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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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Vertebrate 3rd-position GC content and dinucleotide-motif preferences.The correlation in human coding regions between 3rd-position GC content and the GCvsAT pressure derived from dinucleotide-motif preferences (see also Methods and previous figures).
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pone-0002145-g008: Vertebrate 3rd-position GC content and dinucleotide-motif preferences.The correlation in human coding regions between 3rd-position GC content and the GCvsAT pressure derived from dinucleotide-motif preferences (see also Methods and previous figures).

Mentions: As mentioned in the Introduction and in the Materials and Methods, we found that GC content and motifs preferences are correlated strongly, positively, and linearly. In Figure 6 we plot the GC content at the three codon positions for each of the aforementioned thirteen groups of GC-sorted human genes against the corresponding GCvsAT pressures (see Materials and Methods) derived from the various preferences for the trinucleotide motifs in the same groups. The R2 for 3rd-position GC content is 98% (99% excluding the group with highest GC) and those for total, 1st-position, and 2nd-position GC are 98, 92, and 88%. The plotted horizontal “” relationship was obtained by randomizing the SC location of each gene before motif-preference estimation, which leaves GC content unchanged but randomizes each gene's motif preferences, resulting in identical, zero-valued GC pressures in each of the thirteen groups. In Figure 7 we present the other vertebrates' plots of GC123 vs. the total GC pressure. The R2s are again striking, falling below 95% only in Fugu (90%). When using the GC pressure derived from dinucleotide preferences and genes sorted by GC3, the R2 is 98% (Fig. 8). Remarkably, for the human case no exclusion of individual di- or tri-nucleotide preferences –or of pairs thereof– from the GC-pressure sums lowers the R2 below 89%, with CC, AA, CTT, CCC, CAA delivering the top reductions (not shown).


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

Antezana MA, Jordan IK - PLoS ONE (2008)

Vertebrate 3rd-position GC content and dinucleotide-motif preferences.The correlation in human coding regions between 3rd-position GC content and the GCvsAT pressure derived from dinucleotide-motif preferences (see also Methods and previous figures).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g008: Vertebrate 3rd-position GC content and dinucleotide-motif preferences.The correlation in human coding regions between 3rd-position GC content and the GCvsAT pressure derived from dinucleotide-motif preferences (see also Methods and previous figures).
Mentions: As mentioned in the Introduction and in the Materials and Methods, we found that GC content and motifs preferences are correlated strongly, positively, and linearly. In Figure 6 we plot the GC content at the three codon positions for each of the aforementioned thirteen groups of GC-sorted human genes against the corresponding GCvsAT pressures (see Materials and Methods) derived from the various preferences for the trinucleotide motifs in the same groups. The R2 for 3rd-position GC content is 98% (99% excluding the group with highest GC) and those for total, 1st-position, and 2nd-position GC are 98, 92, and 88%. The plotted horizontal “” relationship was obtained by randomizing the SC location of each gene before motif-preference estimation, which leaves GC content unchanged but randomizes each gene's motif preferences, resulting in identical, zero-valued GC pressures in each of the thirteen groups. In Figure 7 we present the other vertebrates' plots of GC123 vs. the total GC pressure. The R2s are again striking, falling below 95% only in Fugu (90%). When using the GC pressure derived from dinucleotide preferences and genes sorted by GC3, the R2 is 98% (Fig. 8). Remarkably, for the human case no exclusion of individual di- or tri-nucleotide preferences –or of pairs thereof– from the GC-pressure sums lowers the R2 below 89%, with CC, AA, CTT, CCC, CAA delivering the top reductions (not shown).

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