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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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Simulated occurrence-preference R2s as a function of GC content.On the left are the occurrence-preference R2s (vertical axis) for trinucleotides in groups of 1000 simulated sequences whose every site was hit at least ten times with 64×4 matrices estimated from Homo-chimp/macaque intron alignments of increasing GC, plotted against the GC of the simulated sequences (horizontal axis). At the top left are results with 64×4s lacking strand effects (i.e., complementary substitutions were pooled to estimate rates) in absence of selection, flanked by the human non-genic pattern. In the middle on the left are results with 64×4s with full strand effects and no selection, flanked by the pattern of human introns. At the bottom left are results with Grantham non-synonymous selection (see M&Ms) and 64×4s with and without strand effects (thicker and thickest lines), flanked by the pattern of human coding DNA. Additionally, in thinnest lines on the left, are results with 64×4s from human-chimp/baboon non-genic DNA (top; highest GC: 0.48) or with 64×4s from mouse-rat/Homo coding-DNA alignments (middle and bottom; bottom is vs. GC123 which had wider GC excursion). The intronic 64×4 matrix that generated the two no-selection GCs of 0.408 and the GC3 of 0.42 was estimated on the basis of 2.9 million substitutions to human or chimp.
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pone-0002145-g025: Simulated occurrence-preference R2s as a function of GC content.On the left are the occurrence-preference R2s (vertical axis) for trinucleotides in groups of 1000 simulated sequences whose every site was hit at least ten times with 64×4 matrices estimated from Homo-chimp/macaque intron alignments of increasing GC, plotted against the GC of the simulated sequences (horizontal axis). At the top left are results with 64×4s lacking strand effects (i.e., complementary substitutions were pooled to estimate rates) in absence of selection, flanked by the human non-genic pattern. In the middle on the left are results with 64×4s with full strand effects and no selection, flanked by the pattern of human introns. At the bottom left are results with Grantham non-synonymous selection (see M&Ms) and 64×4s with and without strand effects (thicker and thickest lines), flanked by the pattern of human coding DNA. Additionally, in thinnest lines on the left, are results with 64×4s from human-chimp/baboon non-genic DNA (top; highest GC: 0.48) or with 64×4s from mouse-rat/Homo coding-DNA alignments (middle and bottom; bottom is vs. GC123 which had wider GC excursion). The intronic 64×4 matrix that generated the two no-selection GCs of 0.408 and the GC3 of 0.42 was estimated on the basis of 2.9 million substitutions to human or chimp.

Mentions: Figure 25 shows that in sequences generated by the above 64×4 matrices, motif preferences and occurrences relate to each other in very much the same way as in native sequences. The most striking matches are with the non-genic native pattern and, less so, with the intronic native pattern, and are delivered by the intron-derived 64×4s when their strand effects are erased (through pooling of complementary events) and by the 64×4s from non-genic DNA. These similarities include i) the peaking at about 100% R2 of every occurrence-preference R2s when GC is about 0.5; ii) higher R2s for the two 2fold groups and the 6folds when GC is above 0.5 than for the 4fold and the all-motifs group; iii) higher R2s at GC below 0.50 for the all-motifs, 4fold, and 6fold groups than for the two 2fold groups; iv) identical ranking of the R2s of 6folds, 4folds, and all-motifs below 0.5 (but for the no-strand-effect intronic 64×4s this is only so when GC is between 0.43 and 0.5); v) identical ranking above 0.5 GC of the R2s of 2folds, 2f-3aaas, 6folds, 4folds, and all-motifs.


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

Antezana MA, Jordan IK - PLoS ONE (2008)

Simulated occurrence-preference R2s as a function of GC content.On the left are the occurrence-preference R2s (vertical axis) for trinucleotides in groups of 1000 simulated sequences whose every site was hit at least ten times with 64×4 matrices estimated from Homo-chimp/macaque intron alignments of increasing GC, plotted against the GC of the simulated sequences (horizontal axis). At the top left are results with 64×4s lacking strand effects (i.e., complementary substitutions were pooled to estimate rates) in absence of selection, flanked by the human non-genic pattern. In the middle on the left are results with 64×4s with full strand effects and no selection, flanked by the pattern of human introns. At the bottom left are results with Grantham non-synonymous selection (see M&Ms) and 64×4s with and without strand effects (thicker and thickest lines), flanked by the pattern of human coding DNA. Additionally, in thinnest lines on the left, are results with 64×4s from human-chimp/baboon non-genic DNA (top; highest GC: 0.48) or with 64×4s from mouse-rat/Homo coding-DNA alignments (middle and bottom; bottom is vs. GC123 which had wider GC excursion). The intronic 64×4 matrix that generated the two no-selection GCs of 0.408 and the GC3 of 0.42 was estimated on the basis of 2.9 million substitutions to human or chimp.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g025: Simulated occurrence-preference R2s as a function of GC content.On the left are the occurrence-preference R2s (vertical axis) for trinucleotides in groups of 1000 simulated sequences whose every site was hit at least ten times with 64×4 matrices estimated from Homo-chimp/macaque intron alignments of increasing GC, plotted against the GC of the simulated sequences (horizontal axis). At the top left are results with 64×4s lacking strand effects (i.e., complementary substitutions were pooled to estimate rates) in absence of selection, flanked by the human non-genic pattern. In the middle on the left are results with 64×4s with full strand effects and no selection, flanked by the pattern of human introns. At the bottom left are results with Grantham non-synonymous selection (see M&Ms) and 64×4s with and without strand effects (thicker and thickest lines), flanked by the pattern of human coding DNA. Additionally, in thinnest lines on the left, are results with 64×4s from human-chimp/baboon non-genic DNA (top; highest GC: 0.48) or with 64×4s from mouse-rat/Homo coding-DNA alignments (middle and bottom; bottom is vs. GC123 which had wider GC excursion). The intronic 64×4 matrix that generated the two no-selection GCs of 0.408 and the GC3 of 0.42 was estimated on the basis of 2.9 million substitutions to human or chimp.
Mentions: Figure 25 shows that in sequences generated by the above 64×4 matrices, motif preferences and occurrences relate to each other in very much the same way as in native sequences. The most striking matches are with the non-genic native pattern and, less so, with the intronic native pattern, and are delivered by the intron-derived 64×4s when their strand effects are erased (through pooling of complementary events) and by the 64×4s from non-genic DNA. These similarities include i) the peaking at about 100% R2 of every occurrence-preference R2s when GC is about 0.5; ii) higher R2s for the two 2fold groups and the 6folds when GC is above 0.5 than for the 4fold and the all-motifs group; iii) higher R2s at GC below 0.50 for the all-motifs, 4fold, and 6fold groups than for the two 2fold groups; iv) identical ranking of the R2s of 6folds, 4folds, and all-motifs below 0.5 (but for the no-strand-effect intronic 64×4s this is only so when GC is between 0.43 and 0.5); v) identical ranking above 0.5 GC of the R2s of 2folds, 2f-3aaas, 6folds, 4folds, and all-motifs.

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
Related in: MedlinePlus