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Fig. 4 | Genome Biology

Fig. 4

From: Whole-genome sequencing of glioblastoma reveals enrichment of non-coding constraint mutations in known and novel genes

Fig. 4

UCSC genome browser view of SEMA3C and DYNC1I1, key GBM genes with the highest rates of non-coding constraint mutations. For each gene, the NCCM track shows the mutations, color-coded by VAF scores (green VAF 1–10%; fuchsia VAF 11–45%). a For SEMA3C, the 14 NCCMs seen both in introns and in the flanking intergenic regions lie in regions of the genome that are well conserved across mammals and 13 of 14 are associated with at least one additional regulatory annotation. b The sequence logo (MA0148.1) of the FOXA1 TFBS shows that the SEMA3C NCCM9 mutation affects a highly conserved nucleotide that could abate the binding in the mutated site compared to the wild-type. c The affinity profiles, for the same mutated sequence, shows a decreased affinity for the FOXA1 transcription factor, in the mutated compared with the wild-type sequence. d Electrophoretic mobility shift assay of DNA protein binding for SEMA3C wt and SEMA3C NCCM9. Purified nuclear protein from GBM cell line U3065MG was tested for DNA binding to either the predicted SEMA3C wt region dsDNA (lanes 2–3) or the corresponding SEMA3C NCCM9 region dsDNA (lanes 5–6). Unlabeled dsDNA for each region was used as competitor. The total lack of shift in lanes 5–6 confirms abolition of DNA binding capacity as a consequence of the mutation. e In DYNC1I1, the majority of the 20 NCCMs are seen in the intronic regions of the gene and in regions with mammalian conservation. In addition, regulatory annotations associated with promoters and conserved TFBS are also seen

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