SHARCNET Scientific Computing Seminar Series

Wednesday 11 March, 11am-12pm, ERC 1056

Peter K. Rogan, CRC (Tier I) in Genome Bioinformatics, Department of Biochemistry & Department of Computer Science, University of Western Ontario, and

Cytognomix Inc, London ON

Mutation Forecaster, a software resource for genome-scale analysis of complete genes and human genomes

Complete genome sequencing is now feasible, becoming cost effective, and increasingly an essential component of cancer discovery and patient genomic analyses. This has created a bottleneck in interpretation of gene variants, partly because the effects of most variants remain unknown (variants of unknown significance, VUS), and also because interpretation is confounded by the lack of corresponding genetic information from closely related family members.   The VUS problem is now exacerbated by the discovery of massive numbers of variants in each genome, many never before seen. Technologies that prune variants in an individual are essential to perform any large scale gene panel, exome or genome analysis.  The variant analysis approaches I will describe improves complete gene and genome sequence analyses and by detecting dysregulated biochemical pathways.  We stratify variants by mutation severity, which can suggesting or exclude particular therapeutic options (Shirley et al. 2013 <http://www.sciencedirect.com/science/article/pii/S1672022913000296>; Dorman et al. 2014 <http://www.nature.com/srep/2014/141114/srep07063/full/srep07063.html>; Mucaki et al. 2011 <http://www.ncbi.nlm.nih.gov/pubmed/21523855>; Mucaki et al. 2013 <http://onlinelibrary.wiley.com/doi/10.1002/humu.22277/full>, Viner et al. 2014 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983938.1/>).Our patented software computes changes in information content in DNA or RNA sequences. These changes tell us which sequences disrupt the regulation of genes and how severe these changes are.   Our methods have been validated in hundreds of published studies (Caminsky et al. 2014 <http://f1000research.com/articles/3-282/v1>), and use proven information theory, one of the most important scientific advances of the last century. I will introduce a single system that amalgamates several of our software products, and which also queries existing public databases and store results for users. MutationForecaster <http://mutationforecaster.com/> provides basic capabilities offered by others, but also offers proven mutation interpretation  methods not available elsewhere. This leads to more comprehensive mutation results and ultimately, a more complete understanding of the dysregulation of disease genomes.

Since our release of the Mutation Forecaster system in January, we have been gratified to see the level of interest by the biomedical and clinical research communities. There have been 32 registrants from 18 countries.  One subscription has been activated, and others are in progress.

Our fees are reinvested to improve and expand this resource.  For example, we are developing a completely automated workflow for genome scale coding and splicing mutation analysis, and which will automatically prepare written report summaries. Our plans for this product will meet your future needs for mutation interpretation.

Cytognomix has released version 2.0.2 of the  Shannon splicing mutation pipeline for the Qiagen-CLCbio Genomics Workbench versions 7.5.2 and 8.0 and for  Genomics Server versions 6.5.3 and 7.0.  Please contact Qiagen-CLCbio to purchase a license to this software.

Cytognomix is pleased to announce the sale of annual subscriptions of our MutationForecaster system to a molecular diagnostics laboratory at a public hospital in the Toronto metropolitan area in Ontario, Canada. The client is a long time paid subscriber of our ASSEDA product, who now has an express need for higher throughput software to handle results of next generation sequencing studies. MutationForecaster™  is the only efficient and accurate platform for comprehensive, on-demand coding and mRNA splicing mutation analysis on the market.

We find and validate mutations that others cannot.

Contact us or register at mutationforecaster.com.

MutationForecaster is our new, comprehensive genome interpretation suite to interpret and validate mutations that affect mRNA splicing and protein coding. Our products can find and validate mutations that others cannot.

Here`s proof:

(Click any of the images below to view the paper)

We will be announcing our new MutationForecaster system imminently.

You can register now for a subscription. Sign up!

Veridical is now hosted by Cytognomix. The previous Veridical.org website has been migrated to Veridical.cytognomix.com.

This software product has been integrated into our new MutationForecaster webservice.  To validate splicing mutations predicted by the Shannon pipeline,  a set of gene variants (in vcf format) and RNASeq data (in bam format) are uploaded for the same individual.   Control data are built in, the analysis is automated, and results are returned directly to users. Subscriptions to MutationForecaster will be available from Cytognomix in early 2015.

The standalone software is also available from Cytognomix, which licenses it and provides installation support. To further inquire, contact us at  info@cytognomix.com.

We have published a new manuscript which has implications for metaphase chromosome epigenetics. The citation is:

Title: Localized, non-random differences in chromatin accessibility between homologous metaphase chromosomes
Authors: Khan A Wahab, Rogan K Peter, Knoll  Joan,

Journal: Molecular Cytogenetics.2014, 7:70
DOI: 10.1186/s13039-014-0070-y

URL: http://www.molecularcytogenetics.org/content/7/1/70

We have published a review of the literature on information theory-based splicing mutations.  The review includes a large dataset, comprehensive bibliography, and new  software – the Splicing Mutation Calculator – for determining the impact of mutations at natural splice sites, based on the published literature.    There are multiple citations  of this work –

for the Review paper:  Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis [v1; ref status: awaiting peer review, http://f1000r.es/4nq] (doi: 10.12688/f1000research.5654.1), 2014.

for the Dataset:    F1000Research: Dataset 1. Dataset for mRNA splicing mutations in genetic disease, (doi: 10.5256/f1000research.5654.d382482)

for the Software:   The Splicing Mutation Calculator (SMC) is available at http://splicemc.cytognomix.com. Source code: http://dx.doi.org/10.5281/zenodo.12422

Cytognomix’s technology key to new publication on origin of metastasis in breast cancer:

Dorman S, Viner C, Rogan PK. Splicing mutation analysis reveals previously unrecognized pathways in lymph node-invasive breast cancer, Nature Scientific Reports, 4: 7063 (DOI: 10.1038/srep07063), 2014.

Press Release. Dorman et al. Nat. Sci. Reports 2014

Using our patented ab initio scFISH probes, Cytognomix and Western University researchers have discovered important differences between paired chromosomes. No other product on the market can detect these chromosome features. The following article has been accepted for publication in a leading open access journal:

Khan W, Rogan PK, and Knoll JHM. Localized, Non-random Differences in Chromatin Accessibility between Homologous Metaphase Chromosomes, Mol. Cytogenetics, in press.

Stay tuned for the URL of the published paper. It should be available shortly!

Peter Rogan gave an invited presentation titled: “Interpreting pathogenic human genome variation: methods, applications and implications,” at the Patent Examiner Technical Training Program at the US Patent and Trademark Office. The presentation was webcasted  to all USPTO offices across the United States.  The program is focused on providing technical training to Patent Examiners, in this case to the Patent Examiners of Technology Center 1600 that examines patent applications on various aspects of biotechnology inventions.

The patent office recognized his contribution: link

 US Pat. App. No. 13/744459 has been published by the US Patent and Trademark Office. 

The invention is entitled: Stable gene targets in breast cancer and use thereof for optimizing therapy.

US Pat. Application No. 14/154,905 describes our method of predicting cryptic and exon skipping isoforms in mRNA produced by splicing mutations from the combined information contents and the distribution of the splice sites and other regulatory binding sites defining these exons.  Results obtained are highly concordant with result of expression studies.  A paper has been published in Human Mutation

MutationForecaster™ (http://www.mutationforecaster.com) is Cytognomix’s new web-portal for analysis of all types of mutations, interpretation, comparison and management of genetic variant data.  It is an integrated suite of software products where coding, non-coding, copy number variant analyses can be carried out, compared with published or your own databases, maintained or downloaded.

Stay tuned for more developments about this exciting product…

Variant databases are an essential resource for both clinical and research genomics. Has the variant been reported previously in a patient and if so, what was their phenotype? They are used to exclude benign or common variants as pathogenetic, based on their high frequency in asymptomatic individuals. Many researchers curate variant databases of specific loci, regularly contribute known and new to public databases, and several companies release products aimed at compiling and visualizing this data. Determining the frequency and recurrence of variants can only be done through this compilation procedure.  Clinical labs maintain their own databases and regularly query public and commercial variant repositories to make sense of newly generated sequencing findings. Of course, it’s a lot easier to write up a variant if all one has to do is look it up in a database.

There is a fundamental problem with this approach: in a genome of 3.2 billion nucleotides, there are an infinite number of  possible mutations (single and oligo nucleotide changes on each chromosome). There is no database in existence that can catalog all of these effects, nor predict these effects based on prior knowledge of all of the mutation combinations. Only computational modeling of sequence variant effects can possibly provide a means of evaluting newly discovered mutations without explicit reference to a database of prior variants.  The approaches that Cytognomix has developed complement existing databases by confirming evidence of selection against predicted pathogenic variants (low allele frequencies), but more importantly, can predict deleterious effects when the mutation has not been observed previously.