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Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types.

ABSTRACT: Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to control sites with matched sequence composition. There is a strong (1.43-fold) and significant excess of mutations at functional binding sites across TFs, and the mutations that accumulate in cancers are typically more disruptive than variants tolerated in extant human populations at the same sites. CTCF binding sites suffer an exceptionally high mutational load in cancer (3.31-fold excess) relative to control sites, and we demonstrate for the first time that this effect is seen in essentially all cancer types with sufficient data. The sub-set of CTCF sites involved in higher order chromatin structures has the highest mutational burden, suggesting a widespread breakdown of chromatin organization. However, we find no evidence for selection driving these distinctive patterns of mutation. The mutational load at CTCF-binding sites is substantially determined by replication timing and the mutational signature of the tumor in question, suggesting that selectively neutral processes underlie the unusual mutation patterns. Pervasive hyper-mutation within transcription factor binding sites rewires the regulatory landscape of the cancer genome, but it is dominated by mutational processes rather than selection.

SUBMITTER: Kaiser VB

PROVIDER: S-EPMC4973979 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types.

Kaiser Vera B VB Taylor Martin S MS Semple Colin A CA

PLoS genetics 20160804 8

Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putativ ...[more]

PMID: 27490693

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Project description:Transposable elements (TEs) play a pivotal role in shaping diversity in eukaryotic genomes. The covered smut pathogen on barley, Ustilago hordei, encountered a recent genome expansion. Using long reads, we assembled genomes of 6 U. hordei strains and 3 sister species, to study this genome expansion. We found that larger genome sizes can mainly be attributed to a higher genome fraction of long terminal repeat retrotransposons (LTR-RTs). In the studied smut genomes, LTR-RTs fractions are the largest in U. hordei and are positively correlated with the mating-type locus sizes, which is up to ~560 kb in U. hordei. Furthermore, LTR-RTs were found to be associated with higher nucleotide substitution levels, as these occur in specific genome regions of smut species with a recent LTR-RT proliferation. Moreover, genes in genome regions with higher nucleotide substitution levels generally reside closer to LTR-RTs than other genome regions. Genome regions with many nucleotide substitutions encountered an especially high fraction of CG substitutions, which is not observed for LTR-RT sequences. The high nucleotide substitution levels particularly accelerate the evolution of secretome genes, as their more accessory nature results in substitutions that often lead to amino acid alterations. IMPORTANCE Genomic alteration can be generated through various means, in which transposable elements (TEs) can play a pivotal role. Their mobility causes mutagenesis in itself and can disrupt the function of the sequences they insert into. They also impact genome evolution as their repetitive nature facilitates nonhomologous recombination. Furthermore, TEs have been linked to specific epigenetic genome organizations. We report a recent TE proliferation in the genome of the barley covered smut fungus, Ustilago hordei. This proliferation is associated with a distinct nucleotide substitution regime that has a higher rate and a higher fraction of CG substitutions. This different regime shapes the evolution of genes in subjected genome regions. We hypothesize that TEs may influence the error-rate of DNA polymerase in a hitherto unknown fashion.

Dataset Information

Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types.

Publications

Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types.

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