Directionality of point mutation and 5-methylcytosine deamination rates in the chimpanzee genome

Background The pattern of point mutation is important for studying mutational mechanisms, genome evolution, and diseases. Previous studies of mutation direction were largely based on substitution data from a limited number of loci. To date, there is no genome-wide analysis of mutation direction or methylation-dependent transition rates in the chimpanzee or its categorized genomic regions. Results In this study, we performed a detailed examination of mutation direction in the chimpanzee genome and its categorized genomic regions using 588,918 SNPs whose ancestral alleles could be inferred by mapping them to human genome sequences. The C→T (G→A) changes occurred most frequently in the chimpanzee genome. Each type of transition occurred approximately four times more frequently than each type of transversion. Notably, the frequency of C→T (G→A) was the highest in exons among the genomic categories regardless of whether we calculated directly, normalized with the nucleotide content, or removed the SNPs involved in the CpG effect. Moreover, the directionality of the point mutation in exons and CpG islands were opposite relative to their corresponding intergenic regions, indicating that different forces govern the nucleotide changes. Our analysis suggests that the GC content is not in equilibrium in the chimpanzee genome. Further quantitative analysis revealed that the 5-methylcytosine deamination rates at CpG sites were highly dependent on the local GC content and the lengths of SNP flanking sequences and varied among categorized genomic regions. Conclusion We present the first mutational spectrum, estimated by three different approaches, in the chimpanzee genome. Our results provide detailed information on recent nucleotide changes and methylation-dependent transition rates in the chimpanzee genome after its split from the human. These results have important implications for understanding genome composition evolution, mechanisms of point mutation, and other genetic factors such as selection, biased codon usage, biased gene conversion, and recombination

Features of Recent Codon Evolution: A Comparative Polymorphism-Fixation Study

Features of amino-acid and codon changes can provide us important insights on protein evolution. So far, investigators have often examined mutation patterns at either interspecies fixed substitution or intraspecies nucleotide polymorphism level, but not both. Here, we performed a unique analysis of a combined set of intra-species polymorphisms and inter-species substitutions in human codons. Strong difference in mutational pattern was found at codon positions 1, 2, and 3 between the polymorphism and fixation data. Fixation had strong bias towards increasing the rarest codons but decreasing the most frequently used codons, suggesting that codon equilibrium has not been reached yet. We detected strong CpG effect on CG-containing codons and subsequent suppression by fixation. Finally, we detected the signature of purifying selection against A∣U dinucleotides at synonymous dicodon boundaries. Overall, fixation process could effectively and quickly correct the volatile changes introduced by polymorphisms so that codon changes could be gradual and directional and that codon composition could be kept relatively stable during evolution

A compiled and systematic reference map of nucleosome positions across the Saccharomyces cerevisiae genome

Different genome-wide reference maps of Saccharomyces cerevisiae nucleosome positions are compiled and can be visualized on a browser

Identification of conserved gene structures and carboxy-terminal motifs in the Myb gene family of Arabidopsis and Oryza sativa L. ssp. indica

BACKGROUND: Myb proteins contain a conserved DNA-binding domain composed of one to four repeat motifs (referred to as R0R1R2R3); each repeat is approximately 50 amino acids in length, with regularly spaced tryptophan residues. Although the Myb proteins comprise one of the largest families of transcription factors in plants, little is known about the functions of most Myb genes. Here we use computational techniques to classify Myb genes on the basis of sequence similarity and gene structure, and to identify possible functional relationships among subgroups of Myb genes from Arabidopsis and rice (Oryza sativa L. ssp. indica). RESULTS: This study analyzed 130 Myb genes from Arabidopsis and 85 from rice. The collected Myb proteins were clustered into subgroups based on sequence similarity and phylogeny. Interestingly, the exon-intron structure differed between subgroups, but was conserved in the same subgroup. Moreover, the Myb domains contained a significant excess of phase 1 and 2 introns, as well as an excess of nonsymmetric exons. Conserved motifs were detected in carboxy-terminal coding regions of Myb genes within subgroups. In contrast, no common regulatory motifs were identified in the noncoding regions. Additionally, some Myb genes with similar functions were clustered in the same subgroups. CONCLUSIONS: The distribution of introns in the phylogenetic tree suggests that Myb domains originally were compact in size; introns were inserted and the splicing sites conserved during evolution. Conserved motifs identified in the carboxy-terminal regions are specific for Myb genes, and the identified Myb gene subgroups may reflect functional conservation

A novel statistical method to estimate the effective SNP size in vertebrate genomes and categorized genomic regions

Background The local environment of single nucleotide polymorphisms (SNPs) contains abundant genetic information for the study of mechanisms of mutation, genome evolution, and causes of diseases. Recent studies revealed that neighboring-nucleotide biases on SNPs were strong and the genome-wide bias patterns could be represented by a small subset of the total SNPs. It remains unsolved for the estimation of the effective SNP size, the number of SNPs that are sufficient to represent the bias patterns observed from the whole SNP data. Results To estimate the effective SNP size, we developed a novel statistical method, SNPKS, which considers both the statistical and biological significances. SNPKS consists of two major steps: to obtain an initial effective size by the Kolmogorov-Smirnov test (KS test) and to find an intermediate effective size by interval evaluation. The SNPKS algorithm was implemented in computer programs and applied to the real SNP data. The effective SNP size was estimated to be 38,200, 39,300, 38,000, and 38,700 in the human, chimpanzee, dog, and mouse genomes, respectively, and 39,100, 39,600, 39,200, and 42,200 in human intergenic, genic, intronic, and CpG island regions, respectively. Conclusion SNPKS is the first statistical method to estimate the effective SNP size. It runs efficiently and greatly outperforms the algorithm implemented in SNPNB. The application of SNPKS to the real SNP data revealed the similar small effective SNP size (38,000 – 42,200) in the human, chimpanzee, dog, and mouse genomes as well as in human genomic regions. The findings suggest strong influence of genetic factors across vertebrate genomes

Dynamic placement of the linker histone H1 associated with nucleosome arrangement and gene transcription in early Drosophila embryonic development

The linker histone H1 is critical to maintenance of higher-order chromatin structures and to gene expression regulation. However, H1 dynamics and its functions in embryonic development remain unresolved. Here, we profiled gene expression, nucleosome positions, and H1 locations in early Drosophila embryos. The results show that H1 binding is positively correlated with the stability of beads-on-a-string nucleosome organization likely through stabilizing nucleosome positioning and maintaining nucleosome spacing. Strikingly, nucleosomes with H1 placement deviating to the left or the right relative to the dyad shift to the left or the right, respectively, during early Drosophila embryonic development. H1 occupancy on genic nucleosomes is inversely correlated with nucleosome distance to the transcription start sites. This inverse correlation reduces as gene transcription levels decrease. Additionally, H1 occupancy is lower at the 5\u27 border of genic nucleosomes than that at the 3\u27 border. This asymmetrical pattern of H1 occupancy on genic nucleosomes diminishes as gene transcription levels decrease. These findings shed new lights into how H1 placement dynamics correlates with nucleosome positioning and gene transcription during early Drosophila embryonic development

Differential analysis of chromatin accessibility and histone modifications for predicting mouse developmental enhancers

Enhancers are distal cis-regulatory elements that modulate gene expression. They are depleted of nucleosomes and enriched in specific histone modifications; thus, calling DNase-seq and histone mark ChIP-seq peaks can predict enhancers. We evaluated nine peak-calling algorithms for predicting enhancers validated by transgenic mouse assays. DNase and H3K27ac peaks were consistently more predictive than H3K4me1/2/3 and H3K9ac peaks. DFilter and Hotspot2 were the best DNase peak callers, while HOMER, MUSIC, MACS2, DFilter and F-seq were the best H3K27ac peak callers. We observed that the differential DNase or H3K27ac signals between two distant tissues increased the area under the precision-recall curve (PR-AUC) of DNase peaks by 17.5-166.7% and that of H3K27ac peaks by 7.1-22.2%. We further improved this differential signal method using multiple contrast tissues. Evaluated using a blind test, the differential H3K27ac signal method substantially improved PR-AUC from 0.48 to 0.75 for predicting heart enhancers. We further validated our approach using postnatal retina and cerebral cortex enhancers identified by massively parallel reporter assays, and observed improvements for both tissues. In summary, we compared nine peak callers and devised a superior method for predicting tissue-specific mouse developmental enhancers by reranking the called peaks

Computational and molecular analysis of Myb gene family

Myb proteins are defined by a highly conserved DNA-specific binding domain termed Myb, which is composed of approximately 50 amino acids with constantly spaced tryptophan residues. Multiple copies of Myb domains often exist as tandem repeats within a single protein. There are up to four tandem Myb repeats present in Myb proteins identified to date (termed R0R1R2R3 hereafter).;In our study, we collected additional Myb genes, and performed a series of phylogenetic analyses to explore the evolutionary origin of Myb genes. The results suggest that the Myb gene family originated from an ancient one Myb-box gene. One and two intragenic duplications produced R2R3 and R1R2R3 Myb genes, respectively, which then co-existed in the primitive eukaryotes and gave rise to the currently extant Myb genes. Based on our results, we proposed that plant R1R2R3 Myb genes were derived from R2R3 Myb genes by gain of the R1 repeat through an ancient intragenic duplication; this gain model is more parsimonious than the previous proposal that plant R2R3 Myb genes were derived from RlR2R3 Myb genes by loss of the R1 repeat. The phylogenetic analysis of isolated individual Myb repeats indicates that R2 repeat has evolved more slowly than the R1 and R3 repeats. However, it is not clear which repeat is the most ancient one.;Another goal of our project is to classify and predict functions of Myb genes. We clustered the closely-related Myb genes into subgroups from Arabidopsis and rice on a basis of sequence similarity and phylogeny. The gene structure analysis revealed that both the positions and phases of introns are conserved in the same subgroup, although these differ between subgroups. Conserved motifs were detected in C-terminal coding regions within subgroups, and these motifs exist specifically in Myb genes. We also found that Myb genes with similar functions are clustered together. In contrast, no conserved regulatory elements were identified in the divergent non-coding regions. Additionally, the distribution pattern of introns in the phylogenetic tree indicates that Myb domains originally had a compact size without introns. Non-coding sequences were inserted and the splicing sites were conserved during evolution.</p