1. Doug Brutlag 2011 Genomics & Medicine http://biochem158.stanford.edu/ http://biochem158.stanford.edu/ Doug Brutlag Professor Emeritus of Biochemistry & Medicine Stanford University School of Medicine Structural Variants in the Human Genome http://biochem158.stanford.edu/Structural%20Genomics%20Variants.html

2. Doug Brutlag 2011 Duplications and Deletions in the Human Genome

3. Doug Brutlag 2011 Percentage of Chromosomes Duplicated

4. Doug Brutlag 2011 The Spectrum of Variation in the Human Genome Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

5. Doug Brutlag 2011 Repeated Elements in the Human Genome ERVs, LINES, SINES and ALUs ERVs-Endogenous Retroviruses o 10,000 base long RNA genome o Converted to DNA and integrate into genome with help of RNA reverse transcriptase and integrase enzymes and long tandem repeats (LTRs) o Transcribed into RNA and produce virus (HIV) LINES-Long Interspersed Nuclear Elements o About 868,000 in human genome o 6,500 base pairs long including LTRs o Encode reverse transcriptase and integrase o Copy-paste mechanism to insert elsewhere SINES-Short Interspersed Nuclear Elements o Millions in human genome o 100-400 bases long o Often contain RNA polymerase III promoters but no genes ALUs- The most common SINE o 1,500,000 copies = 11% of human genome o 350 base pairs in length o Contain an RNA Polymerase III promoter, Alu site o Appear to evolve from 7S RNA signal recognition particle

6. Doug Brutlag 2011 Human Genetic Variation 2007 Scientific Breakthrough of the Year 2007 Scientific Breakthrough of the Year Simple

7. Doug Brutlag 2011 Structural Genomic Variants From Charles Lee Science Webinar 2008

8. Doug Brutlag 2011 Unequal Crossing Over Leads to Duplication and Deletion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

9. Doug Brutlag 2011 Intra-Chromosomal Crossing Over Leads to Deletion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

10. Doug Brutlag 2011 Inter-Chromosomal Crossing Over Leads to Inversion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

11. Doug Brutlag 2011 Intra-Chromosomal Crossing Over Can Also Lead to Inversion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

12. Doug Brutlag 2011 Deletions and Insertions at Repeat Sequences Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

13. Doug Brutlag 2011 Variations in Tandem Repeat Arrays Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42 FISH on DNA8 or 12 tandem repeats 4 kb long

14. Doug Brutlag 2011 Mapping Structural Variation in Humans >1 kb segments - Structural Variations are Common 12% of the genome (Redon et al. 2006) -Structural Variations are involved in phenotype variation and disease - Until recently most methods for detection were low resolution (>50 kb) Courtesy of Mike Snyder

15. Doug Brutlag 2011 Why Study Structural Variation? They are common in “normal” human genomes and they are a major cause of phenotypic variation They are common in certain diseases, particularly cancers and behavioral diseases They are now also showing up in rare diseases and common behavioral diseases such as autism, schizophrenia and many neurological disorders Courtesy of Mike Snyder

16. Doug Brutlag 2011 Why Not Studied More? Often involves repeated regions Rearrangements are complex Usually involve repetitive elements Courtesy of Mike Snyder

17. Doug Brutlag 2011 Comparative Genomics Hybridization (CGH)

18. Doug Brutlag 2011 Comparative Micro Arrays (CMA) Using Genome Tiling Arrays 800 bp 25-36mer Courtesy of Mike Snyder

19. Doug Brutlag 2011 Detection of Duplications and Deletions Using Chromosomal Micro-Arrays 10.9 Mbase deletion at 7q11 in Williams-Beuren Syndrome 7.2 Mbase duplication in 11q Miller et al., (2010) American Journal of Human Genetics 86, 749-764.

20. Doug Brutlag 2011 verified Mapping Breakpoints of Partial Trisomies of Chromosome 21 Courtesy of Mike Snyder

21. Doug Brutlag 2011 Paired End Mapping (PEM)

22. Doug Brutlag 2011 ~1,000 Structural Variants > 2.5kb per Person * * Courtesy of Mike Snyder

23. Doug Brutlag 2011 Genomics Distribution of CNV Regions

24. Doug Brutlag 2011 Size Distribution of Copy Number Variations in the Human Genome Courtesy of Mike Snyder

25. Doug Brutlag 2011 Heterogeneity in Olfactory Receptor Genes (Examined 851 Olfactory Receptor Loci) CNVs affect: 93 duplicated genes 151 deleted genes

26. Doug Brutlag 2011 Clos Vougeot in Bourgogne

27. Doug Brutlag 2011 Chef d’Ordre de la Confrerie des Chevalier du Tastevins

28. Doug Brutlag 2011 Charcot-Marie Tooth Hereditary Neuropathy (CMT1) Disease Results From CNV of PMP22 Gene in 17p11.2-12

29. Doug Brutlag 2011 Charcot-Marie Tooth Hereditary Peripheral Neuropathy (CMT1) Caused by Abnormal Myelination of Long Axons

30. Doug Brutlag 2011 Charcot-Marie Tooth Hereditary Peripheral Neuropathy (CMT1) Caused by Abnormal Myelination of Long Axons

31. Doug Brutlag 2011 Charcot-Marie Tooth Hereditary Neuropathy Disease Genes

32. Doug Brutlag 2011 Charcot-Marie Tooth Hereditary Neuropathy (CMT1) Disease Genes

33. Doug Brutlag 2011 Rearrangement Hot Spots Associated with Disease

34. Doug Brutlag 2011 Structural Variations Resulting in Mendelian Inherited Disease Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

35. Doug Brutlag 2011 Behavioral Diseases Associated with Structural Variations

36. Doug Brutlag 2011 Clinical Features Associated with Structural Variations (Continued)

37. Doug Brutlag 2011 Inversions Lead to Instability & Disease

38. Doug Brutlag 2011 dbVAR Database at NCBI http://www.ncbi.nlm.nih.gov/dbvar http://www.ncbi.nlm.nih.gov/dbvar

39. Doug Brutlag 2011 dbVAR Report on PMP22 Gene

40. Doug Brutlag 2011 dbVAR Report on PMP22 Gene

41. Doug Brutlag 2011 Database of Genomics Variants http://projects.tcag.ca/variation/ http://projects.tcag.ca/variation/

42. Doug Brutlag 2011 Database of Genomics Variants http://projects.tcag.ca/variation/ http://projects.tcag.ca/variation/

43. Doug Brutlag 2011 Database of Genomics Variants http://projects.tcag.ca/variation/project.html http://projects.tcag.ca/variation/project.html

44. Doug Brutlag 2011

45. Database of Genomics Variants Browser http://projects.tcag.ca/cgi-bin/variation/gbrowse/hg18/ http://projects.tcag.ca/cgi-bin/variation/gbrowse/hg18/

46. Doug Brutlag 2011 NHGRI Structural Variation Project http://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml http://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml

47. Doug Brutlag 2011 NHGRI Structural Variation Clone Viewer http://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml http://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml

48. Doug Brutlag 2011 Eichler Lab http://eichlerlab.gs.washington.edu/database.html http://eichlerlab.gs.washington.edu/database.html