Transcript Genetic Variations - University of Pittsburgh
Genetic Variations Resources
May 15, 2013 Ansuman Chattopadhyay, PhD, Head Molecular Biology Information Service Health Sciences Library System University of Pittsburgh [email protected]
http://www.hsls.pitt.edu/guides/genetics
Objective Human genetic variations Genetic variations databases Functional analysis of mutations/SNPs
Topics Databases: dbSNP db GAP GenPheni DGV Decipher OMIM HGMD Regulome db Tools HugeNavigator FastSNP SPOT GenomeTrax
Human Genetic Variations
0.4-0.6 % Population 100 % Population 100 % Population Deletions / Inversions / Translocations Chromosomal rearrangements
>5Mb 1Mb
Duplications Deletions Insertions Copy Number Variations (CNVs) In/Del Micro- and Mini satellites
1kb
SNPs
1bp
Human Genome Variations Scherer, S.W. (2009), "Copy number variation", in Scherer, S. (ed.),
Copy Number Variation:
, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London 321,340,1 bp (0.11 % of the genome)
: SNPs
40,568,593 bp (1.35% of the genome) : CNVs
SNP Facts
Life Cycle of SNPs and Mutations
Mutation/ Private SNP
SNPs
Classifications of SNPs Genomic location based
Classifications of SNPs Nucleotide substitution based
Polymorphisms and Disease Markers
International Hap Map Project
http://www.hapmap.org/
Whole-genome genotyping of 10 million SNPs
Technologically daunting
Prohibitively expensive
Researchers tried to downsize the problem of genome-wide genotyping by studying haplotypes.
A haplotype is a contiguous, linear set of SNP alleles along a genome that is inherited as a block.
The Origin of Haplotype
Haplotype Blocks
Haplotype and Tag SNPs
Hap Map Population
http://www.1000genomes.org/about
Bioinformatics Institutions
http://www.ncbi.nlm.nih.gov/ http://www.ebi.ac.uk/
dbSNP
dbSNP Stats http://www.ncbi.nlm.nih.gov/SNP/snp_summary.cgi
as of January 25, 2010
Current Status of dbSNP
http://goo.gl/TwltA
MassGenomics blog by Dan Koboldt
dbSNP Data Types
Ref SNP : rs4244285
Ref SNP : rs4244285
Genetic Terminologies
Ref SNP : rs4244285
Submitted SNP: ss5586415
SNPedia and NextBio http://goo.gl/aOsoX http://goo.gl/Lqqd4
Searching dbSNP Identify SNPs present in a gene sequence SNPs reported to be present in a genomic region
Searching dbSNP UCSC Genome Browser UCSC Table Browser NCBI dbSNP page
http://www.ncbi.nlm.nih.gov/snp
Searching dbSNP
Searching dbSNP
dbSNP Search result Display
GWAS
GWAS Plot
Each SNP is assessed for ‘‘genome-wide’’ significance, after Bonferroni correction.
Publications on HapMap
Hap map GWAS
Genome Wide Association Studies http://www.genome.gov/gwastudies/
Find SNPs for a Disease/Trait CDC developed HuGENavigator : http://hugenavigator.net/
GWAS Integrator
GWAS Integrator
What SNPs are associated with “asthma”?
GWAS Integrator : rs7216389
GWAS Integrator
What SNPs are associated with “asthma”?
GWAS Integrator
GWAS Integrator : rs7216389 Ref: Moffatt Mf etal. childhood asthma. Nature. 2007 Jul 26;448(7152):470-3. Epub 2007 Jul 4. PubMed PMID: 17611496.
GWAS Integrator : rs7216389
Find associated Genes for a Disease/Trait
Gene Prospector: Asthma
Gene Prospector: Asthma
HuGE Navigator An integrated, searchable knowledge base of genetic associations and human genome epidemiology
PheGenI
Clinically Associated Mutations OMIM HGMD
Online Mendelian Inheritance in Man (OMIM)
OMIM
Epigenome and Encyclopedia of DNA Elements Project
Spatiotemporal gene expression EGFR TP53
A movie on regulated transcription
http://vcell.ndsu.edu/animations/regulatedtranscription/index.htm
Epigenetic mechanisms
Source: NCBI
http://www.ncbi.nlm.nih.gov/books/NBK45788/#epi_sci_bkgrd.About_Epigenetics
Genome in 3D http://www.nature.com/nature/journal/v470/n7333/pdf/470289a.pdf
Ch romatin I mmuno P recititation-Seq (ChIP-Seq)
Epigenetic Markers
Landmark Paper
: http://www.nature.com/ng/journal/v39/n3/full/ng1966.html
Histone Modifications
http://goo.gl/GQ9V8 http://www.hsls.pitt.edu/guides/genetics
Encode Project http://www.genome.gov/10005107
http://goo.gl/QeIbQ
Regulome
Regulome db Search rs7216389 rs2853669
Hands-on Exercise on Searching dbSNP Mutations in the human
BRCA1
gene are reported to be associated with the early onset of breast cancer. How many coding nonsynonimous SNPs have been reported to be associated with this gene? How many of these SNPs shows >40% heterozygosity? Pick a SNP from the list and find the position of its protein sequence, which shows aa change due to this SNP .
How many in dels are reported to be present in the chromosome chr21: region 33,031,597-33,041,570 ?
Hands –On Exercise • Identify genes and SNPs associated with your disease/trait of interest • Crohn’s disease , Prostate cancer , LDL cholesterol
Structural Variations
Normal Inversion A C
B B
C A
B
Duplication Deletion Insertion A A A
B D
C
B B
C C CNV
Structural Variations
Structural Variations Databases Database of Genome Variations (DGV) dbVar DECIPHER dbRIP Mitelman Breakpoint Database
DGV
DGV :Genome wide view
DGV
DGV: Chr 1
DGV
Hands-on Exercise Is the CETN1 or Grip1 gene located in a region that is copy number variable? Are there any other genes in this region? Can you find any Inversions or In Dels there as well?
What is the frequency of the CNV reported in the study population?
DGV Genome Browser
DGV: Genome Browser
dbVar
DECIPHER
https://decipher.sanger.ac.uk/application/dashboard
DECIPHER Syndrome Report
DECIPHER Syndrome Report
Structural Variations Databases Genome Variation Database (DGV) dbVar DECIPHER dbRIP Mitelman Breakpoint Database
dbRIP http://dbrip.brocku.ca/searchRIP.html
Mitelman Breakpoint
Hands-On Exercise Generate an integrated variation map with reference SNPs, Mitelman breakpoints and OMIM diseases for chromosome 17; region 7773,000-7792,000 bp . What gene(s) have you found in this region? Answer key: http://www.ncbi.nlm.nih.gov/Class/NAWBIS/Modules/Variation/Exercises/var_qa3.html
Map Viewer Setup http://www.ncbi.nlm.nih.gov/projects/mapview
Map Viewer Setup
Genetic Variations Map
Online Mendelian Inheritance in Man (OMIM)
OMIM
UCSC Table Browser
Hands-on Exercise Find all human genes which have only one exon.
How many of these also show CNVs?
Tips: Use UCSC Table Browser
Biobase Genome Trax and HGMD http://goo.gl/pUhQ4
Variant File : VCF
GenomeTrax Input
GenomeTrax Result
Functional Analysis of SNPs
http://www.hsls.pitt.edu/guides/genetics
SNPs and the Structure of a Gene
http://www.hsls.pitt.edu/guides/genetics
Decision Tree for SNP Analysis
http://www.hsls.pitt.edu/guides/genetics
Exonic Splicing Enhancer/Silencer
http://www.hsls.pitt.edu/guides/genetics
Functional Analysis of SNPs
A gene variant primarily found in African Americans, that slightly increases the risk for developing an irregular heartbeat, known as arrhythmia. The variant occurs in the cardiac sodium channel gene SCN5A which results a change of amino acid at the position of 1102 from serine to tyrosine (S To Y) . Can you predict the effect of this non-synonymous SNP ( rs7626962 ).
Answer http://www.hsls.pitt.edu/guides/genetics
Functional Analysis of SNPs
Functional Analysis of SNPs
Entrez SNP
- Search Entrez SNP by refSNP ID to find SNP information.
Entrez Protein
- Find protein information including its amino acid sequence and the presence of functional domains
NCBI Amino Acid Explorer
- Compare amino acids in terms of physyo-chemical properties
NCBI Mutation Analyzer
- Predict the effect of amino acid change on the protein structure
TMHMM Server v. 2.0
- Predict the presence of transmembrane helix in a protein sequence
Russel etal., Amino Acid Properties Table
- Predict the effect of amino acid change on the protein structure
SNP Gene View for SCN5A
Multiple Sequence Alignment
http://www.hsls.pitt.edu/guides/genetics
Amino Acids Comparison
NCBI Amino Acid Explorer http://www.hsls.pitt.edu/guides/genetics
Compare Amino Acids Properties
Amino Acid Properties Table: http://www.russell.embl.de/aas/ http://www.hsls.pitt.edu/guides/genetics
Amino Acids Substitution Preference
http://www.hsls.pitt.edu/guides/genetics
Tools for Amino Acid Substitution Effect Prediction
SIFT http://sift.jcvi.org/ PolyPhen http://genetics.bwh.harvard.edu/pph/ SNPs3D
http://www.snps3d.org/
pMUT
http://mmb2.pcb.ub.es:8080/PMut/ http://www.hsls.pitt.edu/guides/genetics
Comparison of AAS prediction tools
Pauline C. Ng and Steven Henikoff, Annu. Rev. Genomics Hum. Genet. 2006. 7:61–80
Tools on Functional SNP Analysis
Search.HSLS MolBio link http://search.hsls.pitt.edu/vivisimo/cgi-bin/query meta?v%3aproject=BioInfoTools&v%3afile=viv_B7AUre&v%3aframe=list&v%3astate=root%7cN891&id=N891&act ion=list&
FASTSNP -- an always up-to-date and extendable service for SNP function analysis and prioritization
http://fastsnp.ibms.sinica.edu.tw/ F-SNP: computationally predicted functional SNPs for disease association studies. http://compbio.cs.queensu.ca/F-SNP/ http://www.hsls.pitt.edu/guides/genetics
FASTSNP Analysis
http://www.hsls.pitt.edu/guides/genetics
FASTSNP Analysis
http://www.hsls.pitt.edu/guides/genetics
F-SNP : A Collection of Functional SNPs Specifically Prioritized for Disease Association studies
http://www.hsls.pitt.edu/guides/genetics
F-SNP : A Collection of Functional SNPs Specifically Prioritized for Disease Association Studies
http://www.hsls.pitt.edu/guides/genetics
Tutorials and References Advanced Course on NCBI Resources (Browser: IE, select .html format) Predictive
Functional Analysis
of Polymorphisms: An Overview Authors:Michael R. Barnes Book:Bioinformatics for Geneticists Source:Wiley InterScience: Online Books
Functional In Silico Analysis of Non-Coding SNPs Authors:Thomas Werner Book:Bioinformatics for Geneticists Source:Wiley InterScience: Online Books Predicting the Effects of Amino Acid Substitutions on Protein Function Pauline C. Ng and Steven Henikoff Fred Hutchinson Cancer Research Center, Seattle,Washington 98109;
Thank you!
Any questions?
Carrie Iwema [email protected]
412-383-6887 Ansuman Chattopadhyay [email protected]
412-648-1297 http://www.hsls.pitt.edu/guides/genetics