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Conservation of Neutral Substitution Rate and Substitutional Asymmetries in Mammalian Genes
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
2010 (English)In: Genome Biology and Evolution, ISSN 1759-6653, Vol. 2, no 1, 19-28 p.Article in journal (Refereed) Published
Abstract [en]

Local variation in neutral substitution rate across mammalian genomes is governed by several factors, including sequence context variables and structural variables. In addition, the interplay of replication and transcription, known to induce a strand bias in mutation rate, gives rise to variation in substitutional strand asymmetries. Here, we address the conservation of variation in mutation rate and substitutional strand asymmetries using primate-and rodent-specific repeat elements located within the introns of protein-coding genes. We find significant but weak conservation of local mutation rates between human and mouse orthologs. Likewise, substitutional strand asymmetries are conserved between human and mouse, where substitution rate asymmetries show a higher degree of conservation than mutation rate. Moreover, we provide evidence that replication and transcription are correlated to the strength of substitutional asymmetries. The effect of transcription is particularly visible for genes with highly conserved gene expression. In comparison with replication and transcription, mutation rate influences the strength of substitutional asymmetries only marginally.

Place, publisher, year, edition, pages
2010. Vol. 2, no 1, 19-28 p.
Keyword [en]
neutral substitution rate, substitutional strand asymmetries, transcription-induced mutation, gene expression conservation
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-135745DOI: 10.1093/gbe/evp056ISI: 000280480000003OAI: oai:DiVA.org:uu-135745DiVA: diva2:375503
Available from: 2010-12-08 Created: 2010-12-08 Last updated: 2013-08-30Bibliographically approved
In thesis
1. Nucleotide Substitution Patterns in Vertebrate Genomes
Open this publication in new window or tab >>Nucleotide Substitution Patterns in Vertebrate Genomes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The rates and patterns at which nucleotide substitutions occur vary significantly across the genome sequence of vertebrates. A prominent example is the difference in the rate of evolution of functional sequences versus nonfunctional (neutrally evolving) sequences, which is explained by the influence of natural selection on functional sequences. However, even within neutrally evolving sequences there is striking variation in the rates and patterns of nucleotide substitutions. Unraveling the underlying processes that induce this variation is necessary to understand the basic principles of variation in neutral substitution profiles, which in turn is crucial for the identification of regions in the genome where natural selection acts. This research question builds the main focus of the present thesis. I have studied the causes and consequences of variation in different patterns of nucleotide substitutions. In particular, I have investigated substitutional strand asymmetries in mammalian genes and could show that they result from the asymmetric nature of DNA replication and transcription. Comparative analysis of substitutional asymmetries then suggested that the organization of DNA replication and the level of transcription are conserved among mammals. Further, I have examined the variation in CpG mutation rate among human genes and could show that beside DNA methylation also GC content plays a decisive role in CpG mutability. In addition, I have studied the signatures of GC-biased gene conversion and its impact on the evolution of the GC isochore structure in chicken. By comparison of the results in chicken to previous results in human I found evidence that karyotype stability is critical for the evolution of GC isochores. Finally, beside the empirical studies, I have performed theoretical investigations of substitution rates in functional sequences. More precisely, I have explored the temporal dynamics of estimates of the ratio of non-synonymous to synonymous substitution rates dN/dS in a phylogentic-population genetic framework.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 50 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1048
Keyword
nucleotide substitutions, mutation rate variation, strand asymmetries, CpG effect, GC-biased gene conversion, codon evolution
National Category
Evolutionary Biology Genetics
Research subject
Biology with specialization in Molecular Evolution
Identifiers
urn:nbn:se:uu:diva-198787 (URN)978-91-554-8681-5 (ISBN)
Public defence
2013-06-13, Lindahlsalen, EBC, Norbyvägen 18C, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2013-05-23 Created: 2013-04-25 Last updated: 2015-04-22Bibliographically approved

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Mugal, Carina F.Wolf, JochenEllegren, Hans

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