Replication-Associated Mutational Asymmetry in the Human Genome

During evolution, mutations occur at rates that can differ between the two DNA strands. In the human genome, nucleotide substitutions occur at different rates on the transcribed and non-transcribed strands that may result from transcription-coupled repair. These mutational asymmetries generate trans...

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Bibliographic Details
Published in:Molecular biology and evolution 2011-08, Vol.28 (8), p.2327-2337
Main Authors: Chen, Chun-Long, Duquenne, Lauranne, Audit, Benjamin, Guilbaud, Guillaume, Rappailles, Aurélien, Baker, Antoine, Huvet, Maxime, d'Aubenton-Carafa, Yves, Hyrien, Olivier, Arneodo, Alain, Thermes, Claude
Format: Article
Language:English
Subjects:
Base Composition
Biological Physics
Cell Line
Deoxyribonucleic acid
DNA
DNA polymerase
DNA Replication - genetics
Eukaryotes
Evolution, Molecular
Genome, Human - genetics
Genomes
Germ Cells - metabolism
HeLa Cells
Humans
K562 Cells
Models, Genetic
Mutation
Mutation - genetics
Organ Specificity - genetics
Physics
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Summary:During evolution, mutations occur at rates that can differ between the two DNA strands. In the human genome, nucleotide substitutions occur at different rates on the transcribed and non-transcribed strands that may result from transcription-coupled repair. These mutational asymmetries generate transcription-associated compositional skews. To date, the existence of such asymmetries associated with replication has not yet been established. Here, we compute the nucleotide substitution matrices around replication initiation zones identified as sharp peaks in replication timing profiles and associated with abrupt jumps in the compositional skew profile. We show that the substitution matrices computed in these regions fully explain the jumps in the compositional skew profile when crossing initiation zones. In intergenic regions, we observe mutational asymmetries measured as differences between complementary substitution rates; their sign changes when crossing initiation zones. These mutational asymmetries are unlikely to result from cryptic transcription but can be explained by a model based on replication errors and strand-biased repair. In transcribed regions, mutational asymmetries associated with replication superimpose on the previously described mutational asymmetries associated with transcription. We separate the substitution asymmetries associated with both mechanisms, which allows us to determine for the first time in eukaryotes, the mutational asymmetries associated with replication and to reevaluate those associated with transcription. Replication-associated mutational asymmetry may result from unequal rates of complementary base misincorporation by the DNA polymerases coupled with DNA mismatch repair (MMR) acting with different efficiencies on the leading and lagging strands. Replication, acting in germ line cells during long evolutionary times, contributed equally with transcription to produce the present abrupt jumps in the compositional skew. These results demonstrate that DNA replication is one of the major processes that shape human genome composition.
ISSN:0737-4038
1537-1719
DOI:10.1093/molbev/msr056