Genetic Variations
Resources
May 15, 2013
Ansuman Chattopadhyay, PhD,
Head Molecular Biology Information Service
Health Sciences Library System
University of Pittsburgh
ansuman@pitt.edu
http://www.hsls.pitt.edu/guides/genetics
Objective
 Human
 Genetic
genetic variations
variations databases
 Functional
analysis of
mutations/SNPs
Topics
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Databases:
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dbSNP
db GAP
GenPheni
DGV
Decipher
OMIM
HGMD
Regulome db
Tools
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HugeNavigator
FastSNP
SPOT
GenomeTrax
Human Genetic Variations
0.4-0.6 % Population
100 % Population
100 % Population
Deletions / Inversions
/ Translocations
Duplications
Deletions
Insertions
Chromosomal
rearrangements
Copy Number Variations
(CNVs)
In/Del
Micro- and
Minisatellites
SNPs
>5Mb
1Mb
1kb
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
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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
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SNPs present in a gene sequence
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SNPs reported to be present in a
genomic region
Searching dbSNP
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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
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OMIM
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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
Chromatin Immuno-Precititation-Seq
(ChIP-Seq)
Epigenetic Markers
Landmark Paper:
http://www.nature.com/ng/journal/v39/n3/full/ng1966.html
Histone Modifications
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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
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rs7216389
rs2853669
Hands-on Exercise on Searching
dbSNP
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Mutations in the human BRCA1 gene are reported to be
associated with the early onset of breast cancer.
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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
A
B
C
Inversion
C
B
A
Duplication
A
B
B
Deletion
A
C
Insertion
A
D
B
C
CNV
B
C
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
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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
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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?
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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?
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Tips: Use UCSC Table Browser
Biobase Genome Trax and HGMD
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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).
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Answer
http://www.hsls.pitt.edu/guides/genetics
Functional Analysis of SNPs
Functional Analysis of SNPs
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Entrez SNP - Search Entrez SNP by refSNP ID to find SNP information.
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Entrez Protein - Find protein information including its amino acid sequence and the presence of functional
domains
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NCBI Amino Acid Explorer - Compare amino acids in terms of physyo-chemical properties
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NCBI Mutation Analyzer - Predict the effect of amino acid change on the protein structure
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TMHMM Server v. 2.0 - Predict the presence of transmembrane helix in a protein sequence
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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
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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
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SIFT
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PolyPhen
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http://genetics.bwh.harvard.edu/pph/
SNPs3D
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http://sift.jcvi.org/
http://www.snps3d.org/
pMUT
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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
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Search.HSLS MolBio link
http://search.hsls.pitt.edu/vivisimo/cgi-bin/querymeta?v%3aproject=BioInfoTools&v%3afile=viv_B7AUre&v%3aframe=list&v%3astate=root%7cN891&id=N891&act
ion=list&
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FASTSNP -- an always up-to-date and
extendable service for SNP function
analysis and prioritization
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http://fastsnp.ibms.sinica.edu.tw/
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F-SNP: computationally predicted functional
SNPs for disease association studies.
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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
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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
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Pauline C. Ng and Steven Henikoff
Fred Hutchinson Cancer Research Center, Seattle,Washington 98109;
Thank you!
Any questions?
Carrie Iwema
iwema@pitt.edu
412-383-6887
Ansuman Chattopadhyay
ansuman@pitt.edu
412-648-1297
http://www.hsls.pitt.edu/guides/genetics