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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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Dinucleotide occurrences in native vs. simulated non-genic, intronic, and coding DNA as a function of GC content.The R2s and slopes (left, right, vertical axis) of the correlations of dinucleotide occurrences in native non-genic, intronic, and coding DNA (top to bottom) vs. those in simulated DNA generated by 4×4 (grey lines) or 64×4 matrices (black lines) estimated from non-genic, intronic, and coding-region substitutions, as a function of increasing GC total or GC123 (horizontal axis; but the grey-line results in the top two plots were obtained using base-composition predictions rather than simulated occurrences). Thick lines are results with intron-derived matrices and thinner lines in the top plots are results with non-genic-DNA matrices and –in the middle and bottom plots– results with coding-DNA matrices. The intron-derived 64×4s used for the top and bottom plots had no strand effects and so were those for the middle-plot results highlighted with the thickest black line.
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pone-0002145-g031: Dinucleotide occurrences in native vs. simulated non-genic, intronic, and coding DNA as a function of GC content.The R2s and slopes (left, right, vertical axis) of the correlations of dinucleotide occurrences in native non-genic, intronic, and coding DNA (top to bottom) vs. those in simulated DNA generated by 4×4 (grey lines) or 64×4 matrices (black lines) estimated from non-genic, intronic, and coding-region substitutions, as a function of increasing GC total or GC123 (horizontal axis; but the grey-line results in the top two plots were obtained using base-composition predictions rather than simulated occurrences). Thick lines are results with intron-derived matrices and thinner lines in the top plots are results with non-genic-DNA matrices and –in the middle and bottom plots– results with coding-DNA matrices. The intron-derived 64×4s used for the top and bottom plots had no strand effects and so were those for the middle-plot results highlighted with the thickest black line.

Mentions: Figure 30 shows how simulated non-genic occurrences correlate with native ones for increasing non-genic GC content. Here again deliver the 64×4 matrices (with erased strand effects) a much closer fit to the native non-genic occurrences for the 4fold, 6fold, and the all-motifs groups than would a well-fitted 4×4 matrix. The fits for the two 2fold groups was best when using the 64×4s derived from non-genic DNA. The slopes are quite close to 1.0 but decrease towards 0.5 with increasing GC. Finally, Figure 31 shows how simulated dinucleotide occurrences correlate with native ones. The fit is best between the native non-genic or intronic dinucleotide occurrences and those generated by the intronic and non-genic 64×4s. However, even when the fit to the 64×4-generated dinucleotide occurrences is not high –e.g., between native and simulated 3/1 dinucleotides in coding DNA– the fit delivered by 64×4 NBDM is nonetheless almost always better than that with 4×4 matrices or base-composition predictions.


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

Antezana MA, Jordan IK - PLoS ONE (2008)

Dinucleotide occurrences in native vs. simulated non-genic, intronic, and coding DNA as a function of GC content.The R2s and slopes (left, right, vertical axis) of the correlations of dinucleotide occurrences in native non-genic, intronic, and coding DNA (top to bottom) vs. those in simulated DNA generated by 4×4 (grey lines) or 64×4 matrices (black lines) estimated from non-genic, intronic, and coding-region substitutions, as a function of increasing GC total or GC123 (horizontal axis; but the grey-line results in the top two plots were obtained using base-composition predictions rather than simulated occurrences). Thick lines are results with intron-derived matrices and thinner lines in the top plots are results with non-genic-DNA matrices and –in the middle and bottom plots– results with coding-DNA matrices. The intron-derived 64×4s used for the top and bottom plots had no strand effects and so were those for the middle-plot results highlighted with the thickest black line.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g031: Dinucleotide occurrences in native vs. simulated non-genic, intronic, and coding DNA as a function of GC content.The R2s and slopes (left, right, vertical axis) of the correlations of dinucleotide occurrences in native non-genic, intronic, and coding DNA (top to bottom) vs. those in simulated DNA generated by 4×4 (grey lines) or 64×4 matrices (black lines) estimated from non-genic, intronic, and coding-region substitutions, as a function of increasing GC total or GC123 (horizontal axis; but the grey-line results in the top two plots were obtained using base-composition predictions rather than simulated occurrences). Thick lines are results with intron-derived matrices and thinner lines in the top plots are results with non-genic-DNA matrices and –in the middle and bottom plots– results with coding-DNA matrices. The intron-derived 64×4s used for the top and bottom plots had no strand effects and so were those for the middle-plot results highlighted with the thickest black line.
Mentions: Figure 30 shows how simulated non-genic occurrences correlate with native ones for increasing non-genic GC content. Here again deliver the 64×4 matrices (with erased strand effects) a much closer fit to the native non-genic occurrences for the 4fold, 6fold, and the all-motifs groups than would a well-fitted 4×4 matrix. The fits for the two 2fold groups was best when using the 64×4s derived from non-genic DNA. The slopes are quite close to 1.0 but decrease towards 0.5 with increasing GC. Finally, Figure 31 shows how simulated dinucleotide occurrences correlate with native ones. The fit is best between the native non-genic or intronic dinucleotide occurrences and those generated by the intronic and non-genic 64×4s. However, even when the fit to the 64×4-generated dinucleotide occurrences is not high –e.g., between native and simulated 3/1 dinucleotides in coding DNA– the fit delivered by 64×4 NBDM is nonetheless almost always better than that with 4×4 matrices or base-composition predictions.

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