Vous êtes sur la page 1sur 15

Term Paper

On

“Single-nucleotide Polymorphism”

Submitted to: Submitted


by:
Ms. Tulasi Adapa Ojasvi
Ahuja
RE7602B36

3040060064
Contents

 Single-nucleotide polymorphism
 Types of SNPs
 Needles in Haystack
 Use and importance of SNPs
 SNPs and Disease Diagnosis
 SNPs and Drug Development
 SNPs and NCBI
 NCBI's "Discovery Space" Facilitating SNP Research
 Examples of SNPs
 Databases of SNPs
 Nomenclature
 Human Genome Project and SNP Mapping Goals
 FAQs
 Conclusion & Discussion
 References
Single-nucleotide polymorphism

DNA molecule 1 differs from DNA molecule 2 at a single base-pair location (a C/T polymorphism)

A single-nucleotide polymorphism (SNP, pronounced snip) is a DNA sequence variation


occurring when a single nucleotide — A, T, C, or G — in the genome (or other shared
sequence) differs between members of a species (or between paired chromosomes in an
individual). For example, two sequenced DNA fragments from different individuals,
AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say
that there are two alleles : C and T. Almost all common SNPs have only two alleles.

Within a population, SNPs can be assigned a minor allele frequency — the lowest allele
frequency at a locus that is observed in a particular population. This is simply the lesser of the
two allele frequencies for single-nucleotide polymorphisms. There are variations between
human populations, so a SNP allele that is common in one geographical or ethnic group may
be much rarer in another.

"SNP"
In the past, SNPs with a minor allele frequency of greater than or equal to 1% (or 0.5%, etc.)
were given the title "SNP". Some used "mutation" to refer to variations with low allele
frequency. With the advent of a better understanding of evolution, this definition is no longer
necessary, e.g., a database such as dbSNP includes "SNPs" that have lower allele frequency
than 1%.

Types of SNPs

• Non-coding region
• Coding region
o Synonymous
o Nonsynonymous
 Missense

Nonsense
Single nucleotides may be changed (substitution), removed (deletions) or added (insertion) to
a polynucleotide sequence. Ins/del SNP may shift translational frame.

Single nucleotide polymorphisms may fall within coding sequences of genes, non-coding
regions of genes, or in the intergenic regions between genes. SNPs within a coding sequence
will not necessarily change the amino acid sequence of the protein that is produced, due to
degeneracy of the genetic code. A SNP in which both forms lead to the same polypeptide
sequence is termed synonymous (sometimes called a silent mutation) — if a different
polypeptide sequence is produced they are nonsynonymous. A nonsynonymous change may
either be missense or nonsense, where a missense change results in a different amino acid,
while a nonsense change results in a premature stop codon. SNPs that are not in protein-
coding regions may still have consequences for gene splicing, transcription factor binding, or
the sequence of non-coding RNA.

Needles in a Haystack

Finding single nucleotide changes in the human genome seems like


As a result of recent
a daunting prospect, but over the last 20 years, biomedical advances in SNPs
research, diagnostics
researchers have developed a number of techniques that make it for many diseases may
possible to do just that. Each technique uses a different method to improve.
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.

Use and Importance of SNPs


Variations in the DNA sequences of humans can affect how humans develop diseases and
respond to pathogens, chemicals, drugs, vaccines, and other agents. SNPs are also thought to
be key enablers in realizing the concept of personalized medicine. However, their greatest
importance in biomedical research is for comparing regions of the genome between cohorts
(such as with matched cohorts with and without a disease).

The study of single-nucleotide polymorphisms is also important in crop and livestock


breeding programs (see genotyping). See SNP genotyping for details on the various methods
used to identify SNPs.

They are usually biallelic and thus easily assayed.

SNPs and Disease Diagnosis

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 SNP patterns.

SNPs and Drug Development

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

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

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". 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 medicine.

Examples
• rs6311 and rs6313 are SNPs in the HTR2A gene on human chromosome 13.
• A SNP in the F5 gene causes a hypercoagulability disorder with the variant Factor V
Leiden.
• rs3091244 is an example of a triallelic SNP in the CRP gene on human chromosome
1.
• TAS2R38 codes for PTC tasting ability, and contains 6 annotated SNPs.
Databases
As there are for genes, there are also bioinformatics databases for SNPs. dbSNP is a SNP
database from National Center for Biotechnology Information (NCBI). SNPedia is a wiki-
style database from a hybrid organization. The OMIM database describes the association
between polymorphisms and, e.g., diseases in text form, while HGVbaseG2P allows users to
visually interrogate the actual summary-level association data.

Nomenclature
The nomenclature for SNPs can be confusing: several variations can exist for an individual
SNP and consensus has not yet been achieved. One approach is to write SNPs with a prefix,
period and greater than sign showing the wild-type and altered nucleotide or amino acid; for
example, c.76A>T.

Human Genome Project SNP Mapping Goals


In 1998, as part of their last 5-year plan, the DOE and NIH Human Genome programs
established goals to identify and map SNPs. These goals follow.

• Develop technologies for rapid, large-scale identification and scoring of SNPs and
other DNA sequence variants.
• Identify common variants in the coding regions of most identified genes.
• Create a SNP map of at least 100,000 markers.
• Develop the intellectual foundations for studies of sequence variation.
• Create public resources of DNA samples and cell lines.
FAQs

What is The SNP consortium (TSC)?

In April 1999, ten large pharmaceutical companies and the U.K. Wellcome Trust
philanthropy announced the establishment of a consortium lead by Arthur L. Holden to find
and map 300,000 common SNPs. The goal was to generate a widely accepted, high-quality,
extensive, publicly available map using SNPs as markers evenly distributed throughout the
human genome. In the end, many more SNPs (1.8 million total) were discovered. Now that
the SNP discovery phase of the TSC project is essentially complete, emphasis has shifted to
studying SNPs in populations. Various TSC member laboratories are genotyping a subset of
SNPs as part of the Allele Frequency Project. The goal of the TSC allele frequency/genotype
project is to determine the frequency of certain SNPs in three major world populations. See
the TSC website for more information.

Who are members of the SNP consortium?

The international member companies, which together committed at least $30 million to the
consortium's efforts, are APBiotech, AstraZeneca Group PLC, Aventis, Bayer Group AG,
Bristol-Myers Squibb Co., F. Hoffmann-La Roche, Glaxo Wellcome PLC, IBM, Motorola,
Novartis AG, Pfizer Inc., Searle, and SmithKline Beecham PLC. The Wellcome Trust
contributed at least $14 million.
Laboratories funded by these companies to identify SNPs are located at the Whitehead
Institute, Sanger Centre, Washington University (St. Louis), and Stanford University. Data
management and analysis take place at Cold Spring Harbor Laboratory.

See Consortium Updates:

• News related to The SNP Consortium


• SNP Consortium collaborates with HGP, publishes first progress reports, 2000.
Human Genome News.
• International SNP meeting updates, 2000. Human Genome News.

Why should private companies fund a publicly accessible genome map?

The SNP consortium views its map as a way to make available an important, precompetitive,
high-quality research tool that will spark innovative work throughout the research and
industrial communities. The map will be a powerful research tool to enhance the
understanding of disease processes and facilitate the discovery and development of safer and
more effective medications.

Whose DNA was analyzed to create the consortium's SNP map?

The SNP consortium used DNA resources from a pool of samples obtained from 24 people
representing several racial groups. This is a subset of the DNA reference panel for SNP
identification collected by the NIH National Human Genome Research Institute. The
anonymous, voluntary DNA contributions were made with informed consent specifically for
this use.

Are SNP data available to the public?

SNP data were made available through a consortium website at quarterly intervals during the
project's first year and at monthly intervals during the second year. This cycle of releases
ceased in fall 2001 once the discovery phase was finished, but with recent additions of
genotype and allele frequency information, new data were released in fall 2002.

Besides the TSC website, SNP data are also available from the following resources:
• dbSNP database - From the National Center for Biotechnology Information (NCBI).
• HGVbase (Human Genome Variation Database) - A human gene-based
polymorphism database.

Conclusion & Discussion

Single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”), are the most
common type of genetic variation among people. Each SNP represents a difference in a
single DNA building block, called a nucleotide. For example, a SNP may replace the
nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA.

SNPs occur normally throughout a person’s DNA. They occur once in every 300 nucleotides
on average, which means there are roughly 10 million SNPs in the human genome. Most
commonly, these variations are found in the DNA between genes. They can act as biological
markers, helping scientists locate genes that are associated with disease. When SNPs occur
within a gene or in a regulatory region near a gene, they may play a more direct role in
disease by affecting the gene’s function.

Most SNPs have no effect on health or development. Some of these genetic differences,
however, have proven to be very important in the study of human health. Researchers have
found SNPs that may help predict an individual’s response to certain drugs, susceptibility to
environmental factors such as toxins, and risk of developing particular diseases. SNPs can
also be used to track the inheritance of disease genes within families. Future studies will work
to identify SNPs associated with complex diseases such as heart disease, diabetes, and cancer.

Various scientific endeavors had already started even before the completion of the first
human genome reference sequence to identify unique genetic differences between
individuals. 99.9% of one individual DNA sequences will be identical to that of another
person. Of the 0.1% difference, over 80% will be single nucleotide polymorphisms (SNPs). A
SNP is a single base substitution of one nucleotide with another, and both versions are
observed in the general population at a frequency greater than 1%. Human DNA is comprised
of only four chemical entities, e.g. A, G, C, T, whose specific chemical order is the alphabet
of the genome. An example of a SNP is individual "A" has a sequence GAACCT while
individual "B" has sequence GAGCCT, the polymorphism is a A/G. The most recognized
public effort was spearheaded by The SNP Consortium (TSC) whose mission was to
determine and map about 300,000 evenly spaced single nucleotide polymorphisms within the
human genome.

Current estimates are that SNPs occur as frequently as every 100-300 bases. This implies in
an entire human genome there are approximately 10 to 30 million potential SNPs. More than
4 million SNPs have been identified and the information has been made publicly available
through the efforts of TSC and others. Many of these SNPs have unknown associations.
Compilation of public SNPs by NCBI has produced a subset of SNPs defined as a non-
redundant set of markers that are used for annotation of reference genome sequence and are
thus referred to as reference SNPs (rsSNPs). Over 2.6 million SNPs have currently been
assigned as "rsSNPs".
References

 en.wikipedia.org/wiki/Single-nucleotide_polymorphism

 www.ncbi.nlm.nih.gov/About/primer/snps.html

 las.perkinelmer.com/content/snps/genotyping.asp

 www.medterms.com/script/main/art.asp?articlekey=30716

 encyclopedia.farlex.com/single+nucleotide+polymorphisms

 www.ncbi.nlm.nih.gov/About/primer/snps.html

 www.ornl.gov/sci/techresources/Human.../faq/snps.shtml

Vous aimerez peut-être aussi