Genomics & Medicine http://biochem158.stanford.edu/

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

2. Duplications and Deletionsin the Human Genome

3. Percentage of Chromosomes Duplicated

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

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

6. Human Genetic Variation2007 Scientific Breakthrough of the Year Simple Individual 1 Individual 2 Individual 3 Individual 4

7. Structural Genomic Variants From Charles Lee Science Webinar 2008

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

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

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

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

12. Deletions and Insertions atRepeat Sequences Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

13. Variations in Tandem Repeat Arrays FISH on DNA 8 or 12 tandem repeats 4 kb long Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

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

17. Comparative Genomics Hybridization (CGH)

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

19. Detection of Duplications and DeletionsUsing 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. Mapping Breakpoints of Partial Trisomies of Chromosome 21 verified verified Courtesy of Mike Snyder

21. Paired End Mapping (PEM)

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

23. Genomics Distribution of CNV Regions

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

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

26. Clos Vougeot in Bourgogne

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

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

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

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

31. Charcot-Marie Tooth Hereditary Neuropathy Disease Genes

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

33. Rearrangement Hot SpotsAssociated with Disease

34. Structural Variations Resulting inMendelian Inherited Disease Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42

35. Behavioral DiseasesAssociated with Structural Variations

36. Clinical Features Associated with Structural Variations (Continued)

37. Inversions Lead to Instability & Disease

38. dbVAR Database at NCBIhttp://www.ncbi.nlm.nih.gov/dbvar

39. dbVAR Report on PMP22 Gene

40. dbVAR Report on PMP22 Gene

41. Database of Genomics Variantshttp://projects.tcag.ca/variation/

42. Database of Genomics Variantshttp://projects.tcag.ca/variation/

43. Database of Genomics Variantshttp://projects.tcag.ca/variation/project.html

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

46. NHGRI Structural Variation Projecthttp://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml

47. NHGRI Structural Variation Clone Viewerhttp://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml

48. Eichler Labhttp://eichlerlab.gs.washington.edu/database.html