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Transcript
Genomics & Medicine
http://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
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
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
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 7S RNA signal recognition particle
Doug Brutlag 2011
Human Genetic Variation
2007 Scientific Breakthrough of the Year
Simple
Doug Brutlag 2011
Structural Genomic Variants
From Charles Lee Science Webinar
Doug Brutlag2008
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
25-36mer
Courtesy of Mike Snyder
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.
Doug Brutlag 2011
Mapping Breakpoints of Partial Trisomies
of Chromosome 21
verified
verified
Courtesy of Mike Snyder
Doug Brutlag 2011
Paired End Mapping (PEM)
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
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 (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 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
dbVAR Database at NCBI
http://www.ncbi.nlm.nih.gov/dbvar
Doug Brutlag 2011
dbVAR Report on PMP22 Gene
Doug Brutlag 2011
dbVAR Report on PMP22 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/hg18/
Doug Brutlag 2011
NHGRI Structural Variation Project
http://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 Lab
http://eichlerlab.gs.washington.edu/database.html
Doug Brutlag 2011