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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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Coding-region GC content in vertebrates.The distribution of the GC content at the three codon positions in vertebrate genes. Thickest black line: first-position GC content (GC1); 2nd-thickest black line: GC2; thin black line: GC3; circles: GC123. Lighter lines and circles are for Rattus, platypus, and Danio, respectively.
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pone-0002145-g009: Coding-region GC content in vertebrates.The distribution of the GC content at the three codon positions in vertebrate genes. Thickest black line: first-position GC content (GC1); 2nd-thickest black line: GC2; thin black line: GC3; circles: GC123. Lighter lines and circles are for Rattus, platypus, and Danio, respectively.

Mentions: Figure 7 shows indirectly that the GC3 excursion is quite similar across vertebrates, indicating that the GC content of vertebrate genes and their proximities may be quite similar (since GC3 is well-known to be highly correlated to the GC content of the genomic regions surrounding genes [1]). This motivated Figure 9 that shows the distribution of the various GC contents in vertebrate coding regions. Remarkably, Xenopus GC distributions are very homeotherm-like although its GC3 distribution lacks mass, but not presences, when GC3 is low (consistent with Fugu's lack of “junk” DNA which tends to be AT-rich). Danio's GC3 mass tends to be in the middle of the homeotherm range (and looks like the homeotherm GC123). In general, GC3 excursions are not very different across vertebrates although the low-GC tails tend to be thicker in homeotherms. Note also that the bimodality of human GC123 is almost identical in Canis and that the same applies to GC1, GC2, and GC3 (not shown; hence GC content cannot be what makes us human). Finally, note that in all vertebrates GC123 tends to fall between 0.37 and 0.70.


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

Antezana MA, Jordan IK - PLoS ONE (2008)

Coding-region GC content in vertebrates.The distribution of the GC content at the three codon positions in vertebrate genes. Thickest black line: first-position GC content (GC1); 2nd-thickest black line: GC2; thin black line: GC3; circles: GC123. Lighter lines and circles are for Rattus, platypus, and Danio, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g009: Coding-region GC content in vertebrates.The distribution of the GC content at the three codon positions in vertebrate genes. Thickest black line: first-position GC content (GC1); 2nd-thickest black line: GC2; thin black line: GC3; circles: GC123. Lighter lines and circles are for Rattus, platypus, and Danio, respectively.
Mentions: Figure 7 shows indirectly that the GC3 excursion is quite similar across vertebrates, indicating that the GC content of vertebrate genes and their proximities may be quite similar (since GC3 is well-known to be highly correlated to the GC content of the genomic regions surrounding genes [1]). This motivated Figure 9 that shows the distribution of the various GC contents in vertebrate coding regions. Remarkably, Xenopus GC distributions are very homeotherm-like although its GC3 distribution lacks mass, but not presences, when GC3 is low (consistent with Fugu's lack of “junk” DNA which tends to be AT-rich). Danio's GC3 mass tends to be in the middle of the homeotherm range (and looks like the homeotherm GC123). In general, GC3 excursions are not very different across vertebrates although the low-GC tails tend to be thicker in homeotherms. Note also that the bimodality of human GC123 is almost identical in Canis and that the same applies to GC1, GC2, and GC3 (not shown; hence GC content cannot be what makes us human). Finally, note that in all vertebrates GC123 tends to fall between 0.37 and 0.70.

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