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Genetic Variation and Human Disease
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This guide supports the Galter Library class called Genetic Variation and Human Disease. See our Classes schedule
for the next available offering. If this class is not on our upcoming schedule, it is still available to you or your group by
request.
Background
Two types of genetic variation events are the sources of most human genetic variation:
Single base mutation which substitutes one nucleotide for another
Single Nucleotide Polymorphisms (SNPs)
SNPs are the most common form of polymorphism
Example: a single SNP from T to A on the hemoglobin beta locus of chromosome 11 causes a
missense coding event changing glutamine to valine, leading to the sickle cell anemia phenotype.
Insertion or deletion of one or more nucleotide(s)
Tandem Repeat Polymorphisms
Tandem repeats or variable number of tandem repeats (VNTR) are a very common class of
polymorphism, consisting of variable length of sequence motifs that are repeated in tandem in a
variable copy number
VNTRs are subdivided into two subgroups based on the size of the tandem repeat units.
Microsatellites or Short Tandem Repeat (STR)
repeat unit: 1-6 (dinucleotide repeat: CACACACACACA)
Minisatellites
repeat unit: 14-100
Example: Spinocerebellar ataxia Type10 (SCA10) is caused by the largest tandem repeat seen in the
human genome. Normal population has 10-22 mer pentanucleotide ATTCT repeat in intron 9 of
SCA10 gene; where as SCA10 patients have 800-4500 repeat units, which causes the disease allele
to be up to 22.5 kb larger than the normal one.
Insertion/Deletion Polymorphisms (indels)
Common and widely distributed in the human population
Association between coronary heart disease and a 287 bp indel polymorphism located in intron 16 of
the angiotensin converting enzyme (ACE) have been reported. This indel, known as ACE/ID is
responsible for 50% of the inter-individual variability of plasma ACE concentration.
In addition to the events listed above, gross chromosomal aberrations like deletions, inversions or translocations of
large segments of DNA have been associated with numerous clinically characterized genomic syndromes.
Example: Velocardiofacial syndrome (VCSF), characterized by the presence of features like cleft palate, cardiac
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anomalies and learning disabilities, is associated with a deletion mutation on chromosome 22q11.2.
Very few polymorphisms show direct impact by creating deleterious phenotypes. However, 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 found 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.
Terminology
Allele: Alternative form of a genetic locus; a single allele for each locus is inherited separately 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: The set of alleles on one particular chromosome; each person has two haplotypes in a given region,
and each haplotype will be passed on as a complete unit
SNP or mutation?
A single base change occurring in a population at a frequency of greater than 1% is a SNP
A single base change occurring in a population at a frequency of less than 1% is a mutation
NCBI's dbSNP
NCBI's single nucleotide polymorphism database dbSNP is the most-used SNP database worldwide.
The direct URL for dbSNP is:
http://www.ncbi.nlm.nih.gov/SNP/index.html
but most often SNP records are accessed through links from other databases such as NCBI's Gene or OMIM databases
or from European Bioinformatics Institute (EBI) databases. The URL above is useful for searching submitted SNP
identifiers or searching for batches of SNP or experiments.
In addition to SNPs, dbSNP contains data from small-scale multi-base deletions or insertions (also called deletion
insertion polymorphisms or DIPs) and microsatellite repeat variations (also called short tandem repeats or STRs).
You can view summary statistics for the current build of dbSNP or for past builds. dbSNP also has extensive
documentation and a submission system for researchers to submit SNP data from their own experiments. These
features can be accessed from the menu on the left side of the dbSNP home page.
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When a researcher uploads SNP data, each SNP is assigned a submitted SNP identifier (ss#). Submitted SNPs are then
checked against the current contents of dbSNP. SNPs that are redundant (i.e., match already-submitted SNP types) are
assigned to the appropriate reference SNP (rs#) cluster. Unique SNPs are assigned new rs numbers upon the next build
of dbSNP. Submitted SNP records contain information on the experimental procedures used to identify the SNP, the
research project in which the SNP was identified and more data on the SNP.
A different searchable interface for NCBI's dbSNP is found at the URL:
http://www.ncbi.nlm.nih.gov/snp/
This page allows you to search more efficiently for SNPs associated with a specific gene or disease in specific
organisms or in a particular region of a chromosome. You can do this by using the Limits tab on this page.
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Example: Mutations on BRCA1 gene have been reported to be associated with the early onset of breast cancer. Retrieve
all non-synonymous and validated coding refSNPs for human BRCA1 from dbSNP.
Solution:
Go to the NCBI SNP home page
Enter BRCA1 [Gene Name] in the search box and click Search
Alternately, you can use the Advanced link under the search box to specify exact fields to search
After the search, use the filters on the left to narrow your results
Under Organism(s) select Homo Sapiens
Under Function Class select the types of functional outcomes you are interested in (eg. missense, nonsense,
stop gained, frame shift, etc.)
Go to Validation Status and select all options except "no-info"
You can click on Search Details and review your Query Translation (optional)
Filters for dbSNP Searches
Organism
Variation Class
Clinical Significance
Annotation
Global Minor Allele Frequency
Validation Status
Chromosomes
Map Weight (how many times in genome)
Chromosome Range
Variation Alleles (using IUPAC-International Union of Pure and Applied Chemistry-codes)
% Heterozygosity
Success Rate (likelihood that the SNP is real; = 1 minus false positive rate)
Method Class
Individual SNP maps (Venter, Watson and Chinese_YH1)
Minor Allele Frequency (by HapMap population class)
Search Fields (in which you can choose from a pull-down menu of all SNP record fields to search on)
dbSNP Search Results
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You can view the full record by clicking the rs number.
From the full record, you can view SNPs in Sequence Viewer to see their genomic orientation, plus mapping to mRNA
and protein products. You can also view population diversity for the alleles and the FASTA sequence of the
polymorphism.
The default view of a record from a search of dbSNP is a view of only coding SNPs. To view all SNPs in a gene region,
click on the radio button next to in gene region in the GeneView section of the SNP record, then click Go.
OMIM and GeneReviews
Online Mendelian Inheritance in Man (OMIM) is a database of human gene-phenotype correlations maintained by the
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NCBI. Records in OMIM are presented as summary reviews of the current state of knowledge on known Mendelian
disorders and over 12,000 genes. OMIM records are good starting points for learning disease-gene links, because a great
deal of information can be accessed from each record.
Accessing Allelic Variants in OMIM
You can view a list of allelic variants for a gene from its record in OMIM.
Example: Search OMIM for information on the gene glucose-6-phosphate dehydrogenase (G6PD). What known disorders
are caused by allelic variants in this gene?
Solution:
Start at OMIM
Type G6PD in the search box
Click the first entry (+305900...)
On the record for G6PD, click the Allelic Variants link in the Table of Contents near the upper right of the page.
You can see all of the allelic variants in the record and if any of these variants are linked to diseases or disorders.
Usually, pathological conditions linked to an allelic variant will be listed just below the allele description.
You can also see a table of allelic variants by clicking the See List link in the Table of Contents
Limitations of Allelic Variants in OMIM
Not all possible allelic variants will be listed in OMIM. The Gene View in dbSNP will give you a better listing of all
polymorphisms for a gene. However, the allelic variants in OMIM are usually selected because they have some
significance. Reasons for allelic variants to be included in OMIM include:
the first mutation to be discovered
high population frequency
distinctive phenotype
historic significance
unusual mechanism of mutation
unusual pathogenic mechanism
distinctive inheritance
GeneReviews
GeneReviews is a searchable online resource that maintains expert-authored, peer-reviewed summaries of inherited
conditions. Formerly maintained by GeneTests (see below section on genetic testing), GeneReviews are now part of the
NCBI Bookshelf online at the NCBI. GeneReviews offer more content related to genetic counseling than OMIM and are
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considered an essential resource by many professional genetic counselors.
HapMap and 1000 Genomes Projects
NCBI's dbSNP includes data from both the International HapMap Project and the 1000 Genomes Project. When viewing a
GeneView in dbSNP, you can see which SNPs have been sequenced or mapped by either project in the Validation
column of the gene report.
You can also browse data from the International HapMap project directly from the HapMap Project website. Links in the
left menu will take you to a search interface for the most current data from the project.
Haplotypes are contiguous, linear sets of SNP alleles along a genome that are inherited as a block. Haplotypes can give
information on what markers are inherited together and thus can be used to find markers for disease trait inheritance.
Search by rs number, chromosomal region or gene name
Example: Type ACE in the search box
On the resulting page, click one of the chromosomal regions available to get a more detailed view of a region
Now you can view detailed SNPs in the region, plus haplotype frequencies in each population for each SNP
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Data from the 1000 Genomes Project does not currently have its own separate search interface, but the 1000 Genomes
website has links through which you can download entire sequence datasets for your own research use.
Other Genome Variation Resources
Other genome variation resources and servers are available on the Web.
Select from multiple variation viewing options on the UCSC Genome Browser
Select from multiple variation options in the left menu of the Ensembl genome browser after performing a search
for gene or location
GeneCards from the Weizmann Institute of Science has one of the most convenient "at-a-glance" interfaces for
information on human genes, including variation features. View an example of GeneCards variants for the BRCA1
gene.
The Human Genome Variation Society (HGVS) maintains a list of mutation databases organized by type of
population, disease, locus and other categories.
A search for "variation" at University of Pittsburgh's Online Bioinformatics Resources Collection (OBRC) will
retrieve numerous variation resources.
Genetic Testing
As more phenotype-genotype associations are discovered, genetic testing is becoming more common and more
important.
Consumers have an array of direct-to-consumer (DTC) genetic testing options from companies like 23 and Me,
Navigenics and Pathway Genomics. Individuals can also participate in the Personal Genome Project, in which an
individual's entire genome is sequenced and shared with researchers conducting genomic studies worldwide.
This guide is not dedicated to DTC genetic testing resources. Instead, two resources that catalog genetic testing services
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for medicine and genetics professionals are featured here.
The Genetic Testing Registry (GTR)
The Genetic Testing Registry is the central location in the United States for voluntary submission of genetic test
information by testing providers (although labs outside the USA also provide testing resource information to GTR). GTR is
not intended as a consumer testing information site, and patients and consumers are encouraged to contact a health care
provider or genetics professional on the GTR home page.
Users can search the entire GTR site using keywords, or can search the GTR by specific categories:
Tests - by entering test names, disease names, phenotypes, gene symbols and names, protein names, laboratory
names, directors and locations as search terms
Conditions/Phenotypes - by entering disease names, traits, drugs, proteins and analytes
Genes - by entering gene symbols and names, conditions and phenotypes
Labs - by entering lab names, directors, staff members, locations and services, disease names and phenotypes
GeneReviews - by entering any keyword
Search results can be narrowed by applying filters selected from the left side of the search results page. The GTR
homepage also includes links to a number of other genetic testing resources. Researchers or laboratories who provide
genetic testing can also find links and instructions on submitting genetic testing information to the GTR.
For more information about the GTR, see the GTR FAQs from the Office of Biotechnology Activities.
GeneTests
For a long time, GeneTests was the primary site for genetic counselors and other genomic medicine practitioners for
finding resources to test for specific inherited diseases. Since 2012, there has been a shift in the United States to refer
professionals to the Genetic Testing Registry in preference over GeneTests. However, GeneTests is still maintained as a
reliable source of genetic testing information.
GeneTests can also be searched by
Disorders
Genes
Labs or Clinics
GeneReviews
Panels - to seach for screening panels (as opposed to single gene testing)
Printed: Wednesday, April 26, 2017 1:37 AM
Source: https://galter.northwestern.edu/guides-and-tutorials/genetic-variation-and-human-disease.pdf
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