Genomics Medicine http biochem 158 stanford edu Structural
Genomics & Medicine http: //biochem 158. stanford. edu/ Structural Variants in the Human Genome http: //biochem 158. stanford. edu/Structural%20 Genomics%20 Variants. html Doug Brutlag Professor Emeritus of Biochemistry & Medicine Stanford University School of Medicine Doug Brutlag 2011
Duplications and Deletions in the Human Genome Doug Brutlag 2011
Percentage of Chromosomes Duplicated Doug Brutlag 2011
The Spectrum of Variation in the Human Genome Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7: 407– 42 Doug Brutlag 2011
Repeated Elements in the Human Genome ERVs, LINES, SINES and ALUs • ERVs-Endogenous Retroviruses o o o • LINES-Long Interspersed Nuclear Elements o o • 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 o o o • 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) Millions in human genome 100 -400 bases long Often contain RNA polymerase III promoters but no genes ALUs- The most common SINE o o 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 7 S RNA signal recognition particle Doug Brutlag 2011
Human Genetic Variation 2007 Scientific Breakthrough of the Year Simple Individual 1 Individual 2 Individual 3 Individual 4 Doug Brutlag 2011
Structural Genomic Variants From Charles Lee Science Webinar Doug Brutlag 2008 2011
Unequal Crossing Over Leads to Duplication and Deletion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7: 407– 42 Doug Brutlag 2011
Intra-Chromosomal Crossing Over Leads to Deletion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7: 407– 42 Doug Brutlag 2011
Inter-Chromosomal Crossing Over Leads to Inversion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7: 407– 42 Doug Brutlag 2011
Intra-Chromosomal Crossing Over Can Also Lead to Inversion Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7: 407– 42 Doug Brutlag 2011
Deletions and Insertions at Repeat Sequences Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7: 407– 42 Doug Brutlag 2011
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 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 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 Doug Brutlag 2011
Why Not Studied More? • Often involves repeated regions • Rearrangements are complex • Usually involve repetitive elements Courtesy of Mike Snyder Doug Brutlag 2011
Comparative Genomics Hybridization (CGH) Doug Brutlag 2011
Comparative Micro Arrays (CMA) Using Genome Tiling Arrays 800 bp 25 -36 mer Courtesy of Mike Snyder Doug Brutlag 2011
Detection of Duplications and Deletions Using Chromosomal Micro-Arrays 10. 9 Mbase deletion at 7 q 11 in Williams-Beuren Syndrome 7. 2 Mbase duplication in 11 q Miller et al. , (2010) American Journal of Human Genetics 86, 749 -764. Doug Brutlag 2011
Mapping Breakpoints of Partial Trisomies of Chromosome 21 verified Courtesy of Mike Snyder Doug Brutlag 2011
Paired End Mapping (PEM) Doug Brutlag 2011
~1, 000 Structural Variants > 2. 5 kb per Person * * Courtesy of Mike Snyder Doug Brutlag 2011
Genomics Distribution of CNV Regions Doug Brutlag 2011
Size Distribution of Copy Number Variations in the Human Genome Courtesy of Mike Snyder Doug Brutlag 2011
Heterogeneity in Olfactory Receptor Genes (Examined 851 Olfactory Receptor Loci) CNVs affect: 93 duplicated genes 151 deleted genes Doug Brutlag 2011
Clos Vougeot in Bourgogne Doug Brutlag 2011
Chef d’Ordre de la Confrerie des Chevalier du Tastevins Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Neuropathy (CMT 1) Disease Results From CNV of PMP 22 Gene in 17 p 11. 2 -12 Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Peripheral Neuropathy (CMT 1) Caused by Abnormal Myelination of Long Axons Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Peripheral Neuropathy (CMT 1) Caused by Abnormal Myelination of Long Axons Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Neuropathy Disease Genes Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Neuropathy (CMT 1) Disease Genes Doug Brutlag 2011
Rearrangement Hot Spots Associated with Disease Doug Brutlag 2011
Structural Variations Resulting in Mendelian Inherited Disease Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7: 407– 42 Doug Brutlag 2011
Behavioral Diseases Associated with Structural Variations Doug Brutlag 2011
Clinical Features Associated with Structural Variations (Continued) Doug Brutlag 2011
Inversions Lead to Instability & Disease Doug Brutlag 2011
db. VAR Database at NCBI http: //www. ncbi. nlm. nih. gov/dbvar Doug Brutlag 2011
db. VAR Report on PMP 22 Gene Doug Brutlag 2011
db. VAR Report on PMP 22 Gene Doug Brutlag 2011
Database of Genomics Variants http: //projects. tcag. ca/variation/ Doug Brutlag 2011
Database of Genomics Variants http: //projects. tcag. ca/variation/ Doug Brutlag 2011
Database of Genomics Variants http: //projects. tcag. ca/variation/project. html Doug Brutlag 2011
Doug Brutlag 2011
Database of Genomics Variants Browser http: //projects. tcag. ca/cgi-bin/variation/gbrowse/hg 18/ Doug Brutlag 2011
NHGRI Structural Variation Project http: //www. ncbi. nlm. nih. gov/projects/genome/Structural. Variation/NHGRIStructural. Variation. shtml Doug Brutlag 2011
NHGRI Structural Variation Clone Viewer http: //www. ncbi. nlm. nih. gov/projects/genome/Structural. Variation/NHGRIStructural. Variation. shtml Doug Brutlag 2011
Eichler Lab http: //eichlerlab. gs. washington. edu/database. html Doug Brutlag 2011
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