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= Course Home        =             Modules        =             &nb= sp; Schedule        =             &nb= sp; Exercises        =           Comments        =             Credits
NCBI Advanced Workshop for
Bioinformatics Information Specialists
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=   Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced = Workshop
NCBI Advanced Workshop for
Bioinformatics Information Specialists
<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
1
Genetic Variation Resources
Ansuman Chattopadhyay, Ph.D
Head, Molecular Biology Information Service
Health Sc= iences Library System
University of Pittsburgh
ansuman@pitt.edu


Michele R. Tennant, Ph.D., M.L.I.S.
Health Science Center Librar= ies
and U.F. Gene= tics Institute
University of Florida
michele@library.health.ufl.edu
Presented By =
YiBu Chen, Ph.D.
Bioinformatics Specialist
Norris Medical Library
University of Southern California
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
=   Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced = Workshop
2
Introduction
•Scientists expect that comparison of genomic seque= nces taken from two unrelated individuals will reveal that they are 99.9% identical. The <= span style=3D'position:absolute;top:34.25%;left:7.3%;width:99.43%;height:4.5%'>= 0.1% difference is due to genetic variations, and = mainly one form of variation called single nucleotide polymorphisms. = •These polymorphisms are considered one of the key factors that makes each and= every one of us different and can have a major impact on how = we respond to diseases; environmental insults such= as bacteria, viruses and chem= icals; and drugs and other therapies. This makes genetic = variations of great value for biomedical research = and for developing pharmace= utical products or medical diagnostics. •This module will focus on human genetic variations= and mainly cover Single Nucleotide Polymorphisms (SNP).
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
3
Objectives
•At the en= d of this module participants will be able to:
•Understan= d the basic concepts behind different forms of genetic variations •Understan= d the terminologies used by researchers studying genetic variations •Identify = genetic variation databases and interpret database search results = •Understan= d and use online resources for functional analysis of variation information •Understand the significance of the International= Hap Map Project
<= span style=3D'visibility:hidden'>•
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
4
User Questions - a few examples
•<= /span>The exercises page of this course provides easy = access to all of the user questions (and corresponding strategy files) that are integrated in this module.
•
•<= /span>We will go through a number of the user questions = in this course.
•<= /span>
•<= /span>Because of time limitations, we will not be able to cover all of them, but the= y are available on the course web site for your use at any time.
•
•<= /span>The complete set of course exercises serves as a knowledge base of inform= ation for library-based bioinformatics support staff to facilitate your work with end-users.
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
5

Human Genetic Variations
• Primarily two ty= pes of genetic mutation events create all forms of = variations:
<= span style=3D'font-size:83%;visibility:hidden'>•
•Single base mutation which substitutes one nucleotide for another

-Single Nucleotide Polymorphisms (SNP)

 <= span style=3D'font-size:83%'>•Insertion or deletion of one or more nucleotide(s)

-Tandem Repeat Polymorphisms

-Insertion/Deletion Polymorphis= ms
<= span style=3D'font-size:83%;visibility:hidden'>•
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
6

Single Nucleotide Polymorphisms
Single nucleotide polymorphisms (SNP) are DNA sequence variations
that occur when a single nucleotide (A,T,C,or G) in the genome sequence is alte= red.
For example, a SNP might change the DNA sequence AAGGCTAA to ATG= GCTAA.
SNPS are the most common class of polymorphisms.

example:
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18 July 2007 =
  Genetic Variat= ion Resources
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Advanced Workshop
7

Tandem Repeat Polymorphisms
• Tandem repeats or variable number of tandem repeats (VNTR) are a very common class of polymorphism, consisting of variable length of <= span style=3D'font-size:90%'>sequence motifs that are repeated in tandem in a variable copy number.
–
–<= /span>VNTRs are subdivided into two subgroups based on t= he size of the tandem repeat units.
–= 3;
•<= /span>Microsatellites or Short Tandem Repeat (STR)=
repeat unit: 1-6 (dinucleotide repeat: CACACACACACA)
•<= /span>Minisatellites
repeat unit: 14-1= 00
•= 3;
• example:

Spinocerebellar ataxia Type10 (= SCA10) (OMIM:+603516) is caused by largest tandem repeat seen in human genome. Normal population has <= span style=3D'font-size:90%'>10-22 mer pentanucleotide ATTCT repeat in intron 9= of SCA10 gene; where as= SCA10 patients have 800-4500 repeat units, which causes the <= span style=3D'font-size:90%'>disease allele up to 22.5 kb larger than the norma= l one.
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  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
8

Insertion/Deletion Polymorphisms
= 3;
R= 26;
R= 26; Insertion/Deletion (INDEL) polymorphisms are quite c= ommon and widely distributed throughout the human genome.
–
–Sequence repetitiveness in the form of direct or inverted tandem repeat have been shown to predispose DNA to localized rearrangements between = homologous repeats. Such rearrangements are though= t to be one of the reason= which create INDEL polymorphism.
R= 26;
R= 26; example:

Association between coronary he= art disease and a 287 bp Indel Polymorphism located in intron 16 of the angiotensin converting enzyme <= span style=3D'font-size:90%'>(ACE) have been reported (OMIM 106180). This Indel, known as ACE/ID is respo= nsible for 50% of the inter individual variability of plasma ACE <= span style=3D'font-size:90%'>concentration.
R= 26;
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  Genetic Variat= ion Resources
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9

Chromosome Aberrations
•    Gross chromosomal aberrations like deletions, inversions or translocations with a large segment of DNA sequences were thought to be quite ra= re. Although numerous clinically characterized genomic syndromes have been reported to be associated with chromosomal aberrations. = ;
•
• <= /span>example:
•
Velocardiofacial syndrome (VCSF) characterized by the presence of features like cleft palate, cardiac anomalies and learning disabilities is associated with a deletion mutation on chromosome 22q11.2. (OMIM:192430)
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  Genetic Variat= ion Resources
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Advanced Workshop
10

Estimated Numbers
= 3;
<= span style=3D'visibility:hidden'>•
•SNPs app= ear at 0.3-1-kb average intervals, considering the size of entire human genome, which is 3X107 bp, the total number scales u= p to 5-10 million.

•In sillico estimation of potentially polymorphic VNTR are over = 100,000 across the human genome.

•The short insertion/deletions are very difficult to quantify and the n= umber is likely to fall in between SNPs and VNTR
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
11

Polymorphisms and Disease Markers
= 3;
<= span style=3D'visibility:hidden'>•
•Very few= of these polymorphisms show direct impact on deleterious = phenotype.

•The non-disease-causing polymorphisms when mapped to the genome, may serve as markers to identify and map other genes that = do cause disease when mutated.

•If these non-disease-causing variations are fou= nd to be inherited with a particular trait, but do not cause = the trait, they may provide evidence of where the trait's gene is located in the genome.
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
12

Common Terminologies
= 3;
•
• Allele: Alternative form= of a genetic locus; a single allele for each locus is inherited separate= ly from each parent.

Polymorphism: Difference in DNA sequence among individuals.

Linkage Disequilibrium (LD): If two alleles tend to be inherited together more often than would be predicted, then the alleles are in linkage disequilibrium.

Haplotype refers to the set of alleles on one particul= ar chromosome. Each person has two haplotypes in a given region, and each haplotype will be passed on as a complete unit. <= /span>
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
13

Transitions and Transversions
= 3;
• SNPs include single base substitutions such as:
•
• Transitions: change of one p= urine (A,G) for a purine, or a pyrimidine (C,T) for a pyrimidine;
•&#= 13;
• Transversions: change of a p= urine (A,G) for a pyrimidine (C,T), or vice versa.
•&#= 13;
• CpG dinucleotides are first methylated and then deami= nated to form either CpA or TpG. G>A and C>T transitions accounting for 25% of all SNPs in hum= an = genome.
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
14

SNPs and Mutations
• Terminology for variation at= a single nucleotide posit= ion is defined by allele freque= ncy.
•&#= 13;
–<= /span>A single base change, occurring in a population at a frequency of >1% is termed a <= /span>single nucleotide polymorphism (SNP).
–<= /span>When a single base change occurs at <1% it is considered to be a mutation.
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
15

Life Cycle of SNPs and Mutations
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18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
16

Classification of SNPs
• SNPs may occur at any position in the following gene structure and = based on its location it can be classified as: intronic, exonic,  or promoter region etc.
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file:///C:/584BB24E/variation_files/slide0024.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="us-ascii" Slide 1
<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
17

Coding SNPs=
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
18
Genetic Variations Databases<= /div>
R= 26;
•= dbSNP
–= http://www.ncbi.nlm.nih.gov/SNP/index.html = 3;
•O= nline Mendelian Inheritance in Man (OMIM)
= –= http://www.ncbi.nlm.nih.gov/sites/entrez?db=3DOMIM
•= International HapMap Project
= –= http://www.hapmap.org/
•= Genome Variation Server (Seattle SNPs)
= –= http://gvs.gs.washington.edu/GVS/
R= 26;
R= 26;
•
•
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
19

dbSNP
&= #8226;URL: = http://www.ncbi.nlm.nih.gov/SNP/index.html
• <= /div>
= 226;The Single Nucleotide Polymorphism database (dbSNP) is a public- d= omain archive for a broad collection of simple genetic p= olymorphisms.
• <= /div>
= 226;This collection of polymorphisms includes:
–Single-base nucleotide substitutions (also know= n as single nucleotide polymorphisms or SNPs)
–Small-scale multi-base deletions or insertions (also called deletion insertion polymorphisms or DIPs),
–Microsatellite repeat variations (also called s= hort tandem repeats or STRs).
•
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<= ![if !vml]>
18 July 2007 =
  Genetic Variat= ion Resources
  Course Home        = ;            Modules        = ;            &n= bsp; Schedule        = ;            &n= bsp; Exercises        = ;          Comments        = ;            Credits
Advanced Workshop
20

dbSNP : Statistics
<= span class=3DHBB style=3D'position:absolute;left:-4.39%'>•= http://www.ncbi.nlm.nih.gov/SNP/snp_summary.cgi 
<= span style=3D'visibility:hidden'>•
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