OGI’s Early Stage Investment in Cytognomix Contributes to the Success of the Shannon Human Splicing Pipeline

IFOM-IEO. May 10, 02:00 PM

“Discovery and predicted consequences of non-coding sequence variants affecting gene expression on a genome-scale and in inherited breast cancer.”

(http://www.semm.it/seminars.php)

The IFOM-IEO Campus is a new biomedical research centre, created by the joint efforts of the FIRC Institute of Molecular Oncology Foundation (IFOM) and the Department of Experimental Oncology of the European Institute of Oncology (IEO), which have expanded and integrated their research activities on a common campus.

The IFOM-IEO Campus is located in Milan, the heart of the commercial/industrial north of Italy, where it benefits from numerous interactions with other scientific and medical organizations in the area (see participants below). The Campus is also home to the Ph.D programs of the European School of Molecular Medicine (SEMM), which it is running in collaboration with the University of Milan, the University of Naples “Federico II” and the Italian Institute of Technology (IIT) in Genoa.

Host: Dr. Paolo Peterlongo

Fondazione IRCCS Istituto Nazionale dei Tumori, May 15, 2013. 02:00 PM

“Discovery and predicting impact of non-coding sequence variants that affect gene expression on a genome scale and in inherited breast cancer”

Since its  founding of the objectives of the Istituto Nazionale dei Tumori via Venezian were defined as follows:

• Research in the field of cancer to better understand the biological mechanisms and systems to continuously improve diagnosis and treatment.
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• The diagnosis and treatment of cancer, with the methods that are recognized internationally as the most valid.
• The oncology information of citizens and the training of medical and nursing staff involved in the treatment of cancer.

Host: Dr. Paolo Radice – S.C. Medicina Predittiva: basi molecolari del rischio genetico e TestGenetici, Dipartimento di Medicina Predittiva e per la Prevenzione.

Ben Shirley, Chief Software Architect of the Shannon pipeline for human mRNA splicing mutation analysis presented a webinar today including a live demonstration of the software’s capabilities. We received a number of favorable comments on this LinkedIn Network Discussion.

The presentation was recorded and will be available in the future for viewing. Please bookmark this webpage. We will share the URL of the recorded presentation when it becomes available.

The presentation was recorded in Adobe Connect. The URL to watch it is: http://ogi.adobeconnect.com/p6u1uglzuos/

Peter Rogan is giving a platform presentation on: “Genome-wide prediction and validation of mRNA splicing mutations in cancer” at the HGVS meeting in Paris, France on June 8, 2013.  The meeting will be held at the Hotel’Concorde’La’Fayette, just preceding the annual European Society of Human Genetics conference, at which Dr. Rogan will also be presenting a paper.

The Ontario Genomics Institute (OGI) and Cytognomix Inc. are hosting a 30 minute webinar about the Shannon Human Splicing Pipeline – software for genome-scale splicing mutation analysis on April 24th at 1 PM EST.  We require all attendees to register for the webinar on April 24, 2013 at 1:00 PM (EST) at the OGI website:  https://ogi.factorial.ca/Forms/fm_forms.jsp?token=HwkGRx0GZl5aSxdR

The Shannon Human Splicing Pipeline is an information theory-based tool for splicing mutation detection and analysis on a genome-scale. It offers high-throughput variant analysis and can examine – for example – 211,049 variants in 1 hour 12 minutes on an I7-based CPU. The software has been implemented for the CLC-Bio Genomics Workbench platform. Variants are annotated to indicate the context of novel mutations as well as common and rare SNPs with splicing effects. Potential natural and cryptic mRNA splicing variants are identified, and null mutations are distinguished from leaky mutations. Variants determined to be potentially deleterious can be viewed in tabular format, as plots, or genome browser tracks. A post-hoc filtering process can further reduce the number of resulting variants. Some pipeline results will be examined, pipeline implementation will be described, and the post-hoc filtering process will be discussed.  Check out our recently published paper:   Shirley BC, Mucaki EJ, Whitehead T, Costea PI, Akan P, Rogan PK. Interpretation, Stratification and Evidence for Sequence Variants Affecting mRNA Splicing in Complete Human Genome Sequences. Genomics Proteomics Bioinformatics. 2013 Mar 14. doi:pii: S1672-0229(13)00029-6. 10.1016/j.gpb.2013.01.008. [Epub ahead of print] PubMed PMID: 23499923

The presentation will be led by Ben Shirley, the chief developer of the Shannon Human Splicing Pipeline. The webinar will be appropriate for all levels of researchers interested in using the software to reduce a genome-scale list of splicing variants to a tractable set of potentially deleterious mutations, suitable for further analysis in the laboratory.

On the day of the webinar, you will be able to access the webinar by clicking here and entering as a guest.

Please be sure to provide your name, title, institution and valid email address so that we can send you an email with webinar details and instructions.

Cytognomix is presenting the following paper  at the Joint HGM 2013 and 21st International Congress of Genetics meeting in Singapore  in the April 15 poster session (9:30-10 AM, 12:30-1:30 PM) on Cancer Genetics and Genomics (T05):

STRATEGY FOR IDENTIFICATION, PREDICTION, AND PRIORITIZATION OF NON-CODING VARIANTS OF UNCERTAIN SIGNIFICANCE IN HERITABLE BREAST CANCER.

P. Rogan 1,*, E. Mucaki 1, A. Stuart 2, E. Dovigi 1, C. Viner 3, B. Shirley 3, J. Knoll 2, P. Ainsworth 2  1Departments of Biochemistry, 2Pathology, and  3Computer Science, University of Western Ontario, London, Canada

Objectives: Non-coding sequence variants have been proven to significantly contribute to the phenotypes of high penetrance disorders. We develop an approach to predict pathogenic non-coding variants of uncertain significance(VUS) based on information theory-based analysis of changes in DNA and RNA sequences bound by regulatory factors.

Methods: Complete gene sequences are captured, enriching for non-coding variants in genes known to harbor mutations that increase breast cancer risk. Oligo baits covering the complete coding and intergenic regions 10kb up- and downstream of ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2 and TP53 were used in solution hybridization. Probe design captures both repeat-free and divergent repeat sequences that are effectively single copy. After Illumina sequencing of 21 high risk patient samples lacking coding mutations, information analysis prioritized non-coding variants within sequence elements recognized by proteins or protein complexes. VUS are being screened for mutations affecting essential binding sites recognized in mRNA splicing, by transcription factors (TFBS), and by protein interacting with untranslated regions (UTR). Information models for exon recognition predict the relative abundance of natural, cryptic, and mutant splice isoforms resulting from predicted mutations. A similar approach is introduced to detect mutations that alter strengths of TFBS and UTR binding sites. Information weight matrices were determined by entropy minimization of ENCODE ChIP-seq regions for 60 transcription factors embedded within DNAse I hypersensitive domains.

Results: The matrices were used to evaluate novel variants discovered by sequence analysis of breast cancer patients for alteration the TFBS binding strengths. This analysis prioritized 9 splicing, 8 TFBS, and 2 UTR variants as most likely to affect gene expression, potentially affecting 6 protein coding genes in the patient samples (from 7,909 variants in 7 genes).

Conclusion: This strategy more comprehensively covers non-coding regions in breast cancer genes than repeat masking, and introduces a unified framework for systematic interpretation of VUS that affect expression.