Tag Archives: structural variation


Video Tip of the Week: ClinGen, The Clinical Genome Resource

The sequence data tsunami begins to crash into the shore, at the feet of clinicians and patients who want answers and treatment directions. But sometimes the tsunami is washing in debris. As the amount of sequence and variation information grows, some of it comes without clear evaluations of the impacts. Some of it comes with conflicting information. And some of it comes in wrong.

Attempting to wrangle the information into useful understanding and treatments with standardized descriptions, the team building the ClinGen resources published a paper last week that details their efforts. The paper describes their history and goals, and how they are moving to get to a point where they have useful information for and from patients, their doctors, testing labs, and researchers. Because of the different needs of different groups, there are several moving parts to the overall ClinGen collection.

In addition to the paper–and several related articles in this NEJM special report–there are videos on their site that tackle different aspects of the ClinGen projects. I’m going to highlight one of them here as the Tip of the Week, but you should also check out the others that are available on their webinars page or their YouTube channel. This video shows the Dosage Sensitivity Map features.

This video provides some of the history and framework for the ClinGen efforts, and then also introduces one of the tools that they have made available, a dosage sensitivity map. This piece focuses on “evidence based reviews of dosage sensitivity”, and they indicate haploinsufficiency losses of regions, and triplosensitivity duplications of regions. ClinGen dosage scoresThey describe a scoring system they use to rank structural variations (CNVs, SVs), and their curation of the evidence to support or to refute dosage sensitivity. They also note that their process is conservative, and you should keep that in mind as you consider the their team’s review of the evidence. But they are definitely open and interested in feedback and they hope you will contact them if you have a different understanding from their posted evaluations.

To follow along with the video, use this site to explore the features of this part of the ClinGen tool set: http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/. But you can also just click their example genes–for instance, the ZEB2 link shows you a typical page with the score information, links to other resources, and a genome viewer right on the page.  But you can also choose to look at external browsers at NCBI, Ensembl, or UCSC. I clicked the UCSC Genome Browser one to see how it displayed, and they automatically present to you tracks with the relevant ClinGen data loaded.

In other tips I’ll talk about other pieces of the infrastructure that they are building or coordinating with. Some we’ve talked about before–you can see a previous tip that included the ClinVar resource at NCBI that is foundational to the ClinGen suite and is discussed in their paper as well. They also note the importance of the data from OMIM, and how their mutual efforts are providing important feedback loops to be alerted to needed updates.  ClinGen also employs the Human Phenotype Ontology that keeps coming up at OpenHelix lately. Another important piece to this is the standards for naming variants that were recently described by the American College of Medical Genetics and Genomics (paper linked below).

ClinGen, and the various component tools within, are worth looking at, and contributing to, as we try to move more and better information to the clinic for patients and doctors to use effectively. Steven Salzberg has a take on the value of ClinGen here: 17% Of Our Genetic Knowledge Is Wrong.

It’s also very possible that some really important things will happen in the database–new submissions, changes to the status of a variant–that will occur before any papers come out about it. Or it is even possible that a paper never will come out about it. Spend some time learning about the features; I think it will be worth the time.

Quick links:

ClinGen overall project: http://clinicalgenome.org/

ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/

ClinGen Dosage Sensitivity Map: http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/


Rehm, H., Berg, J., Brooks, L., Bustamante, C., Evans, J., Landrum, M., Ledbetter, D., Maglott, D., Martin, C., Nussbaum, R., Plon, S., Ramos, E., Sherry, S., & Watson, M. (2015). ClinGen — The Clinical Genome Resource New England Journal of Medicine DOI: 10.1056/NEJMsr1406261

Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., & Rehm, H. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genetics in Medicine, 17 (5), 405-423 DOI: 10.1038/gim.2015.30

Video Tip of the Week: The New Database of Genomic Variants – DGV2 (edited)

In today’s tip I will briefly introduce you to the beta version of the updated DGV resource. The Database of Genomic Variants, or DGV, was created in 2004 at a time early in the understanding of human structural variation, or SV, which is defined by DGV as genomic variation larger than 50bp. DGV has historically provided public access to SV data in humans who are non-diseased. In the past it both accepted direct data submissions on SV and also provided high quality curation and analysis of the data such that it was appropriate for use in biomedical studies.

We’ve had an introductory tutorial on using DGV for years, and we’ve posted on changes at DGV in the past, so we were quite interested to read in their recent newsletter that there is a newly updated beta version of the DGV resource. The increase in SV data being generated by many large-scale sequencing projects as well as individual labs, has made it difficult for the DGV to continue to collect SV data, to provide a stable and comprehensive data archive AND to manually curate it at the level they have in the past. Therefore the DGV team is now partnering with DGVa at EBI and dbVar at NCBI. DGVa and dbVar will accept SV data submissions, and will function as public data archives (PDA) and, according to the publication sited below, DGVa and dbVar will:

 “...provide stable and traceable identifiers and allow for a single point of access for data collections, facilitating download and meta-analysis across studies.

DGV will no longer accept data submissions, but will instead use accessioned SV data from the archives and focus on providing the scientific community and public at-large with a subset of the data. Again quoting from the paper referenced below:

The main role of DGV going forward will be to curate and visualize selected studies to facilitate interpretation of SV data, including implementing the highest-level quality standards required by the clinical and diagnostic communities.

The original DGV resource is still available while comments are collected on the updated beta site. For more information on the updated DGV I suggest you check out this documentation from the DGV team: From their FAQ – “What is the data model used for DGV2?” and from a link in their top navigation area – “DGV Beta User Tutorial“. Be sure to check out the new displays & data that’s available, and most importantly to send your comments & suggestions to the group so that they can design a resource best suited for your needs.

Quick Links:

Original Database of Genomic Variants: http://projects.tcag.ca/variation/

New beta version of the Updated DGV: http://dgvbeta.tcag.ca/dgv/app/home

Introductory OpenHelix on Original DGV: http://www.openhelix.com/cgi/tutorialInfo.cgi?id=88

DGV Beta User Tutorial from DGV: http://dgvbeta.tcag.ca/dgv/docs/20111019-DGV_Beta_User_Tutorial.pdf

Church, D., Lappalainen, I., Sneddon, T., Hinton, J., Maguire, M., Lopez, J., Garner, J., Paschall, J., DiCuccio, M., Yaschenko, E., Scherer, S., Feuk, L., & Flicek, P. (2010). Public data archives for genomic structural variation Nature Genetics, 42 (10), 813-814 DOI: 10.1038/ng1010-813
(Free access from PubMed Central here)

Edit, March 5, 2012 – I wanted to add a clarification that we recieved through our contact link. I am pasting it in full, with permission from Margie:

“Hi Jennifer
We at TCAG think you did a great job on your video blog of the New Database of Genomic Variants.
I wanted to make a correction to one of your statements: “The increase in SV data (…) at the level they have in the past.”
We, the DGV team, have built a system that CAN handle the new volumes and types of SV data now being published, and we are able to curate all of these data. The reason we partnered with DGVa and dbVar was primarily to provide stable, “universal” accessions for SV data. We also work with DGVa and dbVar to define standard terminology, data types, and data exchange formats.
I just wanted to make sure it was clear that we are fully capable to handle the SV data being published now. Our reason for partnership was to foster standardized data and open data sharing across systems.
Thanks again for your blog post!
Margie Manker”