Doug Brutlag 201 Genomics & Medicine http://biochem158.stanford.edu/ Doug Brutlag Professor Emeritus of Biochemistry & Medicine Stanford University School of Medicine Structural Variants in the Human Genom http://biochem158.stanford.edu/Structural%20Genomics%20Variants.ht
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Doug Brutlag 2011
Genomics & Medicinehttp://biochem158.stanford.edu/
Doug BrutlagProfessor Emeritus of Biochemistry & Medicine
Stanford University School of Medicine
Structural Variants in the Human Genomehttp://biochem158.stanford.edu/Structural%20Genomics%20Variants.html
Doug Brutlag 2011
Duplications and Deletionsin the Human Genome
Doug Brutlag 2011
Percentage of Chromosomes Duplicated
Doug Brutlag 2011
The Spectrum of Variationin 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 10,000 base long RNA genomeo 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 genomeo 6,500 base pairs long including LTRso Encode reverse transcriptase and integrase o Copy-paste mechanism to insert elsewhere
• SINES-Short Interspersed Nuclear Elementso Millions in human genomeo 100-400 bases longo Often contain RNA polymerase III promoters but no genes
• ALUs- The most common SINEo 1,500,000 copies = 11% of human genomeo 350 base pairs in lengtho Contain an RNA Polymerase III promoter, Alu siteo Appear to evolve from 7S RNA signal recognition particle
Doug Brutlag 2011
Human Genetic Variation2007 Scientific Breakthrough of the Year
Simple
Doug Brutlag 2011
Structural Genomic Variants
From Charles Lee Science Webinar 2008
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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 OverLeads to Deletion
Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42
Doug Brutlag 2011
Inter-Chromosomal Crossing OverLeads to Inversion
Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42
Doug Brutlag 2011
Intra-Chromosomal Crossing OverCan Also Lead to Inversion
Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42
Doug Brutlag 2011
Deletions and Insertions atRepeat Sequences
Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42
Doug Brutlag 2011
Variations in Tandem Repeat Arrays
Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42
FISH on DNA 8 or 12 tandem repeats 4 kb long
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 fordetection 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
25-36mer
Courtesy of Mike Snyder
Doug Brutlag 2011
Detection of Duplications and Deletions
Using Chromosomal Micro-Arrays10.9 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.
Doug Brutlag 2011
verified
verified
Mapping Breakpoints of Partial Trisomies of Chromosome 21
Courtesy of Mike Snyder
Doug Brutlag 2011
~1,000 Structural Variants > 2.5kb 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
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Heterogeneity in Olfactory Receptor Genes
(Examined 851 Olfactory Receptor Loci)
CNVs affect:93 duplicated genes151 deleted genes
Doug Brutlag 2011
Chef d’Ordre de la Confrerie des Chevalier du Tastevins
Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Neuropathy (CMT1) Disease Results From CNV of PMP22 Gene in 17p11.2-12
Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Peripheral Neuropathy (CMT1) Caused by Abnormal Myelination of Long Axons
Doug Brutlag 2011
Charcot-Marie Tooth Hereditary Peripheral Neuropathy (CMT1) 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 (CMT1) Disease Genes
Doug Brutlag 2011
Rearrangement Hot SpotsAssociated with Disease
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Structural Variations Resulting inMendelian Inherited Disease
Sharp, Cheng & Eichler, Annu. Rev. Genomics Hum. Genet. 2006. 7:407–42
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Behavioral DiseasesAssociated with Structural
Variations
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Clinical Features Associated with Structural Variations (Continued)
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Inversions Lead to Instability & Disease
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dbVAR Database at NCBIhttp://www.ncbi.nlm.nih.gov/dbvar
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dbVAR Report on PMP22 Gene
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dbVAR Report on PMP22 Gene
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Database of Genomics Variantshttp://projects.tcag.ca/variation/
Doug Brutlag 2011
Database of Genomics Variantshttp://projects.tcag.ca/variation/
Doug Brutlag 2011
Database of Genomics Variantshttp://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/hg18/
Doug Brutlag 2011
NHGRI Structural Variation Projecthttp://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml
Doug Brutlag 2011
NHGRI Structural Variation Clone Viewer
http://www.ncbi.nlm.nih.gov/projects/genome/StructuralVariation/NHGRIStructuralVariation.shtml
Doug Brutlag 2011
Eichler Labhttp://eichlerlab.gs.washington.edu/database.html
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