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Nucleotide Substitution Patterns in Vertebrate Genomes
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
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 [en]
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: urn:nbn:se:uu:diva-198787ISBN: 978-91-554-8681-5 (print)OAI: oai:DiVA.org:uu-198787DiVA: diva2:618090
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
List of papers
1. Conservation of Neutral Substitution Rate and Substitutional Asymmetries in Mammalian Genes
Open this publication in new window or tab >>Conservation of Neutral Substitution Rate and Substitutional Asymmetries in Mammalian Genes
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.

Keyword
neutral substitution rate, substitutional strand asymmetries, transcription-induced mutation, gene expression conservation
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-135745 (URN)10.1093/gbe/evp056 (DOI)000280480000003 ()
Available from: 2010-12-08 Created: 2010-12-08 Last updated: 2013-08-30Bibliographically approved
2. Substitution rate variation at human CpG sites correlates with non-CpG divergence, methylation level and GC content
Open this publication in new window or tab >>Substitution rate variation at human CpG sites correlates with non-CpG divergence, methylation level and GC content
2011 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 6, R58- p.Article in journal (Refereed) Published
Abstract [en]

Background: A major goal in the study of molecular evolution is to unravel the mechanisms that induce variation in the germ line mutation rate and in the genome-wide mutation profile. The rate of germ line mutation is considerably higher for cytosines at CpG sites than for any other nucleotide in the human genome, an increase commonly attributed to cytosine methylation at CpG sites. The CpG mutation rate, however, is not uniform across the genome and, as methylation levels have recently been shown to vary throughout the genome, it has been hypothesized that methylation status may govern variation in the rate of CpG mutation.

Results: Here, we use genome-wide methylation data from human sperm cells to investigate the impact of DNA methylation on the CpG substitution rate in introns of human genes. We find that there is a significant correlation between the extent of methylation and the substitution rate at CpG sites. Further, we show that the CpG substitution rate is positively correlated with non-CpG divergence, suggesting susceptibility to factors responsible for the general mutation rate in the genome, and negatively correlated with GC content. We only observe a minor contribution of gene expression level, while recombination rate appears to have no significant effect.

Conclusions: Our study provides the first direct empirical support for the hypothesis that variation in the level of germ line methylation contributes to substitution rate variation at CpG sites. Moreover, we show that other genomic features also impact on CpG substitution rate variation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-162402 (URN)10.1186/gb-2011-12-6-r58 (DOI)000296646600006 ()
Available from: 2011-11-30 Created: 2011-11-30 Last updated: 2017-12-08Bibliographically approved
3. Twisted Signatures of GC-Biased Gene Conversion Embedded in an Evolutionary Stable Karyotype
Open this publication in new window or tab >>Twisted Signatures of GC-Biased Gene Conversion Embedded in an Evolutionary Stable Karyotype
2013 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 30, no 7, 1700-1712 p.Article in journal (Refereed) Published
Abstract [en]

The genomes of many vertebrates show a characteristic heterogeneous distribution of GC content, the so-called GC isochore structure. The origin of isochores has been explained via the mechanism of GC-biased gene conversion (gBGC). However, although the isochore structure is declining in many mammalian genomes, the heterogeneity in GC content is being reinforced in the avian genome. Despite this discrepancy, which remains unexplained, examinations of individual substitution frequencies in mammals and birds are both consistent with the gBGC model of isochore evolution. On the other hand, a negative correlation between substitution and recombination rate found in the chicken genome is inconsistent with the gBGC model. It should therefore be important to consider along with gBGC other consequences of recombination on the origin and fate of mutations, as well as to account for relationships between recombination rate and other genomic features. We therefore developed an analytical model to describe the substitution patterns found in the chicken genome, and further investigated the relationships between substitution patterns and several genomic features in a rigorous statistical framework. Our analysis indicates that GC content itself, either directly or indirectly via interrelations to other genomic features, has an impact on the substitution pattern. Further, we suggest that this phenomenon is particularly visible in avian genomes due to their unusually low rate of chromosomal evolution. Because of this, interrelations between GC content and other genomic features are being reinforced, and are as such more pronounced in avian genomes as compared with other vertebrate genomes with a less stable karyotype.

National Category
Evolutionary Biology Genetics
Research subject
Biology with specialization in Molecular Evolution
Identifiers
urn:nbn:se:uu:diva-198785 (URN)10.1093/molbev/mst067 (DOI)000321056200019 ()
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2017-12-06Bibliographically approved
4. Why time matters: Codon evolution and the temporal dynamics of dN/dS
Open this publication in new window or tab >>Why time matters: Codon evolution and the temporal dynamics of dN/dS
(English)Manuscript (preprint) (Other academic)
National Category
Evolutionary Biology Genetics
Research subject
Biology with specialization in Molecular Evolution
Identifiers
urn:nbn:se:uu:diva-198786 (URN)
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2013-08-30

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