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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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GC content and the departure of codon occurrences from base-composition expectations.The difference between the occurrence of each of the 61 sense codons from the occurrence expected given the base composition that best fits the total codon occurrences in each GC3-sorted group of coding regions, plotted by increasing GC3. In each plot the third base is labelled as in the top left.
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pone-0002145-g013: GC content and the departure of codon occurrences from base-composition expectations.The difference between the occurrence of each of the 61 sense codons from the occurrence expected given the base composition that best fits the total codon occurrences in each GC3-sorted group of coding regions, plotted by increasing GC3. In each plot the third base is labelled as in the top left.

Mentions: The results above using groups of CDSs sorted by GC motivated us to study how individual codon frequencies and trinucleotide motif preferences change with increasing GC3 (Fig. 11 and 12). Additionally, to gain a better understanding of motif preferences we present in Figure 13 the departure of each individual codon occurrence from that expected given the base composition which fits best the codon occurrences in each GC3-sorted group (i.e., that minimizing the sum of the every absolute difference between an observed and a predicted codon frequency, with granularity 0.001). The lowest occurrences are those of trinucleotides containing CG and TA dinucleotides; furthermore their reaction to changing GC3 is quite restricted. Another remarkable trend is that all T- and A-ending codons decrease in frequency with GC3, CGT being the only exception (always low), which contrasts clearly with the often large differences among the increases of C- and G-ending codons. Of the latter the G-ending codons are those with most variable behavior while C-ending ones increase monotonically with higher GC3 almost without exception. The most extreme increases in occurrence in response to higher GC3 are those of CTG, GCC, and GTG, and the largest decreases are those of AAA and GAA. Note that these results for plain codon occurrences, and similar ones below for dinucleotides, suffice to conclude that neither GC content nor base composition can possibly account for the occurrence of individual codons in groups comprising many coding regions (where the fact that the contrasted groups contain many genes makes it hard to invoke constraints arising from the need of individual genes to encode peculiar proteins).


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

Antezana MA, Jordan IK - PLoS ONE (2008)

GC content and the departure of codon occurrences from base-composition expectations.The difference between the occurrence of each of the 61 sense codons from the occurrence expected given the base composition that best fits the total codon occurrences in each GC3-sorted group of coding regions, plotted by increasing GC3. In each plot the third base is labelled as in the top left.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g013: GC content and the departure of codon occurrences from base-composition expectations.The difference between the occurrence of each of the 61 sense codons from the occurrence expected given the base composition that best fits the total codon occurrences in each GC3-sorted group of coding regions, plotted by increasing GC3. In each plot the third base is labelled as in the top left.
Mentions: The results above using groups of CDSs sorted by GC motivated us to study how individual codon frequencies and trinucleotide motif preferences change with increasing GC3 (Fig. 11 and 12). Additionally, to gain a better understanding of motif preferences we present in Figure 13 the departure of each individual codon occurrence from that expected given the base composition which fits best the codon occurrences in each GC3-sorted group (i.e., that minimizing the sum of the every absolute difference between an observed and a predicted codon frequency, with granularity 0.001). The lowest occurrences are those of trinucleotides containing CG and TA dinucleotides; furthermore their reaction to changing GC3 is quite restricted. Another remarkable trend is that all T- and A-ending codons decrease in frequency with GC3, CGT being the only exception (always low), which contrasts clearly with the often large differences among the increases of C- and G-ending codons. Of the latter the G-ending codons are those with most variable behavior while C-ending ones increase monotonically with higher GC3 almost without exception. The most extreme increases in occurrence in response to higher GC3 are those of CTG, GCC, and GTG, and the largest decreases are those of AAA and GAA. Note that these results for plain codon occurrences, and similar ones below for dinucleotides, suffice to conclude that neither GC content nor base composition can possibly account for the occurrence of individual codons in groups comprising many coding regions (where the fact that the contrasted groups contain many genes makes it hard to invoke constraints arising from the need of individual genes to encode peculiar proteins).

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