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The Centre for Applied Genomics
Company typeGenome Centre
Founded1998
Headquarters
Toronto
,
Canada
Area served
Biomedical Research
Key people
Dr. Stephen W. Scherer, Scientific Director
ServicesExperimentation, Project consultation, Data analysis, Bioinformatics.
Number of employees
70
ParentThe Hospital for Sick Children
Websitehttp://www.tcag.ca/

The Centre for Applied Genomics is a genome centre in the Research Institute of The Hospital for Sick Children, and is affiliated with the University of Toronto. TCAG also operates as a Science and Technology Platform of Genome Canada[1]. Research at TCAG focuses on the genetic and genomic basis of human variability, health and disease, including research on the genetics of autism spectrum disorders and structural variation of the human genome. The Centre is located in the MaRS Discovery District in downtown Toronto, Canada.

History

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The need for a centralized core facility for human genome research at SickKids Hospital prompted the establishment of The Centre for Applied Genomics (TCAG) in 1998. The Founding Director and Associate Director were Drs. Lap-Chee Tsui and Stephen W. Scherer, respectively. Dr. Scherer is now the Scientific Director. Dr. Tsui remains an ex officio member of the Scientific Advisory Board, having left SickKids in 2002 to become President and Vice-Chancellor of the University of Hong Kong.

The Centre for Applied Genomics

Funding from the Canada Foundation for Innovation (CFI) enabled TCAG to form by consolidating existing core facilities including the Medical Research Council of Canada Genome Resource Facility, the Canadian Genetic Diseases Network (CGDN) large insert clone core, the CGDN DNA Sequencing Core and the SickKids Biotechnology Service DNA Sequencing and Synthesis labs. A genome-wide microsatellite genotyping laboratory at the Ottawa Health Research Institute led by Dr. Dennis Bulman was added. Subsequently, operational funding from the CIHR Genomics Special Projects panel provided for additional staff.

In 2001, a proposal entitled "Genome Resource Core Platform" was submitted to the then newly formed Genome Canada. This provided operational support, enhancing existing facilities and adding a mouse genotyping core at the University of Toronto led by Dr. Lucy Osborne. In 2002, SickKids built a new Affymetrix microarray facility. This core has quickly grown to become the largest such service centre in Canada and is in the top ten in North America[2].

In 2004, TCAG entered a second phase of development driven by a $12 million CFI/Ontario Innovation Trust funded project entitled "Integrative Genomics for Health Research"[3], allowing for consolidation of the mouse genotyping core with the SickKids facilities. This award also supported the establishment of an "Ontario Population Genomics Repository" (OPGP) to be used as controls in studies of common diseases. To efficiently complete this project, TCAG partnered with Dr. John McLaughlin's group at Mount Sinai Hospital (Toronto).

In May, 2004, an application to the newly announced CFI Research Hospital Fund resulted in a $10.9 million dollar award to build out lab space and consolidate all operations on the 14th and 15th floors of the Toronto Medical Discovery Tower (TMDT) in the MaRS Discovery District. TCAG was the first occupant of TMDT (in August, 2005), quickly followed by other SickKids scientists. Most recently, investments in computer infrastructure from the 2003 CFI/Ontario Innovation Trust competition have resulted in the establishment of new phases of the high-performance computing cluster (HPF) that is currently used by TCAG and many other users, to allow analysis of large genomic datasets arising from new microarray and sequencing technologies.

Since January, 2006, TCAG has been operating in large part on renewal funds from Genome Canada, administered by the Ontario Genomics Institute.

Research

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Current research at TCAG centres around large-scale projects performed by facility personnel, including support of Genome Canada projects, and a significant focus on the genetics of autism spectrum disorders and structural variation of the human genome.

Past research at TCAG is reflected by numerous peer-reviewed scientific publications. In the first quarter of 2008, TCAG Scientific Directors, Associate Scientists and staff co-authored 22 peer-reviewed manuscripts dependent in some way (either entirely, or in part) on the platform infrastructure, as documented in PubMed[4]. Since 2002, nearly 250 such papers have been published[5]. Support of other researchers worldwide is found in many similar publications, with at least 120 papers in scholarly journals, book chapters, or graduate thesis dissertations acknowledging support or use of database resources during 2007 alone[6]

A few of the most significant historical papers include:

  • Discovery of genes involved in predisposition to medulloblastoma (Michael Taylor and James Rutka with TCAG support)[7]
  • Gene identification in Shwachman-Diamond syndrome (with Johanna Rommens and others)[8]
  • Gene identification in Lafora Epilepsy (with Berge Minassian)[9] and its canine counterpart[10].
  • A disease-relevant MECP2 isoform involved in Rett Syndrome[11]
  • Involvement of the SUMO4 gene in type I diabetes[12]
  • Severe expressive-language delay related to duplication of the Williams–Beuren locus[13]

TCAG was also integral to publications describing the decoding of human chromosome 7[14], the discovery of large-scale copy number variation in the human genome[15][16], and the analysis of the first diploid human genome sequence (with the J. Craig Venter Institute).[17]

Genome Canada Projects

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As a Science and Technology Platform of Genome Canada, TCAG currently supports nine large-scale projects, including research on autism spectrum disorders, structural variation of the human genome, integrative biology, conditional mouse mutagenesis, interactions of signaling molecules, type I diabetes, cancer stem cells, Cystic Fibrosis, and biodiversity, from Genome Canada's Competition III.[18]

Databases

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TCAG also hosts and curates websites and databases developed from supported projects, namely The Chromosome 7 Database, The Database of Genomic Variants[19], the Segmental Duplication Database, the Autism Chromosome Rearrangement Database, and others [20]. These databases contain publicly-available information.

Core Facilities

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TCAG DNA Synthesis Facility

TCAG employs a variety of genomic technologies to support different types of experimentation. These are organized into separate Core Facilities, with dedicated managers.

DNA Sequencing and Synthesis

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The DNA Sequencing and Synthesis Core Facility has a dedicated manager for DNA Synthesis. The DNA Sequencing component shares a manager with the Genetic and Statistical Analysis Core Facility. This latter manager is responsible for the genotyping functions within that facility.

The facility uses conventional capillary Sanger sequencing on Applied Biosystems 3730xl instruments, governed by a Laboratory Information Management System (LIMS). Additionally, next-generation sequencing (NGS) using the Illumina Genome Analyzer (Solexa 1G) and Applied Biosystems SOLiD instruments have been recently implemented. A key component of this facility is the use of high-performance computing and bioinformatics support for NGS analysis and assembly.

The Oligonucleotide Synthesis component of this facility makes conventional, long (up to 120 bases) and modified oligonucleotides, and purifies these by desalting, cartridge or high-performance liquid chromatography (HPLC).

Microarray and Gene Expression

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The Microarray and Gene Expression Core Facility has a dedicated manager, and operates Affymetrix and Agilent technologies. All Illumina technologies are contained within the Genetic Analysis Core Facility. Affymetrix MegAllele and Single Nucleotide Polymorphism (SNP) microarrays, Affymetrix gene expression, tiling, promoter and exon microarrays, and Agilent oligonucleotide microarrays are all run. Additionally, there are a wide variety of analytical software packages available for on-site data analysis.

Cytogenomics and Genome Resources

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The Cytogenomics and Genome Resources Core Facility has a single manager between these two functions. Cytogenomics includes karyotyping and spectral (SKY) karyotyping (for mouse, human, and other species), fluorescent in situ hybridization (FISH) mapping, transgenic insertion site mapping (G-to-FISH mapping) and clone labeling for FISH experiments. The Genome Resources components includes a clone repository (Mammalian Gene Collection (MGC) cDNA (mouse and human), genomic clones including human bacterial artificial chromosomes (BACs)) and provides project consultation and design assistance (annotation, database queries, probe selection). It also provides cDNA library screening and quantitative PCR.

Genetic and Statistical Analysis

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This Core Facility shares a manager (of the Genetic Analysis, or genotyping component) with the DNA Sequencing and Synthesis facility. The Statistical Analysis component has its own dedicated manager.

The Genetic Analysis area includes all Illumina technologies, including genome-wide (Infinium) and custom content (iSelect and GoldenGate) genotyping, methylation, microRNA, and gene expression microarrays. It also performs capillary-based genotyping (Applied Biosystems Taqman and SNaPshot, microsatellites), custom genotyping (e.g. heteroduplex analysis), mouse genotyping (for cross progeny and genetic linkage analysis), and methylation analysis (for epigenetics research).

The Statistical Analysis component provides project consultation and power analysis, statistical analysis (genetic, microarray, and pathway data, epidemiology, population genetics), and copy number variation analysis, as well as developing new statistical methods.

Biobanking

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The Biobanking Core Facility has its own dedicated manager. It performs white cell immortalization (from blood) and banking, fibroblast culture and banking, culture and banking of other cell types including non-human cells, genomic DNA preparation from blood, saliva, tissues or cells, and whole-genome amplification (WGA).

Funding Sources

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TCAG is funded by several agencies, including the Canada Foundation for Innovation (CFI), Genome Canada through the Ontario Genomics Institute, the Ontario Ministry of Research and Innovation, and the Wellcome Trust. Additionally, philanthropic donations are administered by The Hospital for Sick Children Foundation, and specific research projects are funded by a wide variety of agencies and charitable foundations.

Organization and Management

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Scientific Director

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The Scientific Director of TCAG is Dr. Stephen W. Scherer, Senior Staff Scientist and Associate Chief of The Hospital for Sick Children's Research Institute and a professor at the University of Toronto.[21]

Scientific Management Committee

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TCAG is governed by a Scientific Management Committee, who meet regularly to discuss high-level strategic planning. The Scientific Management Committee consists of:

  • Dr. Joseph Beyene
  • Dr. Dennis Bulman
  • Dr. Jayne Danska
  • Dr. Lucy Osborne
  • Dr. Andrew Paterson
  • Dr. Peter Ray
  • Dr. Johanna Rommens

Dr. Osborne is located at the University of Toronto, Dr. Bulman at the Ottawa Health Research Institute, and the others at The Hospital for Sick Children.

Associate Investigators

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Since 2006, TCAG has appointed Associate Investigators, who are typically junior faculty members of a university or similar academic institution. These associates consult on their specific areas of expertise, and assist in identification and implementation of new technologies. At present, there are five Associate Investigators: Drs. Andy Boright (UHN), Mary Shago (SickKids), Esteban Parra (UTM), Mark Silverberg (MSH), and John Vincent (CAMH).

Scientific Advisory Board

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High-level scientific oversight of TCAG's scientific mandate and operations is provided through an external Scientific Advisory Board (SAB). The SAB members are:

References

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  1. ^ Genome Canada Science and Technology Platforms [1]
  2. ^ Data provided by Affymetrix, Inc.
  3. ^ Integrative Genomics for Health Research news item (Ontario Innovation Trust website) [2]
  4. ^ PubMed search for publications authored by these individuals, January through March 2008 [3]
  5. ^ PubMed search for publications authored by these individuals, 2002 through present [4]
  6. ^ Google Scholar full-text search results: publications referring to The Centre for Applied Genomics or the Database of Genomic Variants, either in the Acknowledgments section or body text, and published either electronically or in print. Strategies used were: “TCAG” (ignoring hits from other TCAG acronyms and various DNA sequences), “The Centre for Applied Genomics”, American spelling, “The Center for Applied Genomics” (ignoring hits from facilities with similar names), “DGV”, “Database of Genomic Variants”, “Data Base of Genomic Variants” (including hits from the hyphenated form, “Data-base”), “Toronto Database” (ignoring non-relevant hits from non-DGV databases).
  7. ^ Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002 Jul;31(3):306-10. PMID 12068298
  8. ^ Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003 Jan;33(1):97-101. PMID 12496757
  9. ^ Chan EM, Young EJ, Ianzano L, et al. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 2003 Oct;35(2):125-7. PMID 12958597
  10. ^ Lohi H, Young EJ, Fitzmaurice SN, et al. Expanded repeat in canine epilepsy. Science. 2005 Jan 7;307(5706):81. PMID 15637270
  11. ^ Mnatzakanian GN, Lohi H, Munteanu I, et al. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet. 2004 Apr;36(4):339-41. Epub 2004 Mar 21. Erratum in: Nat Genet. 2004 May;36(5):540. PMID 15034579
  12. ^ Qu H, Bharaj B, Liu XQ, et al. Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes. Nat Genet. 2005 Feb;37(2):111-2; author reply 112-3. PMID 15678135
  13. ^ Somerville MJ, Mervis CB, Young EJ, et al. Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med. 2005 Oct 20;353(16):1694-701. PMID 16236740
  14. ^ Scherer SW, Cheung J, MacDonald JR, et al. Human chromosome 7: DNA sequence and biology. Science. 2003 May 2;300(5620):767-72. PMID 12690205
  15. ^ Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet. 2004 Sep;36(9):949-51. PMID 15286789
  16. ^ Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in the human genome. Nature. 2006 Nov 23;444(7118):444-54. PMID 17122850
  17. ^ Levy S, Sutton G, Ng PC, et al. The diploid genome sequence of an individual human. PLoS Biol. 2007 Sep 4;5(10):e254. PMID 17803354
  18. ^ Summary of Competition III projects on the Genome Canada website. [5]
  19. ^ Database of Genomic Variants [6]
  20. ^ Databases section of the TCAG website [7]
  21. ^ Steve Scherer biographical web page. [8]


[edit]

TCAG website at www.tcag.ca
Database of Genomic Variants

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