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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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Preferences and occurrences in coding and intronic DNA vs. in non-genic DNA.The correlation between motif preferences and occurrences (left, right) in non-genic DNA (horizontal axis) vs. those in coding and intronic DNA (vertical axis, empty and solid circles). Pluses on the top right are for across-codon motif occurrences (23/1+3/12; vertical axis) and, in the bottom plots, for the dinucleotide occurrences in human spleen cells tabulated in Setlov (1976; left, vertical axis) and for the corresponding chi values derived from Setlov's dinucleotide occurrences (right, vertical axis). See also Methods and Figure 20.
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pone-0002145-g021: Preferences and occurrences in coding and intronic DNA vs. in non-genic DNA.The correlation between motif preferences and occurrences (left, right) in non-genic DNA (horizontal axis) vs. those in coding and intronic DNA (vertical axis, empty and solid circles). Pluses on the top right are for across-codon motif occurrences (23/1+3/12; vertical axis) and, in the bottom plots, for the dinucleotide occurrences in human spleen cells tabulated in Setlov (1976; left, vertical axis) and for the corresponding chi values derived from Setlov's dinucleotide occurrences (right, vertical axis). See also Methods and Figure 20.

Mentions: Since primary-structural patterns in non-coding DNA are likely to be due to mutation pressure and genetic drift, we plot coding-region di- and tri-nucleotide occurrences and preferences against those in intronic and non-genic DNA (Figure 20 and Figure 21). Figure 20 shows that the preference R2s are much higher than the occurrence R2s ranging from 73 to 80%, indicating that similar forces structure intronic and coding-region motif preferences. Note also that both the dinucleotide occurrences tabulated by Setlov [8] and the motif preferences inferrable from these occurrences are highly correlated to the corresponding intronic values, indicating that these 1970s data provided already very accurate information about whole-genome motif preferences. In Figure 21 we plot coding-region and intronic dinucleotide and trinucleotide occurrences and preferences against those in non-genic DNA. Coding-vs.-nongenic occurrence R2s are low but preference R2s are quite high especially for dinucleotides (94% vs. 84%). Intronic-vs.-nongenic occurrence and preference R2s are high and become very high when one excludes outlayer base runs. For instance, the trinucleotide preference-preference R2 becomes 97% if one excludes TTT, AAA, CCC, and GGG, indicating that coding-region and intronic motif preferences are structured by the same forces underlying the motif preferences of non-genic DNA, i.e., of most of the genome. The dinucleotide occurrences and preferences in Setlov's data [8] are also very correlated to those in the non-genic DNA dataset, with the occurrence R2 reaching 96% when one excludes TT and AA. This is another clear indication that these 1970s data contained very useful information on whole-genome motif preferences.


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

Antezana MA, Jordan IK - PLoS ONE (2008)

Preferences and occurrences in coding and intronic DNA vs. in non-genic DNA.The correlation between motif preferences and occurrences (left, right) in non-genic DNA (horizontal axis) vs. those in coding and intronic DNA (vertical axis, empty and solid circles). Pluses on the top right are for across-codon motif occurrences (23/1+3/12; vertical axis) and, in the bottom plots, for the dinucleotide occurrences in human spleen cells tabulated in Setlov (1976; left, vertical axis) and for the corresponding chi values derived from Setlov's dinucleotide occurrences (right, vertical axis). See also Methods and Figure 20.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002145-g021: Preferences and occurrences in coding and intronic DNA vs. in non-genic DNA.The correlation between motif preferences and occurrences (left, right) in non-genic DNA (horizontal axis) vs. those in coding and intronic DNA (vertical axis, empty and solid circles). Pluses on the top right are for across-codon motif occurrences (23/1+3/12; vertical axis) and, in the bottom plots, for the dinucleotide occurrences in human spleen cells tabulated in Setlov (1976; left, vertical axis) and for the corresponding chi values derived from Setlov's dinucleotide occurrences (right, vertical axis). See also Methods and Figure 20.
Mentions: Since primary-structural patterns in non-coding DNA are likely to be due to mutation pressure and genetic drift, we plot coding-region di- and tri-nucleotide occurrences and preferences against those in intronic and non-genic DNA (Figure 20 and Figure 21). Figure 20 shows that the preference R2s are much higher than the occurrence R2s ranging from 73 to 80%, indicating that similar forces structure intronic and coding-region motif preferences. Note also that both the dinucleotide occurrences tabulated by Setlov [8] and the motif preferences inferrable from these occurrences are highly correlated to the corresponding intronic values, indicating that these 1970s data provided already very accurate information about whole-genome motif preferences. In Figure 21 we plot coding-region and intronic dinucleotide and trinucleotide occurrences and preferences against those in non-genic DNA. Coding-vs.-nongenic occurrence R2s are low but preference R2s are quite high especially for dinucleotides (94% vs. 84%). Intronic-vs.-nongenic occurrence and preference R2s are high and become very high when one excludes outlayer base runs. For instance, the trinucleotide preference-preference R2 becomes 97% if one excludes TTT, AAA, CCC, and GGG, indicating that coding-region and intronic motif preferences are structured by the same forces underlying the motif preferences of non-genic DNA, i.e., of most of the genome. The dinucleotide occurrences and preferences in Setlov's data [8] are also very correlated to those in the non-genic DNA dataset, with the occurrence R2 reaching 96% when one excludes TT and AA. This is another clear indication that these 1970s data contained very useful information on whole-genome motif preferences.

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