AsymTools

What is AsymTools?

AsymTools is a framework for visualizing mutational strand asymmetries related to the processes of DNA transcription and replication. 

For more information, see Haradhvala et al. Mutational strand asymmetries in cancer genomes reveals mechanisms of DNA damage and repair. Cell (2016). link to paper

How does AsymTools work?

AsymTools inputs a directory with a list of mutations for each cohort of whole-genome sequencing somatic variants. Figures are then generated measuring the transcriptional and replicative asymmetries of these cohorts. This is accomplished by comparing the mutational densities of complementary mutations in regions of the genome enriched for a specific direction of RNA transcription or DNA replication.

RNA transcription direction is determined by RefSeq definitions of tx(-) transcripts (where leftward transcription occurs on the reference strand) and tx(+) (where rightward transcription occurs on the non-reference strand). In tumors subject to certain kinds of DNA damage, transcription-coupled repair (TCR) fixes damaged sites on the transcribed strand, creating a strand asymmetry in the mutational densities of complementary mutations. For example, in lung cancers associated with smoking, carcinogens damage the guanine of C:G base pairs in the genome, resulting in C:G>A:T transversions. Since TCR creates a higher rate of repair when the damaged guanine of a C:G base pair is located on the transcribed strand, we measure a lower mutational density (C>A in tx(+) and G>T in tx(-) regions) when compared with C:G base pairs of the opposite orientation (G>T in tx(+) and C>A in tx(-)). This is visualized in the plot below created by a run of AsymTools on a cohort of eight TCGA lung adenocarcinomas with strong evidence of smoking-associated mutagenesis.

 

DNA replication direction is determined using replication-timing profiles. Early-to-late timing transition regions (TTRs) correspond to DNA replication enriched in a certain direction. We define regions of negative slope as “left-replicating.” In these regions we predict the reference strand to be primarily replicated as the leading strand template. Regions of positive slope are defined as “right-replicating” and correspond to the reference strand being copied as the lagging strand template. For example, tumors with mutant polymerase epsilon exonuclease proofreading (POLE) display high levels of C>A mutations on the leading strand template. Thus we expect to see higher densities of C>A than G>T in left-replicating regions (where the cytosine is located on the leading strand) and higher densities of G>T than C>A in right-replicating regions (where the cytosine is located on the lagging strand). This can be visualized in the AsymTools plot below on a cohort of 10 colorectal and 2 endometrial mutant-POLE TCGA samples.

AsymTools provides additional figures to characterize the asymmetry, including how it is affected by various covariates. Finally AsymTools outputs an “asymmetry map” which summarizes the asymmetries present in each cohort.

 

How do I get AsymTools?

Please visit our download page.