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Expression changes and chromatin architecture modifications in WBS cells.

<p>Changes in expression and chromatin structure in WBS (GM13472) versus Ctrl (GM07006) cells. Changes in histone marks are presented as the log2-fold ratio between WBS and Ctrl cells. Statistical analysis was performed by a 2-sample t-Test. Values in italics are not statistically different.</p><p>AREL  =  average relative expression level, BDL  =  below detection line, NS  =  no regions within gene were defined as significantly changed,</p><p>*most significant block according to SICER within the gene (FDR<1%).</p

Extensive chromatin interactions of seven genes flanking the WBSCR on human chromosome 7 (HSA7) in cells from a healthy control individual.

<p>(<b>A</b>) Windowed and normalized 4C signal of each of the seven viewpoints along the entire HSA7. The black ticks below each graph show the location of the Bricks (Blocks of Regulators In Chromosomal Kontext). The gene density across HSA7, as well as the windowed profiles of H4K20me1 and H3K27me3 marks in the same cell line are shown below. Some examples of strong correlation of gene-dense regions and high density of H4K20me1 marks with highly interacting regions are highlighted in blue. The mapping of the assessed genes/viewpoints and of the WBSCR is indicated at the bottom. The red box specifies the close-up shown in panel B. (<b>B</b>) Close-up of the windowed 4C signal of the seven viewpoints around the WBSCR for the region indicated with a red box on HSA7 (top panel). The windowed 4C signal is shown in grey, while the profile corrected 4C signal (after removal of the highly interacting neighboring background signal) is overlaid in black. The position of all genes are displayed at the bottom, and the mapping of the assessed viewpoints is highlighted by red and green arrows indicating if the corresponding genes are down- or upregulated in cells from WBS patients, respectively. Black arrows underscore the mapping of the viewpoint that is not modified in gene expression (<i>ZNF107</i>) and the newly identified interacting partners <i>AUTS2</i> and <i>CALN1</i>. The location of the WBSCR is indicated by a purple horizontal bar. A close-up of interactions within this WBSCR is provided in <b>Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079973#pone.0079973.s004" target="_blank">Figure S4</a></b>.</p

Identification of regulatory deletions telomeric to <i>PAX6</i>.

<p>Regulatory deletions telomeric to <i>PAX6</i> were identified in individual 1514 (chr11:30,874,642–31,654,833), individual 753 (chr11:30,967,000–31,704,000), individual 555 (chr11:31,108,579–31,649–842), individual 2014 (chr11:31,234,395–31,751,815) and individual 659 (chr11:31,379,000–31,708,000). The schematic diagram shows how the ‘critical region’ (delimited by grey dotted lines) required for <i>PAX6</i> transcriptional activation was delineated by combining our data with published deletions with known coordinates [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref055" target="_blank">55</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref067" target="_blank">67</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref068" target="_blank">68</a>]. <i>PAX6</i> regulatory deletions from the present study are shown by red blocks. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are based on the Human Genome Assembly hg18.</p

Details of the clinical diagnoses and genetic pathology identified in individuals in this study.

<p>Details of the clinical diagnoses and genetic pathology identified in individuals in this study.</p

Identification of a potential <i>PITX2</i> regulatory deletion.

<p>Genome-wide array CGH identified a deletion of approximately 3.5 Mb in individual 1194 (chr4:111,994,000–115,504,000) (red bar). The deletion is located telomeric to the <i>PITX2</i> gene on chromosome 4. The positions of conserved elements (CE) in the deleted region, as identified by Volkmann et al., 2011 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref047" target="_blank">47</a>] are marked by orange ellipses. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are shown on the x-axis and are based on the Human Genome Assembly hg18.</p

Mutation analysis of the <i>FOXC1</i> locus.

<p><b>(A)</b> Genome-wide array CGH identified two deletions encompassing the <i>FOXC1</i> gene in individuals 1449 (chr6:1,543,591–1,675,085) and 1246 (chr6:1,543,591–1,675,085). <b>(B)</b> Direct sequencing of the <i>FOXC1</i> coding region identified a heterozygous substitution in individual 1839 (c.235C>A, p.(Pro79Thr)) and another in individual 1634 (c.302T>C, p.(Leu101Pro)). <i>FOXC1</i> mutation screening in unaffected parents of both patients showed that the mutations had occurred <i>de novo</i>. The locations of both mutations within the fork-head domain of the FOXC1 protein are indicated by vertical arrows. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are based on the Human Genome Assembly hg18. The genomic sequence identifier for <i>FOXC1</i> is NG_009368.</p

Identification of <i>PAX6</i> whole-gene deletions.

<p>Genome-wide array CGH analysis identified a 650 kb deletion in individual 2193 (chr11:31,199,000–31,849,000), a 520 kb deletion in individual 377 (chr11:31,394,000–31,914,000), a 154 kb deletion in individual 1510 (chr11:31,779,000–31,933,000) and a 96 kb deletion in individual 1977 (chr11:31,698,271–31,794,414), all involving <i>PAX6</i>. Red bars show the position of the deletions. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are based on the Human Genome Assembly hg18.</p