1. Copyright OpenHelix. No use or reproduction without express written consent1

2. Database of Genomic Variants A curated catalog of structural variation in the human genome Materials prepared by: Cynthia Perreault-Micale, Ph.D. www.openhelix.com Updated: Q3 2010 Version 2

3. Copyright OpenHelix. No use or reproduction without express written consent3 Database of Genomic Variants Agenda Introduction & Credits Basic Browsing & Searching Genome Browser Sequence Searching Additional Resources Summary Exercises Database of Genomic Variants: http://projects.tcag.ca/variation/

4. Copyright OpenHelix. No use or reproduction without express written consent4 CNVs - A New & Exciting Field Human genome “completion” We are 99.9% identical to each other Most human variability due to SNPs CNVs are challenging central dogmas! DGV launched to house all this new data DGV citation: Iafrate, et. al. Nature Genetics 36, 949 - 951 (2004) http://www.nature.com/ng/journal/v36/n9/abs/ng1416.html

5. Copyright OpenHelix. No use or reproduction without express written consent5 Relevant Terminology Structural variant - genomic alteration, non-SNPs, DNA segment >1kb, majority are Copy Number Variants (CNVs) CNVs - duplication or deletion event involving DNA >1kb InDel - insertion or deletion event involving DNA >1kb Segmental Duplication - duplicated region > 1kb with identity >90%, interchromosomal (nonhomologous chromosomes) or intrachromosomal (single chromosome) Find these & more in Feuk, et. al. Nat Rev Genet. 2006 Feb;7(2):85-97. http://www.nature.com/nrg/journal/v7/n2/abs/nrg1767.html A A A B BB C B C C Normal CNV Deletion InversionInsertion A B C A D C B InDels = Insertion/Deletion

6. Copyright OpenHelix. No use or reproduction without express written consent6 Curated Structural Variant Data DGV Data Many technology platforms & analysis techniques used – arrays, next generation sequencing, in silico, & more (Pinto et al. Human Molecular Genetics, 2007 http://hmg.oxfordjournals.org/cgi/content/full/16/R2/R168 ) Variation in general population (non-diseased samples) But don’t underestimate the extreme medical relevance

7. Copyright OpenHelix. No use or reproduction without express written consent7 Homepage http://projects.tcag.ca/variation/ Hosted by The Centre for Applied Genomics Curated data, peer-reviewed User-friendly with many browsing & searching options Genome Browser Table format Search options Overview References for included data

8. Copyright OpenHelix. No use or reproduction without express written consent8 Variants Are All Over the Human Genome Chromosome # Blue: CNVs Red: Inversion breakpoints Green: Segmental duplications Many variants are in our genome & the majority are CNVs CNV detection has lagged behind SNPs & large cytogenetic changes because of their mid-range size Technological advances are allowing rapid discovery What you see here may only be the tip of the iceberg!

9. Copyright OpenHelix. No use or reproduction without express written consent9 Medical Relevance of CNVs Zhang et al., Cytogenet Genome Res. 2006;115(3-4):205-14. CNVs can overlap with genes regulating our environmental interaction Lee et al., Nat Genet 2007; 39:S48-S54. May allow us to adapt to environment Diagnostic probe issues: CNVs can overlap regions associated with genomic disorders Clinical cytogenetic diagnostics: is CNV benign, pathogenic, or of unknown clinical significance? More & better data are needed

10. Copyright OpenHelix. No use or reproduction without express written consent10 Detailed Variant Information & Links ID Graphic Details & links DGV data track

11. Copyright OpenHelix. No use or reproduction without express written consent11 Helpful Information - Homepage Navigation Bar Submit data FAQs Citations Advisory Board Cytogenet Genome Res 2006;115:205-214 (DOI: 10.1159/000095916)

12. Copyright OpenHelix. No use or reproduction without express written consent12 Database of Genomic Variants Agenda Introduction & Credits Basic Browsing & Searching Genome Browser Sequence Searching Additional Resources Summary Exercises Database of Genomic Variants: http://projects.tcag.ca/variation/

13. Copyright OpenHelix. No use or reproduction without express written consent13 http://projects.tcag.ca/variation/ Browsing Many options on homepage Select genome assembly “View Data by Chromosome” will present data in a table format Simply click on a chromosome to browse

14. Copyright OpenHelix. No use or reproduction without express written consent14 Browsing Chromosome 11 Data Click here to reach a Locus record OMIM

15. Copyright OpenHelix. No use or reproduction without express written consent15 Locus Record List of variants, methodology used & study cohort details An interactive graphical display of chromosomal position, genes & variants in this region

16. Copyright OpenHelix. No use or reproduction without express written consent16 Top of Locus Record - An Interactive Graphic CNVs InDels Segmental duplications Genes Segmental duplication colors represent sequence identity: Red: 99-100% Purple: 96-98.99% Green: 93-95.99% Blue: 90-92.99% CNVs & InDels colors: Blue: Loss Red: Gain Green: Gain/Loss To Glossary Ruler & Bands

17. Copyright OpenHelix. No use or reproduction without express written consent17 Locus Record - Lower Section Variations are assigned a stable ID number If the same region is identified in several studies each is given a unique ID Click on ID for Variation page The Variant page provides many variant-specific details & links

18. Copyright OpenHelix. No use or reproduction without express written consent18 Variation Record - Browser Links DGV data track Link to the corresponding region in Ensembl or UCSC Genome Browsers

19. Copyright OpenHelix. No use or reproduction without express written consent19 Variation Record - More Details & Links Variation Type, Gap, Known Genes linked to Entrez Gene Methods & Reference Frequency & study details Field Definitions The article that DGV variant data were curated from

20. Copyright OpenHelix. No use or reproduction without express written consent20 http://projects.tcag.ca/variation/ Keyword Search The keyword can be a clone name, accession number, cytogenetic band or gene names Select Exact Match or not We will enter the name of a gene shown to be important in Paget’s disease Click on Search SQSTM1

21. Copyright OpenHelix. No use or reproduction without express written consent21 Results SQSTM1 Look more closely in the Genome Browser This gene’s location is copy number variable

22. Copyright OpenHelix. No use or reproduction without express written consent22 Data Interpretation Caveats A new and rapidly evolving field Experimental limitations to be aware of Caveats are dependent on technique used For example, BAC arrays can overestimate CNV boundaries Yet Oligo & SNP arrays do not Find this in FAQs of the “About The Project” section on homepage

23. http://projects.tcag.ca/variation/ Copyright OpenHelix. No use or reproduction without express written consent23 Example 2 You may also just want to enter the cytogenetic region of interest Genome-wide linkage scan showed major susceptibility locus at 10p13 Just enter 10p13 to peruse the genes & variants in this region 10p13

24. Copyright OpenHelix. No use or reproduction without express written consent24 Cytogenetic Band Search Results This region shows many different variants There are both CNVs & InDels Utilize same options from these search results as we just reviewed to investigate further, i.e. link to Variant pages & Genome Browser CNVs InDels Options

25. http://projects.tcag.ca/variation/ Copyright OpenHelix. No use or reproduction without express written consent25 Overview One more quick way to browse from the homepage “View Data by Genome” provides an overview of the variants on each chromosome Click anywhere on image to open Click to open

26. Copyright OpenHelix. No use or reproduction without express written consent26 Variants/Chromosome Blue: CNVs Red: Inversion breakpoints Green: Segmental duplications Click on any cytoband to see variant list

27. Copyright OpenHelix. No use or reproduction without express written consent27 Database of Genomic Variants Agenda Introduction & Credits Basic Browsing & Searching Genome Browser Sequence Searching Additional Resources Summary Exercises Database of Genomic Variants: http://projects.tcag.ca/variation/

28. http://projects.tcag.ca/variation/ Copyright OpenHelix. No use or reproduction without express written consent28 Genome Browser Several ways to access the Genome Browser Open directly from your search results Or from homepage Click Linked to Browser

29. Copyright OpenHelix. No use or reproduction without express written consent29 Browser Basics Preferences saved Instructions, Examples, Help, Reset & Search box Tracks - upload your own or add remotely Change Tracks to customize your views

30. Copyright OpenHelix. No use or reproduction without express written consent30 Genome Browser Search Example Our example will be the gene WBSCR16 Enter search term into Landmark or Region box Click on Search

31. Copyright OpenHelix. No use or reproduction without express written consent31 Results Overview panel: genomic context, landmarks, red line indicates region displayed below Detail panel: enlarged view, groups of data (tracks), many links Annotation Tracks, Display Settings

32. Copyright OpenHelix. No use or reproduction without express written consent32 Overview Panel Many viewing & navigation choices Recenter detail panel by clicking on ruler, zoom by dropdown menu Change magnification/position by Scroll/Zoom Use >, >>, for large scrolls, use + or – for fine adjustments Options

33. Copyright OpenHelix. No use or reproduction without express written consent33 Detail Panel - Groups of Data (Annotation Tracks) Click to browser Bands Genes S. Dupl. CNVs Variation record Info will vary - no InDel or inversions here, for example Entrez Nucleotide

34. Copyright OpenHelix. No use or reproduction without express written consent34 Tracks turn tracks on or off here Or change properties here Category Tracks in category

35. Copyright OpenHelix. No use or reproduction without express written consent35 Track Properties Refresh We will add SNPs & Clones & remove UCSC segmental duplications Click on “Accept Changes and Return” Accept

36. Copyright OpenHelix. No use or reproduction without express written consent36 Customized Tracks UCSC Seg. Dupl. removed SNPs added Clones added Return to default settings Link to Entrez Nucleotide

37. Copyright OpenHelix. No use or reproduction without express written consent37 Database of Genomic Variants Agenda Introduction & Credits Basic Browsing & Searching Genome Browser Sequence Searching Additional Resources Summary Exercises Database of Genomic Variants: http://projects.tcag.ca/variation/

38. Copyright OpenHelix. No use or reproduction without express written consent38 Sequence Search BLAT = BLAST- Like Alignment Tool Speed & capacity advantages Great for locating sequence(s) in a genome or the exon structure of an mRNA http://projects.tcag.ca/variation/ http://genome.cshlp.org/content/12/4/656 Enter sequence

39. Copyright OpenHelix. No use or reproduction without express written consent39 BLAT Search Result Sorted by Score, best match first To Entrez Gene To Variation Page To Locus Page

40. Copyright OpenHelix. No use or reproduction without express written consent40 Alignment Details - Your Query & Genomic Match Genomic match in dark blue capital letters Navigate from here

41. Copyright OpenHelix. No use or reproduction without express written consent41 Scroll to Side-by-Side Alignment Your sequence Genomic ↔

42. Copyright OpenHelix. No use or reproduction without express written consent42 Database of Genomic Variants Agenda Introduction & Credits Basic Browsing & Searching Genome Browser Sequence Searching Additional Resources Summary Exercises Database of Genomic Variants: http://projects.tcag.ca/variation/

43. http://projects.tcag.ca/variation/ Copyright OpenHelix. No use or reproduction without express written consent43 Resources Join the mailing list Read the Newsletter

44. Copyright OpenHelix. No use or reproduction without express written consent44 Downloading Data Older Current Text files All DGV studies Links & Comments

45. Copyright OpenHelix. No use or reproduction without express written consent45 Links, Submissions A collection of complementary resources DGV welcomes data submissions

46. Copyright OpenHelix. No use or reproduction without express written consent46 Database of Genomic Variants Agenda Introduction & Credits Basic Browsing & Searching Genome Browser Sequence Searching Additional Resources Summary Exercises Database of Genomic Variants: http://projects.tcag.ca/variation/

47. Copyright OpenHelix. No use or reproduction without express written consent47 http://projects.tcag.ca/variation/ Summary Easy to use search options Browsing variant data is encouraged

48. Copyright OpenHelix. No use or reproduction without express written consent48 Detailed Search Results

49. Copyright OpenHelix. No use or reproduction without express written consent49 Database of Genomic Variants Agenda Introduction & Credits Basic Browsing & Searching Genome Browser Sequence Searching Additional Resources Summary Exercises Database of Genomic Variants: http://projects.tcag.ca/variation/

50. Copyright OpenHelix. No use or reproduction without express written consent50