regimes than under matched context-independent mutation and that this entails marked differences between the spectra of amino-acid mutations that either mutation regime should generate. In the Discussion we examine the mechanisms likely to underlie NBDM heterogeneity along chromosomes and propose that it reflects how the diversity and activity of lesion-bypass polymerases (LBPs) track the landscapes of scheduled and non-scheduled genome repair, replication, and transcription during the cell cycle. We conclude that the primary structure of vertebrate genic DNA at and below the trinucleotide level has been governed over the long term by highly conserved regimes of NBDM which should be under direct natural selection because they alter drastically missense-mutation rates and hence the somatic and the germline mutational loads. Therefore, the non-coding DNA of vertebrates may have been shaped by NBDM only epiphenomenally, with non-genic DNA being affected mainly when found in the proximity of genes.

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Codon occurrences vs. trinucleotide-motif preferences as a function of GC content.At the top are plotted the R2s and the slopes of the correlations between codon occurrences and corresponding motif preferences for given values of 3rd-position GC content (GC3). The other plots show the situation at the GC3 values delivering peak R2s for, clockwise, 2 fold, 2fold-3aas, 4fold, and 6fold codons/motifs (i.e., 0.67, 0.55, 0.46, and 0.51 GC3; the GC3 delivering the peak all-motifs R2 coincides with that of 2folds-3aas; see also Figure 1). The 33,860 human coding regions were sorted according to 3rd-position GC content and subdivided into 13 groups of equal size.
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pone-0002145-g003: Codon occurrences vs. trinucleotide-motif preferences as a function of GC content.At the top are plotted the R2s and the slopes of the correlations between codon occurrences and corresponding motif preferences for given values of 3rd-position GC content (GC3). The other plots show the situation at the GC3 values delivering peak R2s for, clockwise, 2 fold, 2fold-3aas, 4fold, and 6fold codons/motifs (i.e., 0.67, 0.55, 0.46, and 0.51 GC3; the GC3 delivering the peak all-motifs R2 coincides with that of 2folds-3aas; see also Figure 1). The 33,860 human coding regions were sorted according to 3rd-position GC content and subdivided into 13 groups of equal size.

Mentions: Since GC content can vary markedly along chromosomes [1], we show in Figure 3 how the correlation between codon occurrences and trinucleotide motif preferences reacts to increasing GC content in human coding regions. The 33,860 human genes were sorted by increasing GC content at their third codon positions (GC3) and separated into thirteen groups having equal number of sequences, in order to calculate occurrence-preference R2s within each group as it was done with the whole-genome dataset to generate Figure 1. Almost without exception the R2s change smoothly with increasing GC3, with the peak R2 for all 61 motifs being 43% at 0.55 GC3 and those for 2folds, 2f-3aas, 4folds, and 6folds being 18, 73, 90, and 85% at 0.67, 0.55, 0.51, and 0.47 GC3, respectively. The corresponding plot of the slopes vs. GC3 in the top right of the same figure, shows that only the slopes of 2folds and especially those of 2f-3aas react strongly to GC3. The occurrence-preference plots for the GC3 values that deliver the highest R2s show that the various relationships are similar to the whole-genome ones in Figure 1. All in all, the monotonic reaction of the R2s to GC3 indicates that the whole-genome patterns presented above are indeed “noisy” but in a biologically structured way.


Highly conserved regimes of neighbor-base-dependent mutation generated the background primary-structural heterogeneities along vertebrate chromosomes.

Antezana MA, Jordan IK - PLoS ONE (2008)

Codon occurrences vs. trinucleotide-motif preferences as a function of GC content.At the top are plotted the R2s and the slopes of the correlations between codon occurrences and corresponding motif preferences for given values of 3rd-position GC content (GC3). The other plots show the situation at the GC3 values delivering peak R2s for, clockwise, 2 fold, 2fold-3aas, 4fold, and 6fold codons/motifs (i.e., 0.67, 0.55, 0.46, and 0.51 GC3; the GC3 delivering the peak all-motifs R2 coincides with that of 2folds-3aas; see also Figure 1). The 33,860 human coding regions were sorted according to 3rd-position GC content and subdivided into 13 groups of equal size.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2366069&req=5

pone-0002145-g003: Codon occurrences vs. trinucleotide-motif preferences as a function of GC content.At the top are plotted the R2s and the slopes of the correlations between codon occurrences and corresponding motif preferences for given values of 3rd-position GC content (GC3). The other plots show the situation at the GC3 values delivering peak R2s for, clockwise, 2 fold, 2fold-3aas, 4fold, and 6fold codons/motifs (i.e., 0.67, 0.55, 0.46, and 0.51 GC3; the GC3 delivering the peak all-motifs R2 coincides with that of 2folds-3aas; see also Figure 1). The 33,860 human coding regions were sorted according to 3rd-position GC content and subdivided into 13 groups of equal size.
Mentions: Since GC content can vary markedly along chromosomes [1], we show in Figure 3 how the correlation between codon occurrences and trinucleotide motif preferences reacts to increasing GC content in human coding regions. The 33,860 human genes were sorted by increasing GC content at their third codon positions (GC3) and separated into thirteen groups having equal number of sequences, in order to calculate occurrence-preference R2s within each group as it was done with the whole-genome dataset to generate Figure 1. Almost without exception the R2s change smoothly with increasing GC3, with the peak R2 for all 61 motifs being 43% at 0.55 GC3 and those for 2folds, 2f-3aas, 4folds, and 6folds being 18, 73, 90, and 85% at 0.67, 0.55, 0.51, and 0.47 GC3, respectively. The corresponding plot of the slopes vs. GC3 in the top right of the same figure, shows that only the slopes of 2folds and especially those of 2f-3aas react strongly to GC3. The occurrence-preference plots for the GC3 values that deliver the highest R2s show that the various relationships are similar to the whole-genome ones in Figure 1. All in all, the monotonic reaction of the R2s to GC3 indicates that the whole-genome patterns presented above are indeed “noisy” but in a biologically structured way.

Bottom Line: The best fit, however, is obtained with NBDM regimes lacking strand effects, which indicates that over the long term NBDM switches strands in the germline as one would expect for effects due to loosely contained background transcription.We conclude that the primary structure of vertebrate genic DNA at and below the trinucleotide level has been governed over the long term by highly conserved regimes of NBDM which should be under direct natural selection because they alter drastically missense-mutation rates and hence the somatic and the germline mutational loads.Therefore, the non-coding DNA of vertebrates may have been shaped by NBDM only epiphenomenally, with non-genic DNA being affected mainly when found in the proximity of genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Ecology and Evolution, University of Chicago, Chicago, Illinois, United States of America. marcos.antezana@gmail.com

ABSTRACT
The content of guanine+cytosine varies markedly along the chromosomes of homeotherms and great effort has been devoted to studying this heterogeneity and its biological implications. Already before the DNA-sequencing era, however, it was established that the dinucleotides in the DNA of mammals in particular, and of most organisms in general, show striking over- and under-representations that cannot be explained by the base composition. Here we show that in the coding regions of vertebrates both GC content and codon occurrences are strongly correlated with such "motif preferences" even though we quantify the latter using an index that is not affected by the base composition, codon usage, and protein-sequence encoding. These correlations are likely to be the result of the long-term shaping of the primary structure of genic and non-genic DNA by a regime of mutation of which central features have been maintained by natural selection. We find indeed that these preferences are conserved in vertebrates even more rigidly than codon occurrences and we show that the occurrence-preference correlations are stronger in intronic and non-genic DNA, with the R(2)s reaching 99% when GC content is approximately 0.5. The mutation regime appears to be characterized by rates that depend markedly on the bases present at the site preceding and at that following each mutating site, because when we estimate such rates of neighbor-base-dependent mutation (NBDM) from substitutions retrieved from alignments of coding, intronic, and non-genic mammalian DNA sorted and grouped by GC content, they suffice to simulate DNA sequences in which motif occurrences and preferences as well as the correlations of motif preferences with GC content and with motif occurrences, are very similar to the mammalian ones. The best fit, however, is obtained with NBDM regimes lacking strand effects, which indicates that over the long term NBDM switches strands in the germline as one would expect for effects due to loosely contained background transcription. Finally, we show that human coding regions are less mutable under the estimated NBDM regimes than under matched context-independent mutation and that this entails marked differences between the spectra of amino-acid mutations that either mutation regime should generate. In the Discussion we examine the mechanisms likely to underlie NBDM heterogeneity along chromosomes and propose that it reflects how the diversity and activity of lesion-bypass polymerases (LBPs) track the landscapes of scheduled and non-scheduled genome repair, replication, and transcription during the cell cycle. We conclude that the primary structure of vertebrate genic DNA at and below the trinucleotide level has been governed over the long term by highly conserved regimes of NBDM which should be under direct natural selection because they alter drastically missense-mutation rates and hence the somatic and the germline mutational loads. Therefore, the non-coding DNA of vertebrates may have been shaped by NBDM only epiphenomenally, with non-genic DNA being affected mainly when found in the proximity of genes.

Show MeSH