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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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Occurrence-vs.-preference R2s in vertebrates as a function of GC3.The R2s of the correlation between codon occurrences and corresponding off-frame-motif preferences for increasing GC3 values in the genomes of Rattus, opossum, platypus, Gallus, Xenopus, and Danio. In the Rattus plot the Homo patterns from Fig. 3 are used as background and Fugu's are in the background in the Danio plot.
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pone-0002145-g004: Occurrence-vs.-preference R2s in vertebrates as a function of GC3.The R2s of the correlation between codon occurrences and corresponding off-frame-motif preferences for increasing GC3 values in the genomes of Rattus, opossum, platypus, Gallus, Xenopus, and Danio. In the Rattus plot the Homo patterns from Fig. 3 are used as background and Fugu's are in the background in the Danio plot.

Mentions: In Figures 4 and 5 we show how occurrence-preference R2s and slopes change with GC3 in the other vertebrate genomes. The R2 patterns are remarkably similar across homeotherm vertebrates. The jagged opossum patterns may be due to the inclusion of falsely diagnosed (or newly recruited) genes in the dataset we used. Indeed similar irregularities were also seen with Mus and Canis, but in the Mus case disappeared when using genes with known transcripts or known human homologues (neither is shown; occurrence-preference R2s in non-coding DNA are almost 100% at 0.5 GC and react more strongly to GC changes, see below). Also here platypus' patterns seem fish-like to some extent. An interesting pattern is that the all-motifs and the 6fold lines cross above 0.7 GC3 in homeotherms (including Mus and Canis, not shown) but clearly below 0.7 in poikilotherms. Danio R2 patterns are more homeotherm-like than Fugu's (which were relegated to the background). Note that the 2f-3aas R2s from high-GC rodent genes (in all rodent datasets) are much higher than those from the other vertebrates expect the opossum and may indicate a difference in genome-wide amino-acid selection (see also below). Also the slopes' reaction to GC3 in Figure 5 is remarkably similar across vertebrates albeit less strikingly so than the R2s; and also here are the patterns obtained with known-homologue Rattus and Mus genes clearly smoother than those from the whole-genome dataset. Remarkably, Danio's slopes are homeotherm-like in many respects unlike Fugu's which, like its R2s, are patterned unlike those of the other vertebrates. Finally, it is hard to believe that the highest-GC Xenopus group may not be anomalous since it delivers R2s and slopes unlike those of any vertebrate.


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

Antezana MA, Jordan IK - PLoS ONE (2008)

Occurrence-vs.-preference R2s in vertebrates as a function of GC3.The R2s of the correlation between codon occurrences and corresponding off-frame-motif preferences for increasing GC3 values in the genomes of Rattus, opossum, platypus, Gallus, Xenopus, and Danio. In the Rattus plot the Homo patterns from Fig. 3 are used as background and Fugu's are in the background in the Danio plot.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g004: Occurrence-vs.-preference R2s in vertebrates as a function of GC3.The R2s of the correlation between codon occurrences and corresponding off-frame-motif preferences for increasing GC3 values in the genomes of Rattus, opossum, platypus, Gallus, Xenopus, and Danio. In the Rattus plot the Homo patterns from Fig. 3 are used as background and Fugu's are in the background in the Danio plot.
Mentions: In Figures 4 and 5 we show how occurrence-preference R2s and slopes change with GC3 in the other vertebrate genomes. The R2 patterns are remarkably similar across homeotherm vertebrates. The jagged opossum patterns may be due to the inclusion of falsely diagnosed (or newly recruited) genes in the dataset we used. Indeed similar irregularities were also seen with Mus and Canis, but in the Mus case disappeared when using genes with known transcripts or known human homologues (neither is shown; occurrence-preference R2s in non-coding DNA are almost 100% at 0.5 GC and react more strongly to GC changes, see below). Also here platypus' patterns seem fish-like to some extent. An interesting pattern is that the all-motifs and the 6fold lines cross above 0.7 GC3 in homeotherms (including Mus and Canis, not shown) but clearly below 0.7 in poikilotherms. Danio R2 patterns are more homeotherm-like than Fugu's (which were relegated to the background). Note that the 2f-3aas R2s from high-GC rodent genes (in all rodent datasets) are much higher than those from the other vertebrates expect the opossum and may indicate a difference in genome-wide amino-acid selection (see also below). Also the slopes' reaction to GC3 in Figure 5 is remarkably similar across vertebrates albeit less strikingly so than the R2s; and also here are the patterns obtained with known-homologue Rattus and Mus genes clearly smoother than those from the whole-genome dataset. Remarkably, Danio's slopes are homeotherm-like in many respects unlike Fugu's which, like its R2s, are patterned unlike those of the other vertebrates. Finally, it is hard to believe that the highest-GC Xenopus group may not be anomalous since it delivers R2s and slopes unlike those of any vertebrate.

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