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

dc.contributor.author Antezana, Marcos A. en_US
dc.contributor.author Jordan, I. King en_US
dc.contributor.corporatename University of Chicago. Dept. of Ecology and Evolution en_US
dc.contributor.corporatename Georgia Institute of Technology. School of Biology en_US
dc.date.accessioned 2011-12-22T19:59:37Z
dc.date.available 2011-12-22T19:59:37Z
dc.date.issued 2008-05-14
dc.description © 2008 Antezana, Jordan. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. en_US
dc.description DOI: 10.1371/journal.pone.0002145 en_US
dc.description.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 R2s reaching 99% when GC content is ,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 nongenic 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. en_US
dc.identifier.citation Antezana, M. and I.K. Jordan, 2008. Highly conserved regimes of neighbor-base-dependent mutation generated the background primary-structural heterogeneities along vertebrate chromosomes. PLoS ONE 3: e2145 en_US
dc.identifier.doi 10.1371/journal.pone.0002145
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/1853/42114
dc.language.iso en_US en_US
dc.publisher Georgia Institute of Technology en_US
dc.publisher.original Public Library of Science en_US
dc.subject Vertebrates en_US
dc.subject Non-coding DNA en_US
dc.subject Codons en_US
dc.subject Guanine and cytosine content en_US
dc.subject Sequence motif en_US
dc.title Highly conserved regimes of neighbor-base-dependent mutation generated the background primary-structural heterogeneities along vertebrate chromosomes en_US
dc.type Text
dc.type.genre Article
dspace.entity.type Publication
local.contributor.author Jordan, I. King
local.contributor.corporatename College of Sciences
local.contributor.corporatename School of Biological Sciences
relation.isAuthorOfPublication 1c155699-6f2d-418d-83cd-9e1424896d4f
relation.isOrgUnitOfPublication 85042be6-2d68-4e07-b384-e1f908fae48a
relation.isOrgUnitOfPublication c8b3bd08-9989-40d3-afe3-e0ad8d5c72b5
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