Dataset Information

Methylation-driven model for analysis of dinucleotide evolution in genomes.

ABSTRACT: BACKGROUND:CpGs, the major methylation sites in vertebrate genomes, exhibit a high mutation rate from the methylated form of CpG to TpG/CpA and, therefore, influence the evolution of genome composition. However, the quantitative effects of CpG to TpG/CpA mutations on the evolution of genome composition in terms of the dinucleotide frequencies/proportions remain poorly understood. RESULTS:Based on the neutral theory of molecular evolution, we propose a methylation-driven model (MDM) that allows predicting the changes in frequencies/proportions of the 16 dinucleotides and in the GC content of a genome given the known number of CpG to TpG/CpA mutations. The application of MDM to the 10 published vertebrate genomes shows that, for most of the 16 dinucleotides and the GC content, a good consistency is achieved between the predicted and observed trends of changes in the frequencies and content relative to the assumed initial values, and that the model performs better on the mammalian genomes than it does on the lower-vertebrate genomes. The model's performance depends on the genome composition characteristics, the assumed initial state of the genome, and the estimated parameters, one or more of which are responsible for the different application effects on the mammalian and lower-vertebrate genomes and for the large deviations of the predicted frequencies of a few dinucleotides from their observed frequencies. CONCLUSIONS:Despite certain limitations of the current model, the successful application to the higher-vertebrate (mammalian) genomes witnesses its potential for facilitating studies aimed at understanding the role of methylation in driving the evolution of genome dinucleotide composition.

SUBMITTER: Sun JH

PROVIDER: S-EPMC7140373 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Methylation-driven model for analysis of dinucleotide evolution in genomes.

Sun Jian-Hong JH Ai Shi-Meng SM Liu Shu-Qun SQ

Theoretical biology & medical modelling 20200408 1

<h4>Background</h4>CpGs, the major methylation sites in vertebrate genomes, exhibit a high mutation rate from the methylated form of CpG to TpG/CpA and, therefore, influence the evolution of genome composition. However, the quantitative effects of CpG to TpG/CpA mutations on the evolution of genome composition in terms of the dinucleotide frequencies/proportions remain poorly understood.<h4>Results</h4>Based on the neutral theory of molecular evolution, we propose a methylation-driven model (MDM ...[more]

PMID: 32264909

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Project description:BACKGROUND: The Human Papillomavirus (HPV) genome is divided into early and late coding sequences, including 8 open reading frames (ORFs) and a regulatory region (LCR). Viral gene expression may be regulated through epigenetic mechanisms, including cytosine methylation at CpG dinucleotides. We have analyzed the distribution of CpG sites and CpG islands/clusters (CGI) among 92 different HPV genomes grouped in function of their preferential tropism: cutaneous or mucosal. We calculated the proportion of CpG sites (PCS) for each ORF and calculated the expected CpG values for each viral type. RESULTS: CpGs are underrepresented in viral genomes. We found a positive correlation between CpG observed and expected values, with mucosal high-risk (HR) virus types showing the smallest O/E ratios. The ranges of the PCS were similar for most genomic regions except E4, where the majority of CpGs are found within islands/clusters. At least one CGI belongs to each E2/E4 region. We found positive correlations between PCS for each viral ORF when compared with the others, except for the LCR against four ORFs and E6 against three other ORFs. The distribution of CpG islands/clusters among HPV groups is heterogeneous and mucosal HR-HPV types exhibit both lower number and shorter island sizes compared to cutaneous and mucosal Low-risk (LR) HPVs (all of them significantly different). CONCLUSIONS: There is a difference between viral and cellular CpG underrepresentation. There are significant correlations between complete genome PCS and a lack of correlations between several genomic region pairs, especially those involving LCR and E6. L2 and L1 ORF behavior is opposite to that of oncogenes E6 and E7. The first pair possesses relatively low numbers of CpG sites clustered in CGIs while the oncogenes possess a relatively high number of CpG sites not associated to CGIs. In all HPVs, E2/E4 is the only region with at least one CGI and shows a higher content of CpG sites in every HPV type with an identified E4. The mucosal HR-HPVs show either the shortest CGI size, followed by the mucosal LR-HPVs and lastly by the cutaneous viral subgroup, and a trend to the lowest CGI number, followed by the cutaneous viral subgroup and lastly by the mucosal LR-HPVs.

Project description:During the long history of biological evolution, genome structures have undergone enormous changes. Nevertheless, some traits or vestiges of the primordial genome (defined as the most primitive nucleic acid genome for life on earth in this paper) may remain in modern genetic systems. It is of great importance to find these traits or vestiges for the study of the origin and evolution of genomes. As the shorter is a sequence, the less probable it would be modified during genome evolution. And if mutated, it would be easier to reappear at the same site or another site. Consequently, the genomic frequencies of very short nucleotide sequences, such as dinucleotides, would have considerable chances to be conserved during billions of years of evolution. Prokaryotic genomes are very diverse and with a wide range of GC content. Therefore, in order to find traits or vestiges of the primordial genome remained in modern genetic systems, we have studied the characteristics of dinucleotide frequencies across bacterial and archaeal genomes. We analyzed the dinucleotide frequency patterns of the whole-genome sequences from more than 1300 prokaryotic species (bacterial and archaeal genomes available as of December 2012). The results show that the frequencies of the dinucleotides AC, AG, CA, CT, GA, GT, TC, and TG are well-conserved across various genomes, while the frequencies of other dinucleotides vary considerably among species. The dinucleotide frequency conservation/variation pattern seems to correlate with the distributions of dinucleotides throughout a genome and across genomes. Further analysis indicates that the phenomenon would be determined by strand symmetry of genomic sequences (the second parity rule) and GC content variations among genomes. We discussed some possible origins of strand symmetry. And we propose that the phenomenon of frequency conservation of some dinucleotides may provide insights into the genomic composition of the primordial genetic system.

Project description:Structural and biochemical constraints force some segments of proteins to evolve more slowly than others, often allowing identification of conserved structural or sequence motifs that can be associated with substrate binding properties, chemical mechanisms, and molecular functions. We have assessed the functional and structural constraints imposed by cofactors on the evolution of new functions in a superfamily of flavoproteins characterized by two-dinucleotide binding domains, the "two dinucleotide binding domains" flavoproteins (tDBDF) superfamily. Although these enzymes catalyze many different types of oxidation/reduction reactions, each is initiated by a stereospecific hydride transfer reaction between two cofactors, a pyridine nucleotide and flavin adenine dinucleotide (FAD). Sequence and structural analysis of more than 1,600 members of the superfamily reveals new members and identifies details of the evolutionary connections among them. Our analysis shows that in all of the highly divergent families within the superfamily, these cofactors adopt a conserved configuration optimal for stereospecific hydride transfer that is stabilized by specific interactions with amino acids from several motifs distributed among both dinucleotide binding domains. The conservation of cofactor configuration in the active site restricts the pyridine nucleotide to interact with FAD from the re-side, limiting the flow of electrons from the re-side to the si-side. This directionality of electron flow constrains interactions with the different partner proteins of different families to occur on the same face of the cofactor binding domains. As a result, superimposing the structures of tDBDFs aligns not only these interacting proteins, but also their constituent electron acceptors, including heme and iron-sulfur clusters. Thus, not only are specific aspects of the cofactor-directed chemical mechanism conserved across the superfamily, the constraints they impose are manifested in the mode of protein-protein interactions. Overlaid on this foundation of conserved interactions, nature has conscripted different protein partners to serve as electron acceptors, thereby generating diversification of function across the superfamily.

Dataset Information

Methylation-driven model for analysis of dinucleotide evolution in genomes.

Publications

Methylation-driven model for analysis of dinucleotide evolution in genomes.

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