Just the Facts: A Basic Introduction to the Science Underlying NCBI Resources
SNPs: VARIATIONS ON A THEME
Wouldn't it be wonderful if you knew exactly what measures you
could take to stave off, or even prevent, the onset of disease? Wouldn't it be
a relief to know that you are not allergic to the drugs your doctor just
prescribed? Wouldn't it be a comfort to know that the treatment regimen you are
undergoing has a good chance of success because it was designed just for you? With the
availability of millions of SNPs, biomedical researchers
now believe that such exciting medical advances are not that far away.
What Are SNPs and How Are They Found?
|Although many SNPs do not produce
physical changes in people, scientists believe that other SNPs
may predispose people to disease and even influence their response to
A Single Nucleotide Polymorphism, or SNP (pronounced "snip"),
is a small genetic change, or variation, that can occur within a
person's DNA sequence. The genetic code is specified by the four nucleotide
"letters" A (adenine), C (cytosine), T (thymine), and G (guanine).
SNP variation occurs when a single nucleotide, such as an A, replaces one of
the other three nucleotide letters—C, G, or T.
An example of a SNP is the alteration of the DNA segment AAGGTTA
to ATGGTTA, where the second "A" in the first snippet
is replaced with a "T". On average, SNPs occur in the
human population more than 1 percent of the time. Because only
about 3 to 5 percent of a person's DNA sequence codes for the production
of proteins, most SNPs are found outside of "coding sequences".
SNPs found within a coding sequence are of particular interest to
researchers because they are more likely to alter the biological function
of a protein. Because of the recent advances in technology, coupled with
the unique ability of these genetic variations to facilitate gene
identification, there has been a recent flurry of SNP discovery
Needles in a Haystack
|As a result of recent
advances in SNPs research, diagnostics for many diseases
Finding single nucleotide changes in the human genome seems like
a daunting prospect, but over the last 20 years, biomedical researchers
have developed a number of techniques that make it possible to do just that. Each
technique uses a different method to compare selected regions of a DNA sequence
obtained from multiple individuals who share a common trait. In each test, the
result shows a physical difference in the DNA samples only when a SNP is detected
in one individual and not in the other.
Many common diseases in humans are not caused by a genetic variation
within a single gene but are influenced by complex interactions
among multiple genes as well as environmental and lifestyle factors.
Although both environmental and lifestyle factors add tremendously
to the uncertainty of developing a disease, it is currently difficult
to measure and evaluate their overall effect on a disease process.
Therefore, we refer here mainly to a person's genetic predisposition,
or the potential of an individual to develop a disease based on
genes and hereditary factors.
Genetic factors may also confer susceptibility or resistance to
a disease and determine the severity or progression of disease.
Because we do not yet know all of the factors involved in these intricate
pathways, researchers have found it difficult to develop screening
tests for most diseases and disorders. By studying stretches of
DNA that have been found to harbor a SNP associated with a disease
trait, researchers may begin to reveal relevant genes associated
with a disease. Defining and understanding the role of genetic factors
in disease will also allow researchers to better evaluate the role
non-genetic factors—such as behavior, diet, lifestyle, and
physical activity—have on disease.
Because genetic factors also affect a person's response to drug therapy,
DNA polymorphisms such as SNPs will be useful in helping
researchers determine and understand why individuals differ in their
abilities to absorb or clear certain drugs, as well as to determine
why an individual may experience an adverse side effect to a particular
drug. Therefore, the recent discovery of SNPs promises to revolutionize
not only the process of disease detection but the practice of preventative
and curative medicine.
SNPs and Disease Diagnosis
|It will only be a matter of time before
physicians can screen patients for susceptibility to a disease by analyzing
their DNA for specific SNP profiles.
Each person's genetic material contains a unique SNP pattern that
is made up of many different genetic variations. Researchers have
found that most SNPs are not responsible for a disease state. Instead,
they serve as biological markers for pinpointing a disease on the
human genome map, because they are usually located near a gene found
to be associated with a certain disease. Occasionally, a SNP may
actually cause a disease and, therefore, can be used to search for
and isolate the disease-causing gene.
To create a genetic test that will screen for a disease in which
the disease-causing gene has already been identified, scientists
collect blood samples from a group of individuals affected by the
disease and analyze their DNA for SNP patterns. Next, researchers
compare these patterns to patterns obtained by analyzing the DNA
from a group of individuals unaffected by the disease. This type
of comparison, called an "association study", can detect
differences between the SNP patterns of the two groups, thereby
indicating which pattern is most likely associated with the disease-causing
gene. Eventually, SNP profiles that are characteristic of a variety of diseases will be established.
Then, it will only be a matter of time before physicians can screen individuals
for susceptibility to a disease just by analyzing their DNA samples for specific
SNPs and Drug Development
|Using SNPs to study the genetics of drug
response will help in the creation of "personalized" medicine.
As mentioned earlier, SNPs may also be associated with the absorbance
and clearance of therapeutic agents. Currently, there is no simple
way to determine how a patient will respond to a particular medication.
A treatment proven effective in one patient may be ineffective in
others. Worse yet, some patients may experience an adverse immunologic
reaction to a particular drug. Today, pharmaceutical companies are
limited to developing agents to which the "average" patient will
respond. As a result, many drugs that might benefit a small number
of patients never make it to market.
In the future, the most appropriate drug for an individual could
be determined in advance of treatment by analyzing a patient's SNP
profile. The ability to target a drug to those individuals most
likely to benefit, referred to as "personalized medicine",
would allow pharmaceutical companies to bring many more drugs to
market and allow doctors to prescribe individualized therapies specific
to a patient's needs.
SNPs and NCBI
|Most SNPs are not responsible for a disease
state. Instead, they serve as biological markers for pinpointing a disease on
the human genome map.
Because SNPs occur frequently throughout the genome and tend to
be relatively stable genetically, they serve as excellent biological
markers. Biological markers are segments of DNA with an identifiable
physical location that can be easily tracked and used for constructing
a chromosome map that shows the positions of known genes, or other markers,
relative to each other. These maps allow researchers to study and pinpoint traits
resulting from the interaction of more than one gene. NCBI plays
a major role in facilitating the identification and cataloging of
SNPs through its creation and maintenance of the public SNP database
(dbSNP). This powerful
genetic tool may be accessed by the biomedical community worldwide
and is intended to stimulate many areas of biological research,
including the identification of the genetic components of disease.
NCBI's "Discovery Space" Facilitating SNP Research
|Figure 1. The NCBI Discovery Space.
| Records in dbSNP are cross-annotated within
other internal information resources such as PubMed, genome project sequences, GenBank
records, the Entrez Gene database, and the dbSTS database of sequence
tagged sites. Users may query dbSNP directly or start a search in any part
of the NCBI discovery space to construct a set of dbSNP records that satisfy
their search conditions. Records are also integrated with external
information resources through hypertext URLs that dbSNP users can follow to
explore the detailed information that is beyond the scope of dbSNP curation.
Reproduced with permission from Sherry ST, Ward MH, Kholodov M, Baker J, Phan L,
Smigielski EM, Sirotkin K."dbSNP: the NCBI database of genetic variation." Nucleic Acids
Research. 2001; 29:308-311.
To facilitate research efforts, NCBI's dbSNP is included in the
Entrez retrieval system which provides integrated access to
a number of software tools and databases that can aid in SNP analysis. For
example, each SNP record in the database links to additional resources
within NCBI's "Discovery Space", as noted in Figure
1. Resources include: GenBank,
NIH's sequence database; Entrez Gene, a
focal point for genes and associated information; dbSTS,
NCBI's resource containing sequence and mapping data on short genomic landmarks;
human genome sequencing data; and PubMed,
NCBI's literature search and retrieval system. SNP records also link to
various external allied resources.
Providing public access to a site for "one-stop SNP shopping" facilitates scientific research
in a variety of fields, ranging from population genetics and evolutionary biology to large-scale
disease and drug association studies. The long-term investment in such novel and exciting
research promises not only to advance human biology but to revolutionize the practice of modern
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Revised: September 20, 2007.