Divergence of orthologs and homologs of representative functional categories

Molecular function and biological process. Colors towards red signify high relative conservation of the group of genes in a particular genome. Colors towards blue signify low relative conservation. Gray means no statistically significant difference in conservation level compared to the background of the rest of the genome. White cells denote that there is no gene with the GO term and with ortholog/homolog in the other organism. The colored lines on the left of the names of the functional classes correspond to the colors of the categories represented in Figure 5.<p><b>Copyright information:</b></p><p>Taken from "Functional protein divergence in the evolution of "</p><p>http://genomebiology.com/2008/9/2/R33</p><p>Genome Biology 2008;9(2):R33-R33.</p><p>Published online 15 Feb 2008</p><p>PMCID:PMC2374701.</p><p></p

Comparison of epigenetic association between normal and cancer cell lines.

<p>We analyzed (<b>A–C</b>) six normal human cell lines (Gm12878, Hsmm, Huvec, H1hesc, Nhek, Nhlf) and (<b>D</b>) three cancer cell lines (Hepg2, Helas3, K562) for associations between transcription start site inclusion rate and splicing exon inclusion rate and histone modification enrichment for protein-coding genes (<b>A,C,</b> and <b>D</b>) and lincRNAs (<b>B</b>). Values represent the average of Fisher transformed Spearman rank correlations to enable direct comparison. Coefficients are color-coded, with red representing increasingly negative and green representing increasingly positive correlation. Distance from exon categories signifies a region relative to a given exon where histone enrichment was measured; 0 kb represents region within given exon boundaries, and 1 kb, 2 kb, and 5 kb signify regions from the exon boundary either upstream (negative) or downstream (positive).</p

Frequency of histone modification marks found significantly associated with transcription start-site switching (marked red) and splicing (marked green).

<p>Our gene-specific approach identified 840 candidate genes for which transcript diversity significantly associated with histone modification enrichment. Note that transcription start-site switching and splicing of a single gene can be associated with multiple histone marks.</p

Differential H3K4me2 enrichment near exon 3 of HPS4.

<p>The HPS4 gene produces up to 8 isoforms. Three of these isoforms (isoforms 2, 3, and 8 – TSS exon marked with red dashed line) utilize the 3^rd exon as the transcription start site (TSS) and four isoforms (isoforms 4–7, exons marked with green dashed line) utilize the 3^rd exon as an internal exon. Considering the H3K4me2 modification within the exon 3 TSS boundaries (red dashed lines), the enrichment significantly differs between cell lines in which no isoforms with TSS at the 3^rd exon position (isoforms 2, 3, and 8) are expressed (EIR = 0) and cell lines that express isoforms with TSS at the 3^rd exon position.</p

Summary of datasets used in this study.

<p>ENCODE – data generated by the ENCODE consortium <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003611#pcbi.1003611-Consortium1" target="_blank">[8]</a>, available at <a href="http://genome.ucsc.edu/ENCODE/downloads.html" target="_blank">http://genome.ucsc.edu/ENCODE/downloads.html</a>.</p><p>GTF – gene transfer file format used for human genome annotation.</p

Prediction of ETV1 exon 5 inclusion in the Hmec cell line and overall prediction accuracy.

<p>(<b>A</b>) Exon 5 of ETV1 is present in isoforms 9 and 11, but it is spliced in isoforms 10, 12, and 13. Comparing the enrichment of H3K9ac, cell lines from which exon 5 was constitutively spliced (Gm12878 and HepG2) displayed an absence of H3K9ac, whereas the remaining cell lines, including Hmec, showed varying levels of H3K9ac enrichment. Since the Hmec cell line H3K9ac enrichment resembles that of the cell lines in which the 5^th exon was not constitutively spliced out, we predicted that exon 5 in Hmec would only occasionally be excluded. (<b>B</b>) The numbers of exons for which the inclusion pattern was correctly vs. incorrectly predicted in Hmec and Monocytes CD14 cell lines.</p

Prediction accuracy.

<p>(<b>A</b>) Prediction accuracy of exon inclusion categories from leave-one-out cross-validation by cell line being predicted. (<b>B</b>) Prediction accuracy by exon inclusion category comparison. (<b>C</b>) Prediction accuracy of exon inclusion categories for splicing (“SPLICING”) and transcription start-site switching (“TSSS”).</p

DNA polymerase <b>η</b> mutational signatures are found in a variety of different types of cancer

<p>DNA polymerase (pol) η is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol η can compromise genome integrity. We explored whether the mutational signature of pol η could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol η mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase η are a common feature of tumorigenesis. Another peculiarity of pol ηmutational signatures, mutations in Y<u>C</u>G motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol η in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide.</p

Genomic localization of transcriptional regulators and AICDA associates with sites of aberrant DNA methylation.

<p>(A–D) Methylation heterogeneity of promoters of genes that are targets of master regulators. The panels display the distribution of methylation scores (M-scores) for promoters of target genes of (A) BCL6, (B) MYC, (C) EZH2, and (D) AICDA. (E) A schematic overview showing targeted abnormal promoter methylation by master regulators such as MYC, BCL6, EZH2 and AICDA in the lymphoma subtypes.</p

The insulator factor CTCF prevents spreading of aberrant methylation.

<p>(A) Methylation heterogeneity depends on the density of CTCF-binding sites. Methylation state (M-score, left) and inter-sample methylation variation (IQR, right) are shown for CTCF-BS-poor, CTCF-BS-rich, and intermediate regions. (B) Spreading of aberrant methylation from genomic position “<i>i</i>” to “<i>i</i>±1” (i.e. two neighboring sites) when at least one CTCF-BS is present (black vertical dotted line) and when no CTCF-BS is present (light grey vertical dotted line) between “<i>i</i>” and “<i>i</i>±1”, for aberrant hypo-methylation (two left panels) and aberrant hyper-methylation (two right panels). The presence of CTCF-BS more efficiently restricts the spreading of aberrant hypo-methylation. (C) A schematic overview showing spreading of abnormal methylation in the absence of CTCF-binding sites in genomic neighborhood.</p