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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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Trinucleotide preference-occurrence correlations in non-genic and intronic DNA vs. GC content.About 4,700 human nongenic DNA sequences and 54,000 human introns, sorted by increasing GC content and subdivided into 13 groups of equal size. On the top are the occurrence-preference R2s within each GC-defined group of nongenic and intron sequences. In the middle are plots of trinucleotide occurrence against motif preferences for the GC groups that gave highest occurrence-preference R2s (49% non-genic GC and 51% intronic GC). At the bottom are the correlations between the GC content and the difference between the sums of the preferences for trinucleotides containing CorG and TorA (see M&Ms).
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pone-0002145-g022: Trinucleotide preference-occurrence correlations in non-genic and intronic DNA vs. GC content.About 4,700 human nongenic DNA sequences and 54,000 human introns, sorted by increasing GC content and subdivided into 13 groups of equal size. On the top are the occurrence-preference R2s within each GC-defined group of nongenic and intron sequences. In the middle are plots of trinucleotide occurrence against motif preferences for the GC groups that gave highest occurrence-preference R2s (49% non-genic GC and 51% intronic GC). At the bottom are the correlations between the GC content and the difference between the sums of the preferences for trinucleotides containing CorG and TorA (see M&Ms).

Mentions: The plots in Figure 22 show the GC-content reaction of trinucleotide occurrence-preference R2s in intronic and non-genic DNA. Peak occurrence-preference R2s of 97%+ are observed when GC is about 0.5 in intronic and non-genic DNA. These R2 values, however, can be quite low in either type of non-coding DNA, demonstrating again that occurrence-preference R2s do not need to be always high. The plots in the middle for 0.5 GC show that every one of the 64 trinucleotides falls on the regression line without exception, and that the main differences between the reactions to GC of non-genic and intronic occurrence-preference R2s are that the nongenic values for 4folds and 6folds sink more slowly with lower GC than the intronic ones and that the 2fold and 2f-3aas non-genic values sink much faster than the intronic ones. These differences make it remarkable that the non-genic and intronic all-motifs trends be nonetheless very similar (e.g., both have an ∼0.2 R2 at 0.3 GC; see also simulation results below). The bottom plots show again very strong correlations between the actual GC content and the preference-based GCvsAT pressures for each of the two kinds of DNA sequences. Note that the excursion of the intronic GCvsAT pressure is less extreme than the GC123 pressure in Figure 6, ranging between −0.05 and +0.05 rather than between −0.1 and +0.1, while the GCvsAT pressure of non-genic DNA has a range similar to that of the GC123 pressure.


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

Antezana MA, Jordan IK - PLoS ONE (2008)

Trinucleotide preference-occurrence correlations in non-genic and intronic DNA vs. GC content.About 4,700 human nongenic DNA sequences and 54,000 human introns, sorted by increasing GC content and subdivided into 13 groups of equal size. On the top are the occurrence-preference R2s within each GC-defined group of nongenic and intron sequences. In the middle are plots of trinucleotide occurrence against motif preferences for the GC groups that gave highest occurrence-preference R2s (49% non-genic GC and 51% intronic GC). At the bottom are the correlations between the GC content and the difference between the sums of the preferences for trinucleotides containing CorG and TorA (see M&Ms).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2366069&req=5

pone-0002145-g022: Trinucleotide preference-occurrence correlations in non-genic and intronic DNA vs. GC content.About 4,700 human nongenic DNA sequences and 54,000 human introns, sorted by increasing GC content and subdivided into 13 groups of equal size. On the top are the occurrence-preference R2s within each GC-defined group of nongenic and intron sequences. In the middle are plots of trinucleotide occurrence against motif preferences for the GC groups that gave highest occurrence-preference R2s (49% non-genic GC and 51% intronic GC). At the bottom are the correlations between the GC content and the difference between the sums of the preferences for trinucleotides containing CorG and TorA (see M&Ms).
Mentions: The plots in Figure 22 show the GC-content reaction of trinucleotide occurrence-preference R2s in intronic and non-genic DNA. Peak occurrence-preference R2s of 97%+ are observed when GC is about 0.5 in intronic and non-genic DNA. These R2 values, however, can be quite low in either type of non-coding DNA, demonstrating again that occurrence-preference R2s do not need to be always high. The plots in the middle for 0.5 GC show that every one of the 64 trinucleotides falls on the regression line without exception, and that the main differences between the reactions to GC of non-genic and intronic occurrence-preference R2s are that the nongenic values for 4folds and 6folds sink more slowly with lower GC than the intronic ones and that the 2fold and 2f-3aas non-genic values sink much faster than the intronic ones. These differences make it remarkable that the non-genic and intronic all-motifs trends be nonetheless very similar (e.g., both have an ∼0.2 R2 at 0.3 GC; see also simulation results below). The bottom plots show again very strong correlations between the actual GC content and the preference-based GCvsAT pressures for each of the two kinds of DNA sequences. Note that the excursion of the intronic GCvsAT pressure is less extreme than the GC123 pressure in Figure 6, ranging between −0.05 and +0.05 rather than between −0.1 and +0.1, while the GCvsAT pressure of non-genic DNA has a range similar to that of the GC123 pressure.

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