Limits...
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.

Show MeSH

Related in: MedlinePlus

Dinucleotide occurrences and preferences as a function of GC content.From top to bottom are the occurrence frequency of the 16 across-codon (3∥1) dinucleotides, their departure from the expectation given the base composition that best fits codon occurrences (divided by the expectation), and their across-codon preferences, as a function of increasing GC3.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2366069&req=5

pone-0002145-g014: Dinucleotide occurrences and preferences as a function of GC content.From top to bottom are the occurrence frequency of the 16 across-codon (3∥1) dinucleotides, their departure from the expectation given the base composition that best fits codon occurrences (divided by the expectation), and their across-codon preferences, as a function of increasing GC3.

Mentions: Changes in the occurrences of, and in the preferences for, across-codon dinucleotides as a function of GC3 are shown in Figure 14. In general the occurrence of motifs beginning with TorA decreases with increasing GC3 while that of those beginning in CorG increases, which is consistent with these being 3rd-position TorAs and CorGs. Remarkably and almost without exception, when looking at pairs of dinucleotides ending in TorA or CvsG but sharing the first nucleotide, when a dinucleotide is less preferred than its partner, its occurrence is always lower than that of its partner across all GC3 groups. As it was the case for trinucleotides, occurrence changes are not clearly mirrored by similar changes in preferences, which is surprising given that, as it was the case for trinucleotides, the GCvsAT pressure derived from dinucleotides preferences showed a remarkably linear increase with GC3 (see Fig. 8). However, occurrence changes with GC3 are mirrored by changes in the departure of the occurrences from their corresponding base-composition expectations although not always as smoothly or with similar steepness. Note again the lack of correlation that we mentioned above, between the reaction to GC3 of motif preferences and that of occurrence departures from expectation.


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 and preferences as a function of GC content.From top to bottom are the occurrence frequency of the 16 across-codon (3∥1) dinucleotides, their departure from the expectation given the base composition that best fits codon occurrences (divided by the expectation), and their across-codon preferences, as a function of increasing GC3.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g014: Dinucleotide occurrences and preferences as a function of GC content.From top to bottom are the occurrence frequency of the 16 across-codon (3∥1) dinucleotides, their departure from the expectation given the base composition that best fits codon occurrences (divided by the expectation), and their across-codon preferences, as a function of increasing GC3.
Mentions: Changes in the occurrences of, and in the preferences for, across-codon dinucleotides as a function of GC3 are shown in Figure 14. In general the occurrence of motifs beginning with TorA decreases with increasing GC3 while that of those beginning in CorG increases, which is consistent with these being 3rd-position TorAs and CorGs. Remarkably and almost without exception, when looking at pairs of dinucleotides ending in TorA or CvsG but sharing the first nucleotide, when a dinucleotide is less preferred than its partner, its occurrence is always lower than that of its partner across all GC3 groups. As it was the case for trinucleotides, occurrence changes are not clearly mirrored by similar changes in preferences, which is surprising given that, as it was the case for trinucleotides, the GCvsAT pressure derived from dinucleotides preferences showed a remarkably linear increase with GC3 (see Fig. 8). However, occurrence changes with GC3 are mirrored by changes in the departure of the occurrences from their corresponding base-composition expectations although not always as smoothly or with similar steepness. Note again the lack of correlation that we mentioned above, between the reaction to GC3 of motif preferences and that of occurrence departures from expectation.

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