Final Report Summary - I-DCC (“The International Data Coordination Centre”)
Executive Summary:
The goal of I-DCC coordination action was to make the products of the International knockout mouse consortium (IKMC) mutagenesis programmes as widely visible and available to the research and clinical communities. The I-DCC provided a single point of access for all mutant Embryonic stem (ES) cell resources held in repositories worldwide. The I-DCC project has significantly enhanced the end-user value of the IKMC products by integrating other biological information (mouse production, expression, phenotype) with the genes and mutant products in the IKMC catalogue. These additional data sets have been integrated using BioMart technology with an enhanced presentation layer. The BioMarts can also be directly accessed, allowing federation of different data sets using common linking identifiers (gene IDs, ES cell IDs, expression ontologies) and enabling the results to be downloaded.
Project Context and Objectives:
The large-scale mutagenesis programs (EUCOMM/EUCOMMTOOLS, KOMP, NorCOMM, TIGM) have conducted saturation mutagenesis of the mouse genome using both gene targeting and gene trap approaches.
This coordinated, international approach allowed for the global use of mutant ES cells to support the functional annotation of the mammalian genome.The goal of IDCC coordination action was to make the products of the IKMC mutagenesis programs as widely visible and available to the research and clinical communities. The IDCC initially and now the IMPC provide a single point of access for all mutant ES cell resources held in repositories worldwide. Users can search for all IKMC/IMPC products at the website: http://www.mousephenotype.org
The mutagenesis components of the IMPC website rests on three foundations, each of which is built using the complementary expertise of the consortium members:
1) A master gene list of all mouse genes - this is a curated list which allows clear coordination of knockout targets between consortium members. The list is annotated with further information (eg.orthologues cross-references to disease) which help consortium members identify and prioritisetargets.
2) A targeting data repository which stores in a common format the molecular structure of knockout
alleles and products of all knockout programs.
3) A repository of IKMC gene trap ES cell lines, suitably grouped into clusters of insertions with
equivalent mutagenic potential. The repository also serves the mutant molecular structure of each
allele.
The IDCC project has also significantly enhanced the end-user value of the IMPC products by integrating other biological information (mouse production, expression, phenotype) with the genes and mutant products in the IKMC catalogue. These additional data sets have been integrated using BioMart technology with an enhanced presentation layer (see the IMPC project pages and the Martsearch portal). The BioMarts can also be directly accessed, allowing federation of different data sets using common linking identifiers (gene IDs, ES cell IDs, expression ontologies, etc.) and enabling the results to be downloaded.
The IMPC website has been functioning as the central website for the IMPC consortium for almost four years. The site receives over 15,000 visits a month and fields broad-ranging enquiries from scientists regarding the interpretation of data on the website. Initially serving the KOMP, EUCOMM, NorCOMM and TIGM, during this reporting period we have extended the site to report the status and products of the EUCOMMTools and the Sanger MirKO (microRNA) knockout programs. Standardized molecular-level descriptions (sequence, diagrams and browser views) are currently offered for all targeted mutations visible on the site, and soon will be offered for gene trap alleles.
The project was concluded in this final period by using the tools created to describe the molecular structure of gene trap alleles. Furthermore, we have developed interfaces for the International Mouse Phenotyping Consortium (IMPC) to help coordinate the production and phenotyping of mice generated from IKMC ES cell resources.
In summary, the objectives for this reporting period were as follows:
1. To maintain the annotated master gene list
2. To continue to gather and populate the targeting repository with data
3. To continue to develop the display interfaces from the targeting repository
4. To improve the main web portals (A and B)
5. To maintain and improve the BioMart data being presented to the portal
During this reporting period. Many of the alleles generated by the IKMC have been made into mice and systematically phenotyped by the members of the International Mouse Phenotyping Consortium (IMPC). Our data repository of molecular-level descriptions of IKMC alleles and the catalogue of QC-validated targeted and trapped ES cells is the foundation for this international effort. We have responded to the needs of the IMPC by developing an interface (iMITS; www.mousephenotype.org/imits) to coordinate and track the production and phenotyping of mice generated from IKMC ES cell resources. This system will be maintained in future years as a component of the IMPC data coordination activities.
Project Results:
The large-scale mutagenesis programs (EUCOMM/EUCOMMTOOLS, KOMP, NorCOMM, mirKO, TIGM) have produced knock out ES cells for 18,000 protein coding genes in the mouse. This coordinated, international approach by the International Knockout Mouse Consortium (IKMC) reduced redundant effort and allows for the global use of mutant ES cells to support the functional annotation of the mammalian genome.
The goal of IDCC coordination action was to make the products of the IKMC widely visible to the research and clinical communities. The IKMC website has functioned as the central website for the IKMC consortium for almost four years. The site received over 15,000 visits a month and fielded broad-ranging enquiries from scientists regarding the interpretation of data on the website. The website also offered standardized molecular-level descriptions (sequence, diagrams, and project pages) for all targeted alleles.
In the final year of the project, we have transferred the catalogue and the display of mutant ES cells to the website of the International Mouse Phenotyping Consortium (www.mousephenotype.org). The goal of the IMPC is to convert IKMC ES cells into mice for broad-based phenotyping studies and for archiving and distribution of mice to the international scientific community. We have developed interfaces for the International Mouse Phenotyping Consortium (IMPC) to coordinate the production and phenotyping of mice generated from IKMC ES cell resources. By merging the IKMC and IMPC websites, the maintenance and display of IKMC data has been safeguarded for the foreseeable future.
2. Project objectives for the period
In summary, the objectives for this reporting period were as follows:
1. To curate and maintain the annotated master gene list
2. To continue to gather and populate the targeting repository with data
3. To continue to develop the display interfaces from the targeting repository
4. To continue to develop the iMITS interfaces for tracking IMPC mouse production
5. To merge the IKMC website (Portal A) with the IMPC website
6. To maintain and improve the BioMart data being presented to the portal
Merging the IKMC website with the IMPC website has been added as additional objective in this reporting period. Many of the alleles generated by the IKMC will be made into mice and systematically phenotyped by the members of the International Mouse Phenotyping Consortium (IMPC). Our data repository of molecular-level descriptions of IKMC alleles and the catalogue of QC-validated targeted and trapped ES cells is the foundation for this international effort. We have responded to the needs of the IMPC by developing an interface (iMITS; www.mousephenotype.org/imits) to coordinate and track the production and phenotyping of mice generated from IKMC ES cell resources. This system will be maintained in future years as a component of the IMPC data coordination activities.
3. Work progress and achievements during the period
WP 1: Gene List and Gene Annotation
WP leader: M. Ringwald (The Jackson Labs)
Partners: T. Hubbard (WTSI), E. Birney (EMBL), G. Hicks (MICB)
Objectives:
The objective of this work package is to establish and maintain a unified and annotated master gene list for the high-throughput gene targeting and gene trapping projects that will facilitate coordination and prioritization within and between these projects. The work will include the development of a database and of data load and analysis procedures to generate and update the annotated gene list; the implementation of administrative interfaces that provide integrated data access, data management, and querying capabilities for the knockout projects; as well as manual curation and review of these data. The work will take advantage of and expand existing informatics infrastructure and curatorial efforts implemented by the Mouse Genome Informatics (MGI) and the KOMP-Data Coordination Centre (KOMP-DCC) projects.
Deliverables with activity for this reporting period:
D1.1 Unified and annotated master gene list
The design and coordination of IKMC gene targeting experiments requires up-to-date gene model information. To provide the IKMC with a current and unified master gene list, we continued to perform comparison, coordination, and integration of different gene models. By manual curation, in close collaboration with Vega, Ensembl, NCBI, and MGI, we continued to resolve conflicts between gene models and other data issues related to genes assigned to IKMC projects and products. We continued to report new gene associations, and gene merges and splits to the IKMC production centres and repositories.
To provide the research community with up-to-date information about the status of targeting projects and the availability of IKMC products, we continued to annotate the genes with regard to pipeline status information from WP2 and with regard to availability information from the KOMP repository. As the International Mouse Phenotyping Consortium (IMPC) began to generate mice from IKMC ES cells and to phenotype mice, we incorporated pertinent status and mouse availability information as well. We also continued to incorporate MGI’s current gene trap to gene associations for IKMC gene traps, as well as updates, provided by TIGM, on mouse production from TIGM-IKMC gene traps.
We achieved all objectives proposed for D1.1.
D1.2 Maintenance of GFF files for UCSC Genome Browser
In collaboration with WP2, we maintained the GFF files that enable the UCSC Genome Browser to update its IKMC allele tracks on a regular basis. All objectives for D1.2 were achieved.
D1.3. Registration and nomenclature for IKMC alleles
Another important objective of WP1 was to register IKMC targeted mutant allele information in MGI and to provide WP2, the IKMC repositories, and the research community with official allele IDs and nomenclature. To do so, we continued to incorporate IKMC allele information into MGI by using automated load procedures, computational checks, and manual quality controls. We expanded our load and quality control procedures to accommodate new types of IKMC alleles, such as the alleles with artificial introns generated by EUCOMMTOOLS. The registration of knockout alleles and the assignment of official nomenclature is essential for the future integration of biological data from studies of mutant ES cells and mice generated by the IMPC. All objectives for D1.3 were achieved.
Deliverables:
________________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
________________________________________________________________________________________
D1.4 Curate / maintain WP1 6 55.9 R PU 48
gene list, interface
(continuous from
first release through
lifetime of project)
________________________________________________________________________________________
WP 2: Gene Targeting Data Repository
WP leader: W. Skarnes (WTSI)
WP Partners: G. Hicks (MICB), E. Birney (EMBL), M. Ringwald (Jackson Laboratory)
Objectives:
The objective of this work package is:
To coordinate with WP1 to be in synchrony with the “master gene list” and allocation of genes to pipelines, as curated by WP1.
To collect information on targeting vectors and alleles as they are produced by the pipelines.
To transfer information on targeted genes to the annotated gene list on pipeline status.
The IKMC targeting repository has been merged during this reporting period with the iMITS system described in deliverable 4.7 (see 2012 periodic report). This change means that the ES cell resources created by the IKMC are now fully merged with the mouse production application which coordinates and tracks the production of mice generated by the IMPC. In addition, the targeting repository contributes directly to the tracking and display of products on the IMPC portal. In turn, the display of data (graphic, search indices, web pages) for the IKMC resource has been merged with the display of data from iMITS: this ensures that the two data sources will evolve in synchrony for the lifetime of the IMPC. The targeting repository can now be found at www.mousephenotype.org/imits/targ_rep .
Deliverables with activity for this reporting period:
D2.1 Validate / Test a common schema.
The database of the IKMC targeting repository and the IMPC mouse production tracker (iMITS) were merged during this reporting period. The two project codebases were also merged, and are now stored here github.com / mpi2 / imits. This merge is complete and was successful, and it means that the ES Cells stored in the IKMC targeting repository are now directly linked to the microinjections recorded in iMITS, without the need to communicate between systems. This deliverable is (again) complete.
D2.3 Upload and update pipeline data.
We have continued to load data from the EUCOMMTools production effort into the targeting repository during this period, and will continue to do so for all EUCOMMTools production. The repository has also been modified to distinguish EUCOMMTools – specific Artificial Intron Alleles. The targeting repository is not only a catalogue of mutant ES cell alleles but also contains a summary of all quality control assays that were performed to verify mutant alleles at the ES cell production centres, at the ES cell repositories and at the mouse production centres. The repository has been specifically modified to discriminate between QC assays submitted by different centres, as we were seeing that multiple centres (e.g. WTSI and the EUMMCR repository or WTSI and the KOMP repository) assay the same ES cell clones. Future work that will be performed by the IMPC will ensure that all QC assays performed on ES clones and mouse lines are captured in the targeting repository.
This deliverable is complete.
D2.5 Displaying data
The IKMC targeting repository now has two means of displaying data: it directly (and instantly) updates search indices used by the IMPC portal to display allele data to scientists interested in IKMC ES cells and IMPC mice. This ensures that new alleles uploaded from the EUCOMMTools production are immediately visible to the IMPC portal.
The repository also draws both detailed and simplified allele graphics customised on a gene and allele basis. These graphics are served directly to the IMPC portal. The graphic generating code has been reworked to allow it to be as flexible as possible to deal with future changes.
Detailed Graphics: please refer to accompanying documents
Simplified Graphics: please refer to accompanying documents
This deliverable is complete.
Deliverables
________________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
________________________________________________________________________________________
D2.3 Upload and update WP2 1 24 R PU 48
pipeline data
________________________________________________________________________________________
WP 3: Data integration of gene trap resources
WP leader: W. Wurst (IDG)
Partners: J. Hansen (IDG), G. Hicks (MICB), W. Skarnes (WTSI), A. Ballabio (FTELE.IGM)
Objectives:
The objectives of this work package are:
To define standard formats for gene trap allele and vector descriptions
To standardize gene trap sequence tag analysis
To deduce synthetic mutant alleles from gene trap clusters
To forward the results of standardised analyses and synthetic alleles to a central data repository holding both targeted and random traps (in conjunction with WP2).
To use the synthetic alleles as a basis for creating effective display strategies for trapped genes (in conjunction with WP4).
To configure data for display
Deliverables with activity for this reporting period:
The gene trap repository aimed to make a consensus gene-trap annotation pipeline and then compile these annotations, as well as the molecular details on all known gene traps in the IKMC. The data gathered during the lifetime of this project was served (and continues to be served) by the UniTrap BioMart, see WP5.
The ongoing deliveries during this period were D3.5 (data display) and D3.6 (Maintenance and curation of data). Both of these deliverables were significantly influenced by the small number of gene trap alleles chosen for IMPC mouse production. The vast majority of IMPC production employ IKMC targeted mutations. The longevity of the IKMC Targeting Repository (WP2) has been ensured by its integration with iMITS. In the same vein, we have merged the storage of gene-trap alleles with iMITS. This allows the repository of gene-traps to remain relevant to mouse production if required.
In keeping with the choice of alleles for high-throughput IMPC mouse production, we show only those gene-trap alleles that have been chosen for IMPC mouse production.
D3.5 Displaying data
The display of gene-trap alleles relevant to IMPC mouse production is identical to the display of targeted mutations used in mouse production: if an IMPC mutant mouse has been generated using a gene-trap allele, then it will be displayed in the IMPC gene page, with the same information (allele image, genbank file) as a targeted allele:
Links will then direct the user to the repository to order the ES Cell or mouse as needed.
This deliverable is now complete.
D3.6 Maintenance and curation of data
Gene Trap mutant ES Cells relevant to IMPC mouse production are now stored in a “Gene Trap Alleles” inside iMITS / IKMC Targeting Repository with a structure similar to that stored for Targeted alleles. They are found through a “Gene Trap Alleles” inside iMITS (see picture) and can be searched for and browsed like other targeted alleles. Each allele stores the individual mutant ES Cell clones for that allele, the coordinates of the genomic insertion and the mutant sequence of the ES Cell (genomic + cassette sequence).
We will continue to maintain this data – adding extra alleles as they become relevant – for the lifetime of the IMPC project. This deliverable is now complete.
Deliverables:
______________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
______________________________________________________________________________________
D3.6 Maintenance and WP3 2 25.2 R PU 48
curation of data
______________________________________________________________________________________
WP 4: Web Portal
WP leader (Part A): M. Ringwald (Jackson Labs)
WP leader (Part B): E. Birney (EMBL)
Partners: W. Skarnes (WTSI), W. Wurst (IDG), G. Hicks (MICB), A. Ballabio (FTELE.IGM)
Objectives
The purpose of WP4 is
To create a website to display current repository information
To create DAS-tracks that can be served to popular genome browsers, to display this information in its genomic context.
To create a Biomart to house periodic, query-optimised snapshots of the repository. The Biomart will serve DAS-tracks, provide query web-services, and link to other Biomarts (including EnsMart), greatly enhancing the search capability and future utility of the repository.
This reporting period has seen the integration of the IKMC and the IMPC websites. The benefits for the end user are that they only need visit one site to get all IMPC phenotype, mutant mouse and IKMC ES cell information.
Deliverables with activity for this reporting period:
D4.1 Web Portal Part A
We continued to maintain and enhance Part A of the IKMC Web Portal as the central front end for information on IKMC data and resources. As the IMPC project started to generate mice from IKMC ES cells, we expanded the web site to also show, for each IKMC targeting project, the status of IMPC mouse generation and availability. We implemented links to the IMPC production centres from which the respective mice where available. We also indicated the availability of IMPC mouse phenotype data and provided links to corresponding entries on the IMPC web site. We achieved all objectives proposed for D 4.1. The web portal displaying IKMC products will now be maintained by out by the Data Coordination Centre of the IMPC.
D4.2 User Support
The IKMC Web Portal served as the central point of entry to data and resources from the IKMC. The web site was used heavily and the number of user inquiries was increasing steadily. We continued to provide timely user support for researchers that contacted us with questions regarding IKMC data and products. All objectives proposed for D4.2 were achieved. This activity has now been transferred to the IMPC Data Coordination Centre.
D4.4 Enhancement and maintenance of the portals (Web portal Parts A and B)
The first phase of the large-scale mouse phenotyping, coordinated by the International Mouse Phenotyping Consortium (IMPC), is now well underway. It is important that the phenotype data and mutant mice produced by the IMPC as well as the mutant IKMC ES Cells that underlie that effort are all available from a single website (www.mousephenotype.org).
Therefore, we have focused effort during this final reporting period on integrating the IKMC web presence with that of the IMPC. Any user who navigates to www.knockoutmouse.org will be directed instead to www.mousephenotype .org. Note that this site has a direct link to iMITS and the IKMC targeting repository from its front page:
There, they will be able to search for IMPC and IKMC products for their gene (phenotypes, mutant mice and IKMC alleles). All IKMC alleles are presented in summary inside IMPC gene pages (https://www.mousephenotype.org/data/genes/MGI:105369):
The links allow users to view detailed IKMC allele information as well as contact repositories for products. The links to detailed allele information (“Product Details” ) present all the details visible via the IKMC project pages: (http://www.mousephenotype.org/martsearch_ikmc_project/martsearch/ikmc_project/35505):
The integration of the IKMC website with the IMPC website (and this delivery) is now complete and will be maintained by the IMPC Data Coordination Centre.
D4.7 Development of a mouse production and phenotyping tracking system (iMITS)
The iMITS system has continued to evolve during the current reporting period to serve the tracking and reporting needs of the IMPC.
The production reports provided by iMITS are continuously enhanced and modified to serve the needs of the IMPC. In addition, during this current reporting period
It has been integrated with the IKMC Targeting Repository, thereby connecting it directly to all IKMC alleles without the need for cross-system communication
It has leveraged this connectivity to provide high-level overviews of the genotyping assays performed on mutant mice, taking into account both mouse and ES cell qcs: the long-term record of these assays having been performed is important to establish best-practice between mouse production centres.
It has been given a public-facing website (i.e. requiring no login) to allow any scientist to view details of mouse production in progress at any production centre.
It has been enhanced to display mutant mouse data (tm1a and tm1b mice) directly to the IMPC portal:
Deliverables
______________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
______________________________________________________________________________________
D4.4 Enhancement and WP4 6/4 74 R PU 48
Maintenance of portals
D4.6 Second I-DCC Training WP4 1 0 R PU 37
day
D4.7 Development of a WP4 1 8 R PU 36
mouse production and
phenotyping tracking
system (iMITS)
______________________________________________________________________________________
WP5: Integration of Gene Expression Data
WP leader: A. Ballabio (F.TELE)
Partners: M. Ringwald (Jackson Labs), E. Birney (EBI)
Objectives
To gain maximum leverage from gene expression data, we propose to federate other bioinformatics resources that either already exist or are in the process of being constructed by the scientific community.
All BioMart integrations were achieved during the last reporting period. During this period we have ensured that biomart data – most importantly the data in the IKMC Targeting repository and the iMITS biomart – have been kept current with nightly updates.
The BioMarts have been used by many external groups to obtain current IKMC and IMPC data. They will continue to be kept current and maintained here:
http://www.mousephenotype.org/martsearch_ikmc_project/
This work package is now complete. Further work (beyond the scope of this project) integrating gene expression data will be conducted under the guidance of the IMPC.
4. Deliverables and milestones tables
Deliverables (excluding the periodic and final reports)
Table 1. Deliverables
______________________________________________________________________________________
Del. Deliverable WP Lead Nature Dissemination Delivery date Delivered Actual/
name no. benef- level from annex 1 yes/no forecast
iciary delivery date
______________________________________________________________________________________
D1.1 Unified and WP1 6 R PU 0 Yes 0
annotated master
gene list (initial
delivery is
immediate,
but see D1.4)
D1.2 Pubic release of WP1 6 R PU 3 Yes 42 / 3
I-DCC administrative
web interface
D1.3 Public release of WP1 6 R PU 9 Yes 36
gene models and Mart
D2.1 Validate / test WP2 1 R PU 6 Yes 12
a common schema
D2.2 Populate central WP2 1 R PU 12 Yes 12
database with
initial data
D2.4 Develop interfaces WP2 1 R PU 12 Yes 36
to report targeting
pipeline status to WP1
D2.5 Displaying data WP2 1 R PU 12 Yes 36
D3.1 Definition of WP2 1 R PU 12 Yes 36
standard form
D3.2 Establishment of a WP3 2 R PU 12 Yes 36
gene trap data
repository
D3.3 Synthetic gene WP3 2 R PU 12 Yes 36
trap alleles
D4.1 Workshop to discuss WP4 6/4 R PU 3 Yes 3
the structure and
interoperability
of the I-DCC website
D4.2 Portal Part A – WP4 6 R PU 3 Yes 36 / 3
main website
(Jackson Labs and WTSI).
Initial delivery at
month 3: enhancement
in D4.3
D4.3 Portal Part B – WP4 4 R PU 9 Yes 36 / 9
HTGT Mart (WTSI)
D5.1 Integration of WP5 3 R PU 6 Yes 6
EURExpress
D5.2 Meeting with CREATE WP5 3 R PU 6 Yes 6
project to discuss
data integration
(month 6)
D5.3 Integration of GXD WP5 6 R PU 12 Yes 36
D5.4 Integration of WP5 8 R PU 30 Yes 36
selected additional
expression databases
D5.5 Maintenance WP5 6 R PU 48 Yes 36
of mart data
______________________________________________________________________________________
Milestones
Please complete this table if milestones are specified in Annex I of the Grant Agreement.
Milestones will be assessed against the specific criteria and performance indicators as defined in Annex I.
______________________________________________________________________________________
Milestone Milestone Work package Expected Means of
number name involved date verification7
______________________________________________________________________________________
M1 Master Gene 1 6 Links to Central db, or flat file for download,
List issued of genes keyed by MGI id, with cross-references
to other ids.
M2 Initial 2 12 Central DB with all vectors and alleles from all
targeting targeting programs loaded.
data load
M3 Complete 2 12 Feedback to close a loop can be simulated:
Loop: Master in practice feedback will take months to
Gene list to close a loop.
Targeted Data
M4 Trapping data 3 15 Single query against database will
integrated bring back all current targeted and trapped KO’s.
into repository
M5 Portal Part A 2/3/4 15 Basic search for alleles via portal is functional,
done: targeting with graphical display of synthetic alleles
/ trapping is complete.
alleles shown
M6 Mart complete 4 18 Users can make cross-mart searches into KO data.
M7 Initial 5 18 Users can make cross-mart searches from expression
expression data into KO data.
data complete
and integrated
with KO
resources
_____________________________________________________________________________________
SECTION 5 – Project Management
Dr William Skarnes (WTSI, UK) is the I-DCC project coordinator and is responsible for interacting with the European Commission and supervising the management team. The management team comprises project manager Dr. Derek Matthews and Mr Stuart Rayner who is principally concerned with financial aspects of the I-DCC project.
I-DCC Steering Committee: The I-DCC Steering Committee comprises:
P1 (WTSI) – Bill Skarnes; Derek Matthews
P2 (HGMU) – Wolgang Wurst
P3 (FTELE.IGM) – Graciana Diez Roux; Andrea Ballabio
P4 (EMBL) – Ewan Birney
P5 (BSRC Fleming) – Vassilis Aidinis
P6 (JAX) – Martin Ringwald
P7 (MICB) – Geoff Hicks
Attendance of I-DCC members at other meetings:
Bill Skarnes (WTSI)
Dr Skarnes attended the following meetings at which I-DCC matters were discussed and/or presented
- at the International Congress of Applied Biotechnology, Tianjin, China October , 2012
- at the Wellcome Trust Advanced Course “Genetic Manipulation of ES Cells”, Hinxton, UK, October 31 - November 5-19, 2012
- at the IMPC meeting in Toronto, Canada, November 28-30, 2012
- at the SyBOSS open symposium in Kirchberg, Austria, February 1, 2013
- at the Wellcome Trust Researchers meeting, London, UK, February 7-8, 2013
- at the British Society for Gene and Cell Therapy meeting, UK, April 17-19, 2013
- at the Mouse Molecular Genetics Meeting, Hinxton, UK, September 18-21, 2013
- at the IMPC meeting in Toronto, Canada, October 28-30, 2013
- at Wuhan University of Science and Technology, Wuhan, China, November 19th, 2013
Conferences, Publications, Press Releases:
I-DCC-related Publications:
The following publications were accepted during the reporting period that have some component relating to I-DCC activities or deliverables
Nature Methods | Vol.9 No.1 | January 2012. Special feature on single cell methods.
The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data. Koscielny G, Yaikhom G, Iyer V, Meehan TF, Morgan H, Atienza-Herrero J, Blake A, Chen CK, Easty R, Di Fenza A, Fiegel T, Grifiths M, Horne A, Karp NA, Kurbatova N, Mason JC, Matthews P, Oakley DJ, Qazi A, Regnart J, Retha A, Santos LA, Sneddon DJ, Warren J, Westerberg H, Wilson RJ, Melvin DG, Smedley D, Brown SD, Flicek P, Skarnes WC, Mallon AM, Parkinson H. Nucleic Acids Res. 2013 Nov 4. [Epub ahead of print]
Molecular characterization of mutant mouse strains generated from the EUCOMM/KOMP-CSD ES cell resource. Ryder E, Gleeson D, Sethi D, Vyas S, Miklejewska E, Dalvi P, Habib B, Cook R, Hardy M, Jhaveri K, Bottomley J, Wardle-Jones H, Bussell JN, Houghton R, Salisbury J, Skarnes WC; Sanger Mouse Genetics Project, Ramirez-Solis R. Mamm Genome. 2013 Aug;24(7-8):286-94.
Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC; Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP. Cell. 2013 Jul 18;154(2):452-64.
Accessing data from the International Mouse Phenotyping Consortium: state of the art and future plans. Mallon AM, Iyer V, Melvin D, Morgan H, Parkinson H, Brown SD, Flicek P, Skarnes WC. Mamm Genome. 2012 Oct;23(9-10):641-52.
The mammalian gene function resource: the International Knockout Mouse Consortium. Bradley A, Anastassiadis K, Ayadi A, Battey JF, Bell C, Birling MC, Bottomley J, Brown SD, Bürger A, Bult CJ, Bushell W, Collins FS, Desaintes C, Doe B, Economides A, Eppig JT, Finnell RH, Fletcher C, Fray M, Frendewey D, Friedel RH, Grosveld FG, Hansen J, Hérault Y, Hicks G, Hörlein A, Houghton R, Hrabé de Angelis M, Huylebroeck D, Iyer V, de Jong PJ, Kadin JA, Kaloff C, Kennedy K, Koutsourakis M, Lloyd KC, Marschall S, Mason J, McKerlie C, McLeod MP, von Melchner H, Moore M, Mujica AO, Nagy A, Nefedov M, Nutter LM, Pavlovic G, Peterson JL, Pollock J, Ramirez-Solis R, Rancourt DE, Raspa M, Remacle JE, Ringwald M, Rosen B, Rosenthal N, Rossant J, Ruiz Noppinger P, Ryder E, Schick JZ, Schnütgen F, Schofield P, Seisenberger C, Selloum M, Simpson EM, Skarnes WC, Smedley D, Stanford WL, Stewart AF, Stone K, Swan K, Tadepally H, Teboul L, Tocchini-Valentini GP, Valenzuela D, West AP, Yamamura K, Yoshinaga Y, Wurst W. Mamm Genome. 2012 Oct;23(9-10):580-6.
Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project. Ayadi A, Birling MC, Bottomley J, Bussell J, Fuchs H, Fray M, Gailus-Durner V, Greenaway S, Houghton R, Karp N, Leblanc S, Lengger C, Maier H, Mallon AM, Marschall S, Melvin D, Morgan H, Pavlovic G, Ryder E, Skarnes WC, Selloum M, Ramirez-Solis R, Sorg T, Teboul L, Vasseur L, Walling A, Weaver T, Wells S, White JK, Bradley A, Adams DJ, Steel KP, Hrabe de Angelis M, Brown SD, Herault Y. Mamm Genome. 2012 Oct;23(9-10):600-10.
D) Consortium Agreement and amendment:
During the reporting period, due to reorganizations within the UK NHS, the HGRU was transferred from MRC control to the University of Edinburgh (IUEDIN). Whilst no changes were necessary to the DOW it was necessary to enact an amendment for a transfer of rights from MRC to UEDIN so that the financial reporting could be completed. At the time of submission this process is ongoing
Public relations activities:
WTSI members disseminated I-DCC technology/ materials at the Wellcome Trust Advanced Course, Hinxton Hall, 5th – 18th Nov 2012
SECTION 4 – I-DCC ETHICAL AND GENDER ISSUES
Ethical Issues
There are no ethical issues relevant to the I-DCC grant application. All source data is available to the public without restriction.
Gender Issues
No gender issues were identified in Annex 1 part B
Potential Impact:
The IMPC portal is the central point of access to high-throughput phenotype data, IKMC ES cell resources and mutant mouse strains. The progress of mouse production and phenotyping is presented for each gene, with links to repositories that are distributing the mutant mouse strains and the availability of IKMC ES cell resources and the molecular structures of the mutant alleles.
The web portal’s primary function is to display genotype–phenotype data for knockout lines for the biomedical community. The site has been optimized to allow free text queries that return structured data via facets allowing the user to explore the data with a mixture of query terms. Users are able to register for genes of interest and will be alerted via email when the gene changes status, indicating new data are available or a mouse is available.
In addition to the information made accessible through the web portal, the IMPC computational framework allows public access to the raw data using standard software interfaces and web services. The software application source code for these components and statistical analysis tools are also provided for community use.
The services provided by the IMPC fulfil the needs of several user groups representing different strands of the biomedical community including:
1, The community of biomedical researchers accessing statistically significant phenotypic associations for a given gene, e.g. a rare disease researcher searching for specific phenotypes of interest.
2, Researchers requiring mouse specimens or genetic material for which phenotype data are available, e.g. a researcher who wishes to conduct secondary experiments on a well-known gene to augment existing broad-based phenotype data.
3, System biologists and statisticians seeking access to large-scale standardized gene-phenotype datasets to perform their own analysis.
4, Informatics users accessing all, or partial, datasets for inclusion in their own resource set.
5, High-throughput phenotyping centers producing and exporting their data, e.g. KOMP2 or IMPC members.
6, Data wranglers carrying out quality control (QC) checks on the raw data, e.g. correction of data submission errors, detection of baseline drift due to instrumentation, harmonization and standardization of protocols across centers, among others.
7, Funding bodies that are tracking the progress of mouse production and phenotyping efforts, and the state of production, collection and dissemination of the data.
List of Websites:
http://www.mousephenotype.org/
The goal of I-DCC coordination action was to make the products of the International knockout mouse consortium (IKMC) mutagenesis programmes as widely visible and available to the research and clinical communities. The I-DCC provided a single point of access for all mutant Embryonic stem (ES) cell resources held in repositories worldwide. The I-DCC project has significantly enhanced the end-user value of the IKMC products by integrating other biological information (mouse production, expression, phenotype) with the genes and mutant products in the IKMC catalogue. These additional data sets have been integrated using BioMart technology with an enhanced presentation layer. The BioMarts can also be directly accessed, allowing federation of different data sets using common linking identifiers (gene IDs, ES cell IDs, expression ontologies) and enabling the results to be downloaded.
Project Context and Objectives:
The large-scale mutagenesis programs (EUCOMM/EUCOMMTOOLS, KOMP, NorCOMM, TIGM) have conducted saturation mutagenesis of the mouse genome using both gene targeting and gene trap approaches.
This coordinated, international approach allowed for the global use of mutant ES cells to support the functional annotation of the mammalian genome.The goal of IDCC coordination action was to make the products of the IKMC mutagenesis programs as widely visible and available to the research and clinical communities. The IDCC initially and now the IMPC provide a single point of access for all mutant ES cell resources held in repositories worldwide. Users can search for all IKMC/IMPC products at the website: http://www.mousephenotype.org
The mutagenesis components of the IMPC website rests on three foundations, each of which is built using the complementary expertise of the consortium members:
1) A master gene list of all mouse genes - this is a curated list which allows clear coordination of knockout targets between consortium members. The list is annotated with further information (eg.orthologues cross-references to disease) which help consortium members identify and prioritisetargets.
2) A targeting data repository which stores in a common format the molecular structure of knockout
alleles and products of all knockout programs.
3) A repository of IKMC gene trap ES cell lines, suitably grouped into clusters of insertions with
equivalent mutagenic potential. The repository also serves the mutant molecular structure of each
allele.
The IDCC project has also significantly enhanced the end-user value of the IMPC products by integrating other biological information (mouse production, expression, phenotype) with the genes and mutant products in the IKMC catalogue. These additional data sets have been integrated using BioMart technology with an enhanced presentation layer (see the IMPC project pages and the Martsearch portal). The BioMarts can also be directly accessed, allowing federation of different data sets using common linking identifiers (gene IDs, ES cell IDs, expression ontologies, etc.) and enabling the results to be downloaded.
The IMPC website has been functioning as the central website for the IMPC consortium for almost four years. The site receives over 15,000 visits a month and fields broad-ranging enquiries from scientists regarding the interpretation of data on the website. Initially serving the KOMP, EUCOMM, NorCOMM and TIGM, during this reporting period we have extended the site to report the status and products of the EUCOMMTools and the Sanger MirKO (microRNA) knockout programs. Standardized molecular-level descriptions (sequence, diagrams and browser views) are currently offered for all targeted mutations visible on the site, and soon will be offered for gene trap alleles.
The project was concluded in this final period by using the tools created to describe the molecular structure of gene trap alleles. Furthermore, we have developed interfaces for the International Mouse Phenotyping Consortium (IMPC) to help coordinate the production and phenotyping of mice generated from IKMC ES cell resources.
In summary, the objectives for this reporting period were as follows:
1. To maintain the annotated master gene list
2. To continue to gather and populate the targeting repository with data
3. To continue to develop the display interfaces from the targeting repository
4. To improve the main web portals (A and B)
5. To maintain and improve the BioMart data being presented to the portal
During this reporting period. Many of the alleles generated by the IKMC have been made into mice and systematically phenotyped by the members of the International Mouse Phenotyping Consortium (IMPC). Our data repository of molecular-level descriptions of IKMC alleles and the catalogue of QC-validated targeted and trapped ES cells is the foundation for this international effort. We have responded to the needs of the IMPC by developing an interface (iMITS; www.mousephenotype.org/imits) to coordinate and track the production and phenotyping of mice generated from IKMC ES cell resources. This system will be maintained in future years as a component of the IMPC data coordination activities.
Project Results:
The large-scale mutagenesis programs (EUCOMM/EUCOMMTOOLS, KOMP, NorCOMM, mirKO, TIGM) have produced knock out ES cells for 18,000 protein coding genes in the mouse. This coordinated, international approach by the International Knockout Mouse Consortium (IKMC) reduced redundant effort and allows for the global use of mutant ES cells to support the functional annotation of the mammalian genome.
The goal of IDCC coordination action was to make the products of the IKMC widely visible to the research and clinical communities. The IKMC website has functioned as the central website for the IKMC consortium for almost four years. The site received over 15,000 visits a month and fielded broad-ranging enquiries from scientists regarding the interpretation of data on the website. The website also offered standardized molecular-level descriptions (sequence, diagrams, and project pages) for all targeted alleles.
In the final year of the project, we have transferred the catalogue and the display of mutant ES cells to the website of the International Mouse Phenotyping Consortium (www.mousephenotype.org). The goal of the IMPC is to convert IKMC ES cells into mice for broad-based phenotyping studies and for archiving and distribution of mice to the international scientific community. We have developed interfaces for the International Mouse Phenotyping Consortium (IMPC) to coordinate the production and phenotyping of mice generated from IKMC ES cell resources. By merging the IKMC and IMPC websites, the maintenance and display of IKMC data has been safeguarded for the foreseeable future.
2. Project objectives for the period
In summary, the objectives for this reporting period were as follows:
1. To curate and maintain the annotated master gene list
2. To continue to gather and populate the targeting repository with data
3. To continue to develop the display interfaces from the targeting repository
4. To continue to develop the iMITS interfaces for tracking IMPC mouse production
5. To merge the IKMC website (Portal A) with the IMPC website
6. To maintain and improve the BioMart data being presented to the portal
Merging the IKMC website with the IMPC website has been added as additional objective in this reporting period. Many of the alleles generated by the IKMC will be made into mice and systematically phenotyped by the members of the International Mouse Phenotyping Consortium (IMPC). Our data repository of molecular-level descriptions of IKMC alleles and the catalogue of QC-validated targeted and trapped ES cells is the foundation for this international effort. We have responded to the needs of the IMPC by developing an interface (iMITS; www.mousephenotype.org/imits) to coordinate and track the production and phenotyping of mice generated from IKMC ES cell resources. This system will be maintained in future years as a component of the IMPC data coordination activities.
3. Work progress and achievements during the period
WP 1: Gene List and Gene Annotation
WP leader: M. Ringwald (The Jackson Labs)
Partners: T. Hubbard (WTSI), E. Birney (EMBL), G. Hicks (MICB)
Objectives:
The objective of this work package is to establish and maintain a unified and annotated master gene list for the high-throughput gene targeting and gene trapping projects that will facilitate coordination and prioritization within and between these projects. The work will include the development of a database and of data load and analysis procedures to generate and update the annotated gene list; the implementation of administrative interfaces that provide integrated data access, data management, and querying capabilities for the knockout projects; as well as manual curation and review of these data. The work will take advantage of and expand existing informatics infrastructure and curatorial efforts implemented by the Mouse Genome Informatics (MGI) and the KOMP-Data Coordination Centre (KOMP-DCC) projects.
Deliverables with activity for this reporting period:
D1.1 Unified and annotated master gene list
The design and coordination of IKMC gene targeting experiments requires up-to-date gene model information. To provide the IKMC with a current and unified master gene list, we continued to perform comparison, coordination, and integration of different gene models. By manual curation, in close collaboration with Vega, Ensembl, NCBI, and MGI, we continued to resolve conflicts between gene models and other data issues related to genes assigned to IKMC projects and products. We continued to report new gene associations, and gene merges and splits to the IKMC production centres and repositories.
To provide the research community with up-to-date information about the status of targeting projects and the availability of IKMC products, we continued to annotate the genes with regard to pipeline status information from WP2 and with regard to availability information from the KOMP repository. As the International Mouse Phenotyping Consortium (IMPC) began to generate mice from IKMC ES cells and to phenotype mice, we incorporated pertinent status and mouse availability information as well. We also continued to incorporate MGI’s current gene trap to gene associations for IKMC gene traps, as well as updates, provided by TIGM, on mouse production from TIGM-IKMC gene traps.
We achieved all objectives proposed for D1.1.
D1.2 Maintenance of GFF files for UCSC Genome Browser
In collaboration with WP2, we maintained the GFF files that enable the UCSC Genome Browser to update its IKMC allele tracks on a regular basis. All objectives for D1.2 were achieved.
D1.3. Registration and nomenclature for IKMC alleles
Another important objective of WP1 was to register IKMC targeted mutant allele information in MGI and to provide WP2, the IKMC repositories, and the research community with official allele IDs and nomenclature. To do so, we continued to incorporate IKMC allele information into MGI by using automated load procedures, computational checks, and manual quality controls. We expanded our load and quality control procedures to accommodate new types of IKMC alleles, such as the alleles with artificial introns generated by EUCOMMTOOLS. The registration of knockout alleles and the assignment of official nomenclature is essential for the future integration of biological data from studies of mutant ES cells and mice generated by the IMPC. All objectives for D1.3 were achieved.
Deliverables:
________________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
________________________________________________________________________________________
D1.4 Curate / maintain WP1 6 55.9 R PU 48
gene list, interface
(continuous from
first release through
lifetime of project)
________________________________________________________________________________________
WP 2: Gene Targeting Data Repository
WP leader: W. Skarnes (WTSI)
WP Partners: G. Hicks (MICB), E. Birney (EMBL), M. Ringwald (Jackson Laboratory)
Objectives:
The objective of this work package is:
To coordinate with WP1 to be in synchrony with the “master gene list” and allocation of genes to pipelines, as curated by WP1.
To collect information on targeting vectors and alleles as they are produced by the pipelines.
To transfer information on targeted genes to the annotated gene list on pipeline status.
The IKMC targeting repository has been merged during this reporting period with the iMITS system described in deliverable 4.7 (see 2012 periodic report). This change means that the ES cell resources created by the IKMC are now fully merged with the mouse production application which coordinates and tracks the production of mice generated by the IMPC. In addition, the targeting repository contributes directly to the tracking and display of products on the IMPC portal. In turn, the display of data (graphic, search indices, web pages) for the IKMC resource has been merged with the display of data from iMITS: this ensures that the two data sources will evolve in synchrony for the lifetime of the IMPC. The targeting repository can now be found at www.mousephenotype.org/imits/targ_rep .
Deliverables with activity for this reporting period:
D2.1 Validate / Test a common schema.
The database of the IKMC targeting repository and the IMPC mouse production tracker (iMITS) were merged during this reporting period. The two project codebases were also merged, and are now stored here github.com / mpi2 / imits. This merge is complete and was successful, and it means that the ES Cells stored in the IKMC targeting repository are now directly linked to the microinjections recorded in iMITS, without the need to communicate between systems. This deliverable is (again) complete.
D2.3 Upload and update pipeline data.
We have continued to load data from the EUCOMMTools production effort into the targeting repository during this period, and will continue to do so for all EUCOMMTools production. The repository has also been modified to distinguish EUCOMMTools – specific Artificial Intron Alleles. The targeting repository is not only a catalogue of mutant ES cell alleles but also contains a summary of all quality control assays that were performed to verify mutant alleles at the ES cell production centres, at the ES cell repositories and at the mouse production centres. The repository has been specifically modified to discriminate between QC assays submitted by different centres, as we were seeing that multiple centres (e.g. WTSI and the EUMMCR repository or WTSI and the KOMP repository) assay the same ES cell clones. Future work that will be performed by the IMPC will ensure that all QC assays performed on ES clones and mouse lines are captured in the targeting repository.
This deliverable is complete.
D2.5 Displaying data
The IKMC targeting repository now has two means of displaying data: it directly (and instantly) updates search indices used by the IMPC portal to display allele data to scientists interested in IKMC ES cells and IMPC mice. This ensures that new alleles uploaded from the EUCOMMTools production are immediately visible to the IMPC portal.
The repository also draws both detailed and simplified allele graphics customised on a gene and allele basis. These graphics are served directly to the IMPC portal. The graphic generating code has been reworked to allow it to be as flexible as possible to deal with future changes.
Detailed Graphics: please refer to accompanying documents
Simplified Graphics: please refer to accompanying documents
This deliverable is complete.
Deliverables
________________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
________________________________________________________________________________________
D2.3 Upload and update WP2 1 24 R PU 48
pipeline data
________________________________________________________________________________________
WP 3: Data integration of gene trap resources
WP leader: W. Wurst (IDG)
Partners: J. Hansen (IDG), G. Hicks (MICB), W. Skarnes (WTSI), A. Ballabio (FTELE.IGM)
Objectives:
The objectives of this work package are:
To define standard formats for gene trap allele and vector descriptions
To standardize gene trap sequence tag analysis
To deduce synthetic mutant alleles from gene trap clusters
To forward the results of standardised analyses and synthetic alleles to a central data repository holding both targeted and random traps (in conjunction with WP2).
To use the synthetic alleles as a basis for creating effective display strategies for trapped genes (in conjunction with WP4).
To configure data for display
Deliverables with activity for this reporting period:
The gene trap repository aimed to make a consensus gene-trap annotation pipeline and then compile these annotations, as well as the molecular details on all known gene traps in the IKMC. The data gathered during the lifetime of this project was served (and continues to be served) by the UniTrap BioMart, see WP5.
The ongoing deliveries during this period were D3.5 (data display) and D3.6 (Maintenance and curation of data). Both of these deliverables were significantly influenced by the small number of gene trap alleles chosen for IMPC mouse production. The vast majority of IMPC production employ IKMC targeted mutations. The longevity of the IKMC Targeting Repository (WP2) has been ensured by its integration with iMITS. In the same vein, we have merged the storage of gene-trap alleles with iMITS. This allows the repository of gene-traps to remain relevant to mouse production if required.
In keeping with the choice of alleles for high-throughput IMPC mouse production, we show only those gene-trap alleles that have been chosen for IMPC mouse production.
D3.5 Displaying data
The display of gene-trap alleles relevant to IMPC mouse production is identical to the display of targeted mutations used in mouse production: if an IMPC mutant mouse has been generated using a gene-trap allele, then it will be displayed in the IMPC gene page, with the same information (allele image, genbank file) as a targeted allele:
Links will then direct the user to the repository to order the ES Cell or mouse as needed.
This deliverable is now complete.
D3.6 Maintenance and curation of data
Gene Trap mutant ES Cells relevant to IMPC mouse production are now stored in a “Gene Trap Alleles” inside iMITS / IKMC Targeting Repository with a structure similar to that stored for Targeted alleles. They are found through a “Gene Trap Alleles” inside iMITS (see picture) and can be searched for and browsed like other targeted alleles. Each allele stores the individual mutant ES Cell clones for that allele, the coordinates of the genomic insertion and the mutant sequence of the ES Cell (genomic + cassette sequence).
We will continue to maintain this data – adding extra alleles as they become relevant – for the lifetime of the IMPC project. This deliverable is now complete.
Deliverables:
______________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
______________________________________________________________________________________
D3.6 Maintenance and WP3 2 25.2 R PU 48
curation of data
______________________________________________________________________________________
WP 4: Web Portal
WP leader (Part A): M. Ringwald (Jackson Labs)
WP leader (Part B): E. Birney (EMBL)
Partners: W. Skarnes (WTSI), W. Wurst (IDG), G. Hicks (MICB), A. Ballabio (FTELE.IGM)
Objectives
The purpose of WP4 is
To create a website to display current repository information
To create DAS-tracks that can be served to popular genome browsers, to display this information in its genomic context.
To create a Biomart to house periodic, query-optimised snapshots of the repository. The Biomart will serve DAS-tracks, provide query web-services, and link to other Biomarts (including EnsMart), greatly enhancing the search capability and future utility of the repository.
This reporting period has seen the integration of the IKMC and the IMPC websites. The benefits for the end user are that they only need visit one site to get all IMPC phenotype, mutant mouse and IKMC ES cell information.
Deliverables with activity for this reporting period:
D4.1 Web Portal Part A
We continued to maintain and enhance Part A of the IKMC Web Portal as the central front end for information on IKMC data and resources. As the IMPC project started to generate mice from IKMC ES cells, we expanded the web site to also show, for each IKMC targeting project, the status of IMPC mouse generation and availability. We implemented links to the IMPC production centres from which the respective mice where available. We also indicated the availability of IMPC mouse phenotype data and provided links to corresponding entries on the IMPC web site. We achieved all objectives proposed for D 4.1. The web portal displaying IKMC products will now be maintained by out by the Data Coordination Centre of the IMPC.
D4.2 User Support
The IKMC Web Portal served as the central point of entry to data and resources from the IKMC. The web site was used heavily and the number of user inquiries was increasing steadily. We continued to provide timely user support for researchers that contacted us with questions regarding IKMC data and products. All objectives proposed for D4.2 were achieved. This activity has now been transferred to the IMPC Data Coordination Centre.
D4.4 Enhancement and maintenance of the portals (Web portal Parts A and B)
The first phase of the large-scale mouse phenotyping, coordinated by the International Mouse Phenotyping Consortium (IMPC), is now well underway. It is important that the phenotype data and mutant mice produced by the IMPC as well as the mutant IKMC ES Cells that underlie that effort are all available from a single website (www.mousephenotype.org).
Therefore, we have focused effort during this final reporting period on integrating the IKMC web presence with that of the IMPC. Any user who navigates to www.knockoutmouse.org will be directed instead to www.mousephenotype .org. Note that this site has a direct link to iMITS and the IKMC targeting repository from its front page:
There, they will be able to search for IMPC and IKMC products for their gene (phenotypes, mutant mice and IKMC alleles). All IKMC alleles are presented in summary inside IMPC gene pages (https://www.mousephenotype.org/data/genes/MGI:105369):
The links allow users to view detailed IKMC allele information as well as contact repositories for products. The links to detailed allele information (“Product Details” ) present all the details visible via the IKMC project pages: (http://www.mousephenotype.org/martsearch_ikmc_project/martsearch/ikmc_project/35505):
The integration of the IKMC website with the IMPC website (and this delivery) is now complete and will be maintained by the IMPC Data Coordination Centre.
D4.7 Development of a mouse production and phenotyping tracking system (iMITS)
The iMITS system has continued to evolve during the current reporting period to serve the tracking and reporting needs of the IMPC.
The production reports provided by iMITS are continuously enhanced and modified to serve the needs of the IMPC. In addition, during this current reporting period
It has been integrated with the IKMC Targeting Repository, thereby connecting it directly to all IKMC alleles without the need for cross-system communication
It has leveraged this connectivity to provide high-level overviews of the genotyping assays performed on mutant mice, taking into account both mouse and ES cell qcs: the long-term record of these assays having been performed is important to establish best-practice between mouse production centres.
It has been given a public-facing website (i.e. requiring no login) to allow any scientist to view details of mouse production in progress at any production centre.
It has been enhanced to display mutant mouse data (tm1a and tm1b mice) directly to the IMPC portal:
Deliverables
______________________________________________________________________________________
Del. Deliverable WP Lead Estimated Nature Dissemination Delivery
name no. benef- indicative level date
iciary person-months (proj. month)
______________________________________________________________________________________
D4.4 Enhancement and WP4 6/4 74 R PU 48
Maintenance of portals
D4.6 Second I-DCC Training WP4 1 0 R PU 37
day
D4.7 Development of a WP4 1 8 R PU 36
mouse production and
phenotyping tracking
system (iMITS)
______________________________________________________________________________________
WP5: Integration of Gene Expression Data
WP leader: A. Ballabio (F.TELE)
Partners: M. Ringwald (Jackson Labs), E. Birney (EBI)
Objectives
To gain maximum leverage from gene expression data, we propose to federate other bioinformatics resources that either already exist or are in the process of being constructed by the scientific community.
All BioMart integrations were achieved during the last reporting period. During this period we have ensured that biomart data – most importantly the data in the IKMC Targeting repository and the iMITS biomart – have been kept current with nightly updates.
The BioMarts have been used by many external groups to obtain current IKMC and IMPC data. They will continue to be kept current and maintained here:
http://www.mousephenotype.org/martsearch_ikmc_project/
This work package is now complete. Further work (beyond the scope of this project) integrating gene expression data will be conducted under the guidance of the IMPC.
4. Deliverables and milestones tables
Deliverables (excluding the periodic and final reports)
Table 1. Deliverables
______________________________________________________________________________________
Del. Deliverable WP Lead Nature Dissemination Delivery date Delivered Actual/
name no. benef- level from annex 1 yes/no forecast
iciary delivery date
______________________________________________________________________________________
D1.1 Unified and WP1 6 R PU 0 Yes 0
annotated master
gene list (initial
delivery is
immediate,
but see D1.4)
D1.2 Pubic release of WP1 6 R PU 3 Yes 42 / 3
I-DCC administrative
web interface
D1.3 Public release of WP1 6 R PU 9 Yes 36
gene models and Mart
D2.1 Validate / test WP2 1 R PU 6 Yes 12
a common schema
D2.2 Populate central WP2 1 R PU 12 Yes 12
database with
initial data
D2.4 Develop interfaces WP2 1 R PU 12 Yes 36
to report targeting
pipeline status to WP1
D2.5 Displaying data WP2 1 R PU 12 Yes 36
D3.1 Definition of WP2 1 R PU 12 Yes 36
standard form
D3.2 Establishment of a WP3 2 R PU 12 Yes 36
gene trap data
repository
D3.3 Synthetic gene WP3 2 R PU 12 Yes 36
trap alleles
D4.1 Workshop to discuss WP4 6/4 R PU 3 Yes 3
the structure and
interoperability
of the I-DCC website
D4.2 Portal Part A – WP4 6 R PU 3 Yes 36 / 3
main website
(Jackson Labs and WTSI).
Initial delivery at
month 3: enhancement
in D4.3
D4.3 Portal Part B – WP4 4 R PU 9 Yes 36 / 9
HTGT Mart (WTSI)
D5.1 Integration of WP5 3 R PU 6 Yes 6
EURExpress
D5.2 Meeting with CREATE WP5 3 R PU 6 Yes 6
project to discuss
data integration
(month 6)
D5.3 Integration of GXD WP5 6 R PU 12 Yes 36
D5.4 Integration of WP5 8 R PU 30 Yes 36
selected additional
expression databases
D5.5 Maintenance WP5 6 R PU 48 Yes 36
of mart data
______________________________________________________________________________________
Milestones
Please complete this table if milestones are specified in Annex I of the Grant Agreement.
Milestones will be assessed against the specific criteria and performance indicators as defined in Annex I.
______________________________________________________________________________________
Milestone Milestone Work package Expected Means of
number name involved date verification7
______________________________________________________________________________________
M1 Master Gene 1 6 Links to Central db, or flat file for download,
List issued of genes keyed by MGI id, with cross-references
to other ids.
M2 Initial 2 12 Central DB with all vectors and alleles from all
targeting targeting programs loaded.
data load
M3 Complete 2 12 Feedback to close a loop can be simulated:
Loop: Master in practice feedback will take months to
Gene list to close a loop.
Targeted Data
M4 Trapping data 3 15 Single query against database will
integrated bring back all current targeted and trapped KO’s.
into repository
M5 Portal Part A 2/3/4 15 Basic search for alleles via portal is functional,
done: targeting with graphical display of synthetic alleles
/ trapping is complete.
alleles shown
M6 Mart complete 4 18 Users can make cross-mart searches into KO data.
M7 Initial 5 18 Users can make cross-mart searches from expression
expression data into KO data.
data complete
and integrated
with KO
resources
_____________________________________________________________________________________
SECTION 5 – Project Management
Dr William Skarnes (WTSI, UK) is the I-DCC project coordinator and is responsible for interacting with the European Commission and supervising the management team. The management team comprises project manager Dr. Derek Matthews and Mr Stuart Rayner who is principally concerned with financial aspects of the I-DCC project.
I-DCC Steering Committee: The I-DCC Steering Committee comprises:
P1 (WTSI) – Bill Skarnes; Derek Matthews
P2 (HGMU) – Wolgang Wurst
P3 (FTELE.IGM) – Graciana Diez Roux; Andrea Ballabio
P4 (EMBL) – Ewan Birney
P5 (BSRC Fleming) – Vassilis Aidinis
P6 (JAX) – Martin Ringwald
P7 (MICB) – Geoff Hicks
Attendance of I-DCC members at other meetings:
Bill Skarnes (WTSI)
Dr Skarnes attended the following meetings at which I-DCC matters were discussed and/or presented
- at the International Congress of Applied Biotechnology, Tianjin, China October , 2012
- at the Wellcome Trust Advanced Course “Genetic Manipulation of ES Cells”, Hinxton, UK, October 31 - November 5-19, 2012
- at the IMPC meeting in Toronto, Canada, November 28-30, 2012
- at the SyBOSS open symposium in Kirchberg, Austria, February 1, 2013
- at the Wellcome Trust Researchers meeting, London, UK, February 7-8, 2013
- at the British Society for Gene and Cell Therapy meeting, UK, April 17-19, 2013
- at the Mouse Molecular Genetics Meeting, Hinxton, UK, September 18-21, 2013
- at the IMPC meeting in Toronto, Canada, October 28-30, 2013
- at Wuhan University of Science and Technology, Wuhan, China, November 19th, 2013
Conferences, Publications, Press Releases:
I-DCC-related Publications:
The following publications were accepted during the reporting period that have some component relating to I-DCC activities or deliverables
Nature Methods | Vol.9 No.1 | January 2012. Special feature on single cell methods.
The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data. Koscielny G, Yaikhom G, Iyer V, Meehan TF, Morgan H, Atienza-Herrero J, Blake A, Chen CK, Easty R, Di Fenza A, Fiegel T, Grifiths M, Horne A, Karp NA, Kurbatova N, Mason JC, Matthews P, Oakley DJ, Qazi A, Regnart J, Retha A, Santos LA, Sneddon DJ, Warren J, Westerberg H, Wilson RJ, Melvin DG, Smedley D, Brown SD, Flicek P, Skarnes WC, Mallon AM, Parkinson H. Nucleic Acids Res. 2013 Nov 4. [Epub ahead of print]
Molecular characterization of mutant mouse strains generated from the EUCOMM/KOMP-CSD ES cell resource. Ryder E, Gleeson D, Sethi D, Vyas S, Miklejewska E, Dalvi P, Habib B, Cook R, Hardy M, Jhaveri K, Bottomley J, Wardle-Jones H, Bussell JN, Houghton R, Salisbury J, Skarnes WC; Sanger Mouse Genetics Project, Ramirez-Solis R. Mamm Genome. 2013 Aug;24(7-8):286-94.
Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC; Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP. Cell. 2013 Jul 18;154(2):452-64.
Accessing data from the International Mouse Phenotyping Consortium: state of the art and future plans. Mallon AM, Iyer V, Melvin D, Morgan H, Parkinson H, Brown SD, Flicek P, Skarnes WC. Mamm Genome. 2012 Oct;23(9-10):641-52.
The mammalian gene function resource: the International Knockout Mouse Consortium. Bradley A, Anastassiadis K, Ayadi A, Battey JF, Bell C, Birling MC, Bottomley J, Brown SD, Bürger A, Bult CJ, Bushell W, Collins FS, Desaintes C, Doe B, Economides A, Eppig JT, Finnell RH, Fletcher C, Fray M, Frendewey D, Friedel RH, Grosveld FG, Hansen J, Hérault Y, Hicks G, Hörlein A, Houghton R, Hrabé de Angelis M, Huylebroeck D, Iyer V, de Jong PJ, Kadin JA, Kaloff C, Kennedy K, Koutsourakis M, Lloyd KC, Marschall S, Mason J, McKerlie C, McLeod MP, von Melchner H, Moore M, Mujica AO, Nagy A, Nefedov M, Nutter LM, Pavlovic G, Peterson JL, Pollock J, Ramirez-Solis R, Rancourt DE, Raspa M, Remacle JE, Ringwald M, Rosen B, Rosenthal N, Rossant J, Ruiz Noppinger P, Ryder E, Schick JZ, Schnütgen F, Schofield P, Seisenberger C, Selloum M, Simpson EM, Skarnes WC, Smedley D, Stanford WL, Stewart AF, Stone K, Swan K, Tadepally H, Teboul L, Tocchini-Valentini GP, Valenzuela D, West AP, Yamamura K, Yoshinaga Y, Wurst W. Mamm Genome. 2012 Oct;23(9-10):580-6.
Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project. Ayadi A, Birling MC, Bottomley J, Bussell J, Fuchs H, Fray M, Gailus-Durner V, Greenaway S, Houghton R, Karp N, Leblanc S, Lengger C, Maier H, Mallon AM, Marschall S, Melvin D, Morgan H, Pavlovic G, Ryder E, Skarnes WC, Selloum M, Ramirez-Solis R, Sorg T, Teboul L, Vasseur L, Walling A, Weaver T, Wells S, White JK, Bradley A, Adams DJ, Steel KP, Hrabe de Angelis M, Brown SD, Herault Y. Mamm Genome. 2012 Oct;23(9-10):600-10.
D) Consortium Agreement and amendment:
During the reporting period, due to reorganizations within the UK NHS, the HGRU was transferred from MRC control to the University of Edinburgh (IUEDIN). Whilst no changes were necessary to the DOW it was necessary to enact an amendment for a transfer of rights from MRC to UEDIN so that the financial reporting could be completed. At the time of submission this process is ongoing
Public relations activities:
WTSI members disseminated I-DCC technology/ materials at the Wellcome Trust Advanced Course, Hinxton Hall, 5th – 18th Nov 2012
SECTION 4 – I-DCC ETHICAL AND GENDER ISSUES
Ethical Issues
There are no ethical issues relevant to the I-DCC grant application. All source data is available to the public without restriction.
Gender Issues
No gender issues were identified in Annex 1 part B
Potential Impact:
The IMPC portal is the central point of access to high-throughput phenotype data, IKMC ES cell resources and mutant mouse strains. The progress of mouse production and phenotyping is presented for each gene, with links to repositories that are distributing the mutant mouse strains and the availability of IKMC ES cell resources and the molecular structures of the mutant alleles.
The web portal’s primary function is to display genotype–phenotype data for knockout lines for the biomedical community. The site has been optimized to allow free text queries that return structured data via facets allowing the user to explore the data with a mixture of query terms. Users are able to register for genes of interest and will be alerted via email when the gene changes status, indicating new data are available or a mouse is available.
In addition to the information made accessible through the web portal, the IMPC computational framework allows public access to the raw data using standard software interfaces and web services. The software application source code for these components and statistical analysis tools are also provided for community use.
The services provided by the IMPC fulfil the needs of several user groups representing different strands of the biomedical community including:
1, The community of biomedical researchers accessing statistically significant phenotypic associations for a given gene, e.g. a rare disease researcher searching for specific phenotypes of interest.
2, Researchers requiring mouse specimens or genetic material for which phenotype data are available, e.g. a researcher who wishes to conduct secondary experiments on a well-known gene to augment existing broad-based phenotype data.
3, System biologists and statisticians seeking access to large-scale standardized gene-phenotype datasets to perform their own analysis.
4, Informatics users accessing all, or partial, datasets for inclusion in their own resource set.
5, High-throughput phenotyping centers producing and exporting their data, e.g. KOMP2 or IMPC members.
6, Data wranglers carrying out quality control (QC) checks on the raw data, e.g. correction of data submission errors, detection of baseline drift due to instrumentation, harmonization and standardization of protocols across centers, among others.
7, Funding bodies that are tracking the progress of mouse production and phenotyping efforts, and the state of production, collection and dissemination of the data.
List of Websites:
http://www.mousephenotype.org/