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[[Image:dna-SNP.jpg|thumb|DNA strand 1 differs from DNA strand 2 at a single base-pair location (a C/T polymorphism).]]
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==Overview==
A '''single-nucleotide polymorphism''' ('''SNP''') is a [[DNA sequence]] variation occurring when a single [[nucleotide]] &mdash; [[adenine|A]], [[thymine|T]], [[cytosine|C]] or [[guanine|G]] &mdash; in the [[genome]] (or other shared sequence) differs between members of a [[biological species]] or paired [[chromosome]]s in a human. For example, two sequenced DNA fragments from different individuals, AAGC<u>C</u>TA to AAGC<u>T</u>TA, contain a difference in a single nucleotide. In this case we say that there are two ''[[allele]]s''. Almost all common SNPs have only two alleles. The genomic distribution of SNPs is not homogenous; SNPs usually occur in non-coding regions more frequently than in coding regions or, in general, where natural selection is acting and fixating the [[allele]] of the SNP that constitutes the most favorable genetic adaptation.<ref name="Barreiro">{{cite journal | author= Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L. | year=2008| title=Natural selection has driven population differentiation in modern humans. | journal=Nature Genetics| volume=40| pages=340–345| pmid=18246066 | doi=10.1038/ng.78}}</ref> Other factors, like [[genetic recombination]] and mutation rate, can also determine SNP density.<ref name="Nachman">{{cite journal | author=Nachman, Michael W. | year=2001 | title=Single nucleotide polymorphisms and recombination rate in humans | journal=Trends in genetics | volume=17 | issue=9 | pages=481-485 | pmid=11525814 | doi=10.1016/S0168-9525(01)02409-X}}</ref>
SNP density can be predicted by the presence of [[Microsatellite (genetics)|microsatellites]]: AT microsatellites in particular are potent predictors of SNP density, with long (AT)(n) repeat tracts tending to be found in regions of significantly reduced SNP density and low [[GC content]].<ref name="Varela">{{cite journal | author= M.A. Varela and W. Amos | year=2010 | title=Heterogeneous distribution of SNPs in the human genome: Microsatellites as predictors of nucleotide diversity and divergence | journal=Genomics| volume=95| pages=151–159| doi=10.1016/j.ygeno.2009.12.003 | pmid=20026267}}</ref>
Within a population, SNPs can be assigned a [[minor allele frequency]] &mdash; the lowest allele frequency at a [[locus (genetics)|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.
These genetic variations between individuals (particularly in non-coding parts of the genome) are exploited in [[DNA profiling|DNA fingerprinting]], which is used in forensic science . Also, these genetic variations underlie differences in our susceptibility to disease. The severity of illness and the way our body responds to treatments are also manifestations of genetic variations. For example, a single base mutation in the APOE ([[apolipoprotein E]]) gene is associated with a higher risk for Alzheimer disease.<ref name="ApoE">{{Cite pmid| 23159550}}</ref>
== Types ==
{| class="infobox"
|-
! Types of SNPs
|-
|
* Non-coding region
* Coding region
** Synonymous
** Nonsynonymous
*** Missense
*** Nonsense
|}
Single-nucleotide [[polymorphism (biology)|polymorphisms]] may fall within coding sequences of [[gene]]s, [[intron|non-coding regions of genes]], or in the [[intergenic region]]s (regions between genes). SNPs within a coding sequence do not necessarily change the [[amino acid]] sequence of the [[protein]] that is produced, due to [[Genetic code#Degeneracy|degeneracy of the genetic code]].
SNPs in the coding region are of two types, synonymous and nonsynonymous SNPs. Synonymous SNPs do not affect the protein sequence while nonsynonymous SNPs change the amino acid sequence of protein. The nonsynonymous SNPs are of two types: [[Missense mutation|missense]] and [[Nonsense mutations|nonsense]].
SNPs that are not in protein-coding regions may still affect [[gene splicing]], [[transcription factor]] binding, [[messenger RNA]] degradation, or the sequence of [[non-coding RNA]]. Gene expression affected by this type of SNP is referred to as an eSNP (expression SNP) and may be upstream or downstream from the gene.
== Use and importance ==
Variations in the DNA sequences of humans can affect how humans develop [[disease]]s and respond to [[pathogen]]s, [[chemical]]s, [[medication|drugs]], [[vaccine]]s, and other agents. SNPs are also critical for [[personalized medicine]].<ref>{{cite journal |first1=Bruce |last1=Carlson | title=SNPs &mdash; A Shortcut to Personalized Medicine |url=http://www.genengnews.com/gen-articles/snps-a-shortcut-to-personalized-medicine/2507/ |journal=[[Genetic Engineering & Biotechnology News]] |publisher=[[Mary Ann Liebert, Inc.]] |date=2008-06-15 |accessdate=2008-07-06 |volume=28 |issue=12 |quote=(subtitle) Medical applications are where the market's growth is expected}}</ref> However, their greatest importance in biomedical research is for comparing regions of the genome between [[cohort (statistics)|cohort]]s (such as with matched cohorts with and without a disease) in [[Genome-wide association study|genome-wide association studies]].
The study of SNPs is also important in crop and [[livestock]] breeding programs. See [[SNP genotyping]] for details on the various methods used to identify SNPs.
SNPs are usually biallelic and thus easily assayed.<ref>{{cite journal |last1=Sachidanandam |first1=Ravi |last2=Weissman |first2=David |last3=Schmidt |first3=Steven C. |last4=Kakol |first4=Jerzy M. |last5=Stein |first5=Lincoln D. |last6=Marth |first6=Gabor |last7=Sherry |first7=Steve |last8=Mullikin |first8=James C. |last9=Mortimore |first9=Beverley J. |title=A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms |journal=Nature |volume=409 |issue=6822 |pages=928–33 |year=2001 |pmid=11237013 |doi=10.1038/35057149}}</ref>
A single SNP may cause a [[Genetic disorder|Mendelian disease]]. For [[Genetic disorder|complex diseases]], SNPs do not usually function individually, rather, they work in coordination with other SNPs to manifest a disease condition as has been seen in [[Osteoporosis]].<ref>{{cite journal |last1=Singh |first1=Monica |last2=Singh |first2=Puneetpal |last3=Juneja |first3=Pawan Kumar |last4=Singh |first4=Surinder |last5=Kaur |first5=Taranpal |title=SNP–SNP interactions within APOE gene influence plasma lipids in postmenopausal osteoporosis |journal=Rheumatology International |volume=31 |issue=3 |pages=421–3 |year=2010 |pmid=20340021 |doi=10.1007/s00296-010-1449-7}}</ref>
{{As of|2012|06|26}}, dbSNP listed 53,558,214 SNPs in humans.<ref>[http://www.ncbi.nlm.nih.gov/mailman/pipermail/dbsnp-announce/2012q2/000123.html NCBI dbSNP build 137 for human.]</ref>
SNPs have been used in [[genome-wide association studies| genome-wide association studies (GWAS)]], e.g. as
high-resolution markers in [[gene mapping]] related to diseases or normal traits. The knowledge of SNPs will help in understanding [[pharmacokinetics]] (PK) or [[pharmacodynamics]], i.e. how drugs act in individuals with different genetic variants. A wide range of [[human diseases]], i.e Sickle–cell anemia, β Thalassemia and Cystic fibrosis result from SNPs.<ref name="refname">{{Cite pmid|13369537}}</ref><ref>{{Cite pmid|88735}}</ref><ref>{{Cite pmid|1379413}}</ref> Diseases with different SNPs may become relevant pharmacogenomic targets for drug therapy.<ref>Fareed, M., Afzal, M (2013) "Single nucleotide polymorphism in genome-wide association of human population: A tool for broad spectrum service". ''Egyptian Journal of Medical Human Genetics'' 14: 123–134. http://dx.doi.org/10.1016/j.ejmhg.2012.08.001.</ref> Some SNPs are associated with the metabolism of different drugs.<ref>{{Cite pmid|11678778}}</ref><ref>{{Cite pmid|15349140}}</ref><ref>{{Cite pmid|16303243}}</ref> SNPs without an observable impact on the phenotype are still useful as genetic markers in genome-wide association studies, because of their quantity and the stable inheritance over generations.<ref>{{Cite pmid| 21992066}}</ref>
== Examples ==
* [[rs6311]] and [[rs6313]] are SNPs in the [[HTR2A]] gene on human chromosome 13.
* A SNP in the ''[[F5 (gene)|F5]]'' gene causes a hypercoagulability disorder with the variant [[Factor V Leiden]].
* [[rs3091244]] is an example of a triallelic SNP in the [[C-reactive protein|CRP]] gene on human chromosome 1.<ref>{{cite journal |last1=Morita |first1=Akihiko |last2=Nakayama |first2=Tomohiro |last3=Doba |first3=Nobutaka |last4=Hinohara |first4=Shigeaki |last5=Mizutani |first5=Tomohiko |last6=Soma |first6=Masayoshi |title=Genotyping of triallelic SNPs using TaqMan PCR |journal=[[Molecular and Cellular Probes]] |volume=21 |issue=3 |pages=171–6 |year=2007 |pmid=17161935 |doi=10.1016/j.mcp.2006.10.005}}</ref>
* [[TAS2R38]] codes for [[Phenylthiocarbamide|PTC]] tasting ability, and contains 6 annotated SNPs.<ref name="pmid15466815">{{cite journal |last1=Prodi |first1=D.A. |last2=Drayna |first2=D |last3=Forabosco |first3=P |last4=Palmas |first4=MA |last5=Maestrale |first5=GB |last6=Piras |first6=D |last7=Pirastu |first7=M |last8=Angius |first8=A |title=Bitter Taste Study in a Sardinian Genetic Isolate Supports the Association of Phenylthiocarbamide Sensitivity to the TAS2R38 Bitter Receptor Gene |journal=Chemical Senses |volume=29 |issue=8 |pages=697–702 |year=2004 |pmid=15466815 |doi=10.1093/chemse/bjh074}}</ref>
* rs148649884 and rs138055828 in the ''FCN1'' gene encoding M-ficolin crippled the ligand-binding capability of the recombinant M-ficolin.<ref>{{cite journal|last=Ammitzbøll|first=Christian Gytz|title=Non-Synonymous Polymorphisms in the FCN1 Gene Determine Ligand-Binding Ability and Serum Levels of M-Ficolin|journal=PLoS ONE|date=28|year=2012|month=November|volume=7|issue=11|page=e50585|doi=10.1371/journal.pone.0050585|url=http://www.plosone.org/article/metrics/info%3Adoi%2F10.1371%2Fjournal.pone.0050585;jsessionid=4AC8C0328F9F719694C048813A6DE49F}}</ref>
== Databases ==
As there are for genes, [[bioinformatics]] databases exist for SNPs.
''[[dbSNP]]'' is a SNP database from the [[National Center for Biotechnology Information]] (NCBI).
''[[SNPedia]]'' is a wiki-style database supporting personal genome annotation, interpretation and analysis.
The ''[[OMIM]]'' database describes the association between polymorphisms and diseases (e.g., gives diseases in text form), the Human Gene Mutation Database provides gene mutations causing or associated with human inherited diseases and functional SNPs, and [[GWAS Central]] allows users to visually interrogate the actual summary-level association data in one or more [[genome-wide association studies]]. The International SNP Map working group mapped the sequence flanking each SNP by alignment to the genomic sequence of large-insert clones in Genebank. These Alignments were converted to chromosomal coordinates that is show in Table 1 <ref name="A Map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms">{{Cite pmid|11237013}}</ref> Another database is the [[International HapMap Project]], where researches are identifying [[Tag SNP]] to be able to determine the collection of haplotypes present in each subject.
{|class="wikitable"
! Chromosome !! Length(bp) !! All SNPs !! !! TSC SNPs !!
|-
| || || SNPs || kb per SNP || SNPs || kb per SNP
|-
| 1 || 214,066,000 || 129,931 || 1.65 || 75,166 || 2.85
|-
| 2 || 222,889,000 || 103,664 || 2.15 || 76,985 || 2.90
|-
| 3 || 186,938,000 || 93,140 || 2.01 || 63,669 || 2.94
|-
| 4 || 169,035,000 || 84,426 || 2.00 || 65,719 || 2.57
|-
| 5 || 170,954,000 || 117,882 || 1.45 || 63,545 || 2.69
|-
| 6 || 165,022,000 || 96,317 || 1.71 || 53,797 || 3.07
|-
| 7 || 149,414,000 || 71,752 || 2.08 || 42,327 || 3.53
|-
| 8 || 125,148,000 || 57,834 || 2.16 || 42,653 || 2.93
|-
| 9 || 107,440,000 || 62,013 || 1.73 || 43,020 || 2.50
|-
|10 || 127,894,000 || 61,298 || 2.09 || 42,466 || 3.01
|-
|11 || 129,193,000 || 84,663 || 1.53 || 47,621 || 2.71
|-
|12 || 125,198,000 || 59,245 || 2.11 || 38,136 || 3.28
|-
|13 || 93,711,000 || 53,093 || 1.77 || 35,745 || 2.62
|-
|14 || 89,344,000 || 44,112 || 2.03 || 29,746 ||3.00
|-
|15 || 73,467,000 || 37,814 || 1.94 || 26,524 || 2.77
|-
|16 || 74,037,000 || 38,735 || 1.91 || 23,328 || 3.17
|-
|17 || 73,367,000 || 34,621 || 2.12 || 19,396 || 3.78
|-
|18 || 73,078,000 || 45,135 || 1.62 || 27,028 || 2.70
|-
|19 || 56,044,000 || 25,676 || 2.18 || 11,185 || 5.01
|-
|20 || 63,317,000 || 29,478 || 2.15 || 17,051 || 3.71
|-
|21 || 33,824,000 || 20,916 || 1.62 || 9,103 || 3.72
|-
|22 || 33,786,000 || 28,410 || 1.19 || 11,056 || 3.06
|-
|X || 131,245,000 || 34,842 || 3.77 || 20,400 || 6.43
|-
|Y || 21,753,000 || 4,193 || 5.19 || 1,784 || 12.19
|-
|RefSeq || 15,696,674 || 14,534 || 1.08 || ||
|-
|Totals || 2,710,164,000 || 1,419,190 || 1.91 ||887,450 || 3.05
|}
== 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&gt;T.<ref>{{Cite web
| author = J.T. Den Dunnen
| title = Recommendations for the description of sequence variants
| date = 2008-02-20
| accessdate = 2008-09-05
| url = http://www.hgvs.org/mutnomen/recs.html
| publisher = [[Human Genome Variation Society]]
}}</ref><ref>{{cite journal |last1=den Dunnen |first1=Johan T. |last2=Antonarakis |first2=Stylianos E. |title=Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion |journal=Human Mutation |volume=15 |issue=1 |pages=7–12 |year=2000 |pmid=10612815 |doi=10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N}}</ref><ref>{{cite journal |last1=Ogino |first1=Shuji |last2=Gulley |first2=Margaret L. |last3=Den Dunnen |first3=Johan T. |last4=Wilson |first4=Robert B. |author5=Association for Molecular Pathology Training and Education Committee |title=Standard Mutation Nomenclature in Molecular DiagnosticsPractical and Educational Challenges |journal=The Journal of Molecular Diagnostics |volume=9 |issue=1 |pages=1–6 |year=2007 |pmid=17251329 |pmc=1867422 |doi=10.2353/jmoldx.2007.060081}}</ref> SNPs are frequently referred to by their dbSNP rs number, as in the examples above.
== SNP analysis ==
Analytical methods to discover novel SNPs and detect known SNPs include:
* [[DNA sequencing]];<ref name=PMID_11029002>{{ cite journal |last1 = Altshuler |first1 = D |last2 = Pollara |first2 = V J |last3 = Cowles |first3 = C R |last4 = Van Etten |first4 = W J |last5 = Baldwin |first5 = J |last6 = Linton |first6 = L |last7 = Lander |first7 = E S |title = An SNP map of the human genome generated by reduced representation shotgun sequencing |journal = Nature |pmid = 11029002 |pages = 513–6 |issue = 6803 |volume = 407 |year = 2000 |doi=10.1038/35035083}}</ref>
* [[Capillary electrophoresis]];<ref name=PMID_16536443>{{ cite journal |last1 = Drabovich |first1 = A.P. |last2 = Krylov |first2 = S.N. |title = Identification of base pairs in single-nucleotide polymorphisms by MutS protein-mediated capillary electrophoresis |journal = Analytical chemistry |pmid = 16536443 |pages = 2035–8 |issue = 6 |volume = 78 |year = 2006 |doi=10.1021/ac0520386}}</ref>


* [[Mass spectrometry]];<ref name=PMID_10939403>{{ cite journal |last1 = Griffin |first1 = T J |last2 = Smith |first2 = L M |title = Genetic identification by mass spectrometric analysis of single-nucleotide polymorphisms: ternary encoding of genotypes |journal = Analytical chemistry |pmid = 10939403 |pages = 3298–302 |issue = 14 |volume = 72 |year = 2000 |doi=10.1021/ac991390e}}</ref>


[[Image:dna-SNP.jpg|thumb|DNA strand 1 differs from DNA strand 2 at a single base-pair location (a C/T polymorphism).]]
* Single-strand conformation polymorphism (SSCP)
A '''single nucleotide polymorphism''', or '''SNP''' (pronounced ''snip''), is a [[DNA sequence]] variation occurring when a single [[nucleotide]] - [[adenine|A]], [[thymine|T]], [[cytosine|C]], or [[guanine|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, AAGC'''C'''TA to AAGC'''T'''TA, contain a difference in a single nucleotide. In this case we say that there are two ''[[allele]]s'' : C and T. Almost all common SNPs have only two alleles.


Within a population, SNPs can be assigned a [[minor allele frequency]] - the ratio of chromosomes in the population carrying the less common variant to those with the more common variant. It is important to note that 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.  In the past, single nucleotide polymorphisms with a minor allele frequency of greater than or equal to 1% (or 0.5%, etc.) were given the title "SNP," an unwieldy definition.  With the advent of modern [[bioinformatics]] and a better understanding of evolution, this definition is no longer necessary. 
* Electrochemical analysis


Single nucleotide [[polymorphism (biology)|polymorphisms]] may fall within coding sequences of genes, [[intron|non-coding regions of genes]], or in the [[intergenic region]]s between genes. SNPs within a coding sequence will not necessarily change the [[amino acid]] sequence of the [[protein]] that is produced, due to [[Genetic code#Degeneracy of the genetic code|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 ''non-synonymous''. 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]].
* Denaturating [[HPLC]] and [[gel electrophoresis]]


Variations in the DNA sequences of humans can affect how humans develop [[disease]]s and respond to [[pathogen]]s, [[chemical]]s, [[medication|drugs]], [[vaccine]]s, and other agents. 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).
* [[Restriction fragment length polymorphism]]


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.
* Hybridization analysis


== See also ==
== See also ==
*[[Single Base Extension]]
* [[Variome]]
* [[TaqMan]]
* [[Affymetrix]]
* [[Affymetrix]]
* [[International HapMap Project]]
* [[International HapMap Project]]
* [[tag SNP]]
* [[SNP array]]
* [[Short tandem repeat]] (STR)
* [[Single-base extension]]
* [[Snpstr]]
* [[Tag SNP]]
* [[TaqMan]]
* [[Variome]]
 
==Notes==
{{Reflist|2}}


==References==
==References==
*[http://www.nature.com/nrg/journal/v5/n2/glossary/nrg1270_glossary.html Nature Reviews Glossary]
*[http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml Human Genome Project Information] &mdash; SNP Fact Sheet
*[http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml Human Genome Project Information] &mdash; SNP Fact Sheet
*[http://nci.nih.gov/cancertopics/understandingcancer/geneticvariation/Slide1 Relation of SNP's with Cancer]
*[http://nci.nih.gov/cancertopics/understandingcancer/geneticvariation/Slide1 Relation of SNP's with Cancer]


==External links==
==External links==
*[http://www.ncbi.nlm.nih.gov/About/primer/snps.html NCBI resources] - Introduction to SNPs from NCBI
*[http://www.ncbi.nlm.nih.gov/About/primer/snps.html NCBI resources] &mdash; Introduction to SNPs from NCBI
*[http://www.snpedia.com/ SNPedia] a wiki devoted to SNPs
*[http://snp.cshl.org/ The SNP Consortium LTD] — SNP search
*[http://snp.cshl.org/ The SNP Consortium LTD] — SNP search
*[http://www.ncbi.nlm.nih.gov/projects/SNP/ NCBI dbSNP database] — "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"
*[http://www.ncbi.nlm.nih.gov/projects/SNP/ NCBI dbSNP database] — "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"
*[http://www.hgmd.cf.ac.uk/ac/index.php HGMD] — the Human Gene Mutation Database, includes rare mutations and functional SNPs
*[http://www.SNPedia.com/ SNPedia] - a wiki devoted to the medical consequences of DNA variations, including software to analyze personal genomes
*[http://hapmap.org/ International HapMap Project] — "a public resource that will help researchers find genes associated with human disease and response to pharmaceuticals"
*[http://hapmap.org/ International HapMap Project] — "a public resource that will help researchers find genes associated with human disease and response to pharmaceuticals"
*[http://www.glovar.org/ Glovar Variation Browser] — variation information in a genomic context
*[http://www.gwascentral.org GWAS Central] — a central database of summary-level genetic association findings
*[http://www.1000genomes.org/ 1000 Genomes Project] &mdash; A Deep Catalog of Human Genetic Variation
*[http://sift-dna.org SIFT] — "An online tool that predicts the effect of SNPs on protein function"
*[http://genetics.bwh.harvard.edu/pph2/ PolyPhen-2] - "An online tool that predicts the effect of nonsynonymous SNPs on protein function"
*[http://www.mutationtaster.org/ MutationTaster] - "Evaluates disease-causing potential of sequence alterations"
*[http://watcut.uwaterloo.ca/watcut/watcut/template.php WatCut] — an online tool for the design of SNP-RFLP assays
*[http://watcut.uwaterloo.ca/watcut/watcut/template.php WatCut] — an online tool for the design of SNP-RFLP assays
*[http://bioinfo.iconcologia.net/index.php?module=Snpstats SNPStats] — SNPStats, a web tool for analysis of genetic association studies
*[http://insilico.ehu.es/restriction Restriction HomePage] — a set of tools for DNA restriction and SNP detection, including design of mutagenic primers
*[http://insilico.ehu.es/restriction Restriction HomePage] — a set of tools for DNA restriction and SNP detection, including design of mutagenic primers
*[http://www.aacr.org/home/public--media/for-the-media/fact-sheets/cancer-concepts/snps.aspx American Association for Cancer Research Cancer Concepts Factsheet on SNPs]  
*[http://www.aacr.org/home/public--media/for-the-media/fact-sheets/cancer-concepts/snps.aspx American Association for Cancer Research Cancer Concepts Factsheet on SNPs]
*[http://www.pharmgkb.org PharmGKB] - The Pharmacogenetics and Pharmacogenomics Knowledge Base, a   resource for SNPs associated with drug response and disease outcomes.  
*[http://www.pharmgkb.org PharmGKB] &mdash; The Pharmacogenetics and Pharmacogenomics Knowledge Base, a resource for SNPs associated with drug response and disease outcomes.
*[http://www.argusbio.com/sooryakiran/gensnip/gensnip.php GEN-SNiP] - Online tool that identifies polymorphisms in test DNA sequences.
*[http://www.argusbio.com/sooryakiran/gensnip/gensnip.php GEN-SNiP] &mdash; Online tool that identifies polymorphisms in test DNA sequences.
*[http://www.informatics.jax.org/mgihome/nomen/gene.shtml Rules for Nomenclature of Genes, Genetic Markers, Alleles, and Mutations in Mouse and Rat]
*[http://www.informatics.jax.org/mgihome/nomen/gene.shtml Rules for Nomenclature of Genes, Genetic Markers, Alleles, and Mutations in Mouse and Rat]
*[http://www.gene.ucl.ac.uk/nomenclature/guidelines.html HGNC Guidelines for Human Gene Nomenclature]
*[http://www.gene.ucl.ac.uk/nomenclature/guidelines.html HGNC Guidelines for Human Gene Nomenclature]
{{genetics}}
*[http://snpeff.sourceforge.net/ SNP effect predictor with galaxy integration]
*[http://www.hgmd.cf.ac.uk/ac/index.php Human Gene Mutation Database]
*[http://www.gwascentral.org GWAS Central]
*[http://opensnp.org/ Open SNP] — a portal for sharing own SNP test results
*[http://hapmap.ncbi.nlm.nih.gov/whatishapmap.html The HapMap Project]
 
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Revision as of 22:39, 5 November 2013

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


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

A single-nucleotide polymorphism (SNP) 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 biological species or paired chromosomes in a human. 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. Almost all common SNPs have only two alleles. The genomic distribution of SNPs is not homogenous; SNPs usually occur in non-coding regions more frequently than in coding regions or, in general, where natural selection is acting and fixating the allele of the SNP that constitutes the most favorable genetic adaptation.[1] Other factors, like genetic recombination and mutation rate, can also determine SNP density.[2]

SNP density can be predicted by the presence of microsatellites: AT microsatellites in particular are potent predictors of SNP density, with long (AT)(n) repeat tracts tending to be found in regions of significantly reduced SNP density and low GC content.[3]

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.

These genetic variations between individuals (particularly in non-coding parts of the genome) are exploited in DNA fingerprinting, which is used in forensic science . Also, these genetic variations underlie differences in our susceptibility to disease. The severity of illness and the way our body responds to treatments are also manifestations of genetic variations. For example, a single base mutation in the APOE (apolipoprotein E) gene is associated with a higher risk for Alzheimer disease.[4]

Types

Types of SNPs
  • Non-coding region
  • Coding region
    • Synonymous
    • Nonsynonymous
      • Missense
      • Nonsense

Single-nucleotide polymorphisms may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions (regions between genes). SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code.

SNPs in the coding region are of two types, synonymous and nonsynonymous SNPs. Synonymous SNPs do not affect the protein sequence while nonsynonymous SNPs change the amino acid sequence of protein. The nonsynonymous SNPs are of two types: missense and nonsense.

SNPs that are not in protein-coding regions may still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of non-coding RNA. Gene expression affected by this type of SNP is referred to as an eSNP (expression SNP) and may be upstream or downstream from the gene.

Use and importance

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 critical for personalized medicine.[5] 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) in genome-wide association studies.

The study of SNPs is also important in crop and livestock breeding programs. See SNP genotyping for details on the various methods used to identify SNPs.

SNPs are usually biallelic and thus easily assayed.[6] A single SNP may cause a Mendelian disease. For complex diseases, SNPs do not usually function individually, rather, they work in coordination with other SNPs to manifest a disease condition as has been seen in Osteoporosis.[7]

As of 26 June 2012, dbSNP listed 53,558,214 SNPs in humans.[8]

SNPs have been used in genome-wide association studies (GWAS), e.g. as high-resolution markers in gene mapping related to diseases or normal traits. The knowledge of SNPs will help in understanding pharmacokinetics (PK) or pharmacodynamics, i.e. how drugs act in individuals with different genetic variants. A wide range of human diseases, i.e Sickle–cell anemia, β Thalassemia and Cystic fibrosis result from SNPs.[9][10][11] Diseases with different SNPs may become relevant pharmacogenomic targets for drug therapy.[12] Some SNPs are associated with the metabolism of different drugs.[13][14][15] SNPs without an observable impact on the phenotype are still useful as genetic markers in genome-wide association studies, because of their quantity and the stable inheritance over generations.[16]

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.[17]
  • TAS2R38 codes for PTC tasting ability, and contains 6 annotated SNPs.[18]
  • rs148649884 and rs138055828 in the FCN1 gene encoding M-ficolin crippled the ligand-binding capability of the recombinant M-ficolin.[19]

Databases

As there are for genes, bioinformatics databases exist for SNPs. dbSNP is a SNP database from the National Center for Biotechnology Information (NCBI). SNPedia is a wiki-style database supporting personal genome annotation, interpretation and analysis. The OMIM database describes the association between polymorphisms and diseases (e.g., gives diseases in text form), the Human Gene Mutation Database provides gene mutations causing or associated with human inherited diseases and functional SNPs, and GWAS Central allows users to visually interrogate the actual summary-level association data in one or more genome-wide association studies. The International SNP Map working group mapped the sequence flanking each SNP by alignment to the genomic sequence of large-insert clones in Genebank. These Alignments were converted to chromosomal coordinates that is show in Table 1 [20] Another database is the International HapMap Project, where researches are identifying Tag SNP to be able to determine the collection of haplotypes present in each subject.

Chromosome Length(bp) All SNPs TSC SNPs
SNPs kb per SNP SNPs kb per SNP
1 214,066,000 129,931 1.65 75,166 2.85
2 222,889,000 103,664 2.15 76,985 2.90
3 186,938,000 93,140 2.01 63,669 2.94
4 169,035,000 84,426 2.00 65,719 2.57
5 170,954,000 117,882 1.45 63,545 2.69
6 165,022,000 96,317 1.71 53,797 3.07
7 149,414,000 71,752 2.08 42,327 3.53
8 125,148,000 57,834 2.16 42,653 2.93
9 107,440,000 62,013 1.73 43,020 2.50
10 127,894,000 61,298 2.09 42,466 3.01
11 129,193,000 84,663 1.53 47,621 2.71
12 125,198,000 59,245 2.11 38,136 3.28
13 93,711,000 53,093 1.77 35,745 2.62
14 89,344,000 44,112 2.03 29,746 3.00
15 73,467,000 37,814 1.94 26,524 2.77
16 74,037,000 38,735 1.91 23,328 3.17
17 73,367,000 34,621 2.12 19,396 3.78
18 73,078,000 45,135 1.62 27,028 2.70
19 56,044,000 25,676 2.18 11,185 5.01
20 63,317,000 29,478 2.15 17,051 3.71
21 33,824,000 20,916 1.62 9,103 3.72
22 33,786,000 28,410 1.19 11,056 3.06
X 131,245,000 34,842 3.77 20,400 6.43
Y 21,753,000 4,193 5.19 1,784 12.19
RefSeq 15,696,674 14,534 1.08
Totals 2,710,164,000 1,419,190 1.91 887,450 3.05

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.[21][22][23] SNPs are frequently referred to by their dbSNP rs number, as in the examples above.

SNP analysis

Analytical methods to discover novel SNPs and detect known SNPs include:

  • Single-strand conformation polymorphism (SSCP)
  • Electrochemical analysis
  • Hybridization analysis

See also

Notes

  1. ↑ Barreiro LB, Laval G, Quach H, Patin E, Quintana-Murci L. (2008). "Natural selection has driven population differentiation in modern humans". Nature Genetics. 40: 340–345. doi:10.1038/ng.78. PMID 18246066.
  2. ↑ Nachman, Michael W. (2001). "Single nucleotide polymorphisms and recombination rate in humans". Trends in genetics. 17 (9): 481–485. doi:10.1016/S0168-9525(01)02409-X. PMID 11525814.
  3. ↑ M.A. Varela and W. Amos (2010). "Heterogeneous distribution of SNPs in the human genome: Microsatellites as predictors of nucleotide diversity and divergence". Genomics. 95: 151–159. doi:10.1016/j.ygeno.2009.12.003. PMID 20026267.
  4. ↑ PMID 23159550 (PMID 23159550)
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  5. ↑ Carlson, Bruce (2008-06-15). "SNPs — A Shortcut to Personalized Medicine". Genetic Engineering & Biotechnology News. Mary Ann Liebert, Inc. 28 (12). Retrieved 2008-07-06. (subtitle) Medical applications are where the market's growth is expected
  6. ↑ Sachidanandam, Ravi; Weissman, David; Schmidt, Steven C.; Kakol, Jerzy M.; Stein, Lincoln D.; Marth, Gabor; Sherry, Steve; Mullikin, James C.; Mortimore, Beverley J. (2001). "A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms". Nature. 409 (6822): 928–33. doi:10.1038/35057149. PMID 11237013.
  7. ↑ Singh, Monica; Singh, Puneetpal; Juneja, Pawan Kumar; Singh, Surinder; Kaur, Taranpal (2010). "SNP–SNP interactions within APOE gene influence plasma lipids in postmenopausal osteoporosis". Rheumatology International. 31 (3): 421–3. doi:10.1007/s00296-010-1449-7. PMID 20340021.
  8. ↑ NCBI dbSNP build 137 for human.
  9. ↑ PMID 13369537 (PMID 13369537)
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  10. ↑ PMID 88735 (PMID 88735)
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  11. ↑ PMID 1379413 (PMID 1379413)
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  12. ↑ Fareed, M., Afzal, M (2013) "Single nucleotide polymorphism in genome-wide association of human population: A tool for broad spectrum service". Egyptian Journal of Medical Human Genetics 14: 123–134. http://dx.doi.org/10.1016/j.ejmhg.2012.08.001.
  13. ↑ PMID 11678778 (PMID 11678778)
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  14. ↑ PMID 15349140 (PMID 15349140)
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  15. ↑ PMID 16303243 (PMID 16303243)
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  16. ↑ PMID 21992066 (PMID 21992066)
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  17. ↑ Morita, Akihiko; Nakayama, Tomohiro; Doba, Nobutaka; Hinohara, Shigeaki; Mizutani, Tomohiko; Soma, Masayoshi (2007). "Genotyping of triallelic SNPs using TaqMan PCR". Molecular and Cellular Probes. 21 (3): 171–6. doi:10.1016/j.mcp.2006.10.005. PMID 17161935.
  18. ↑ Prodi, D.A.; Drayna, D; Forabosco, P; Palmas, MA; Maestrale, GB; Piras, D; Pirastu, M; Angius, A (2004). "Bitter Taste Study in a Sardinian Genetic Isolate Supports the Association of Phenylthiocarbamide Sensitivity to the TAS2R38 Bitter Receptor Gene". Chemical Senses. 29 (8): 697–702. doi:10.1093/chemse/bjh074. PMID 15466815.
  19. ↑ Ammitzbøll, Christian Gytz (28). "Non-Synonymous Polymorphisms in the FCN1 Gene Determine Ligand-Binding Ability and Serum Levels of M-Ficolin". PLoS ONE. 7 (11): e50585. doi:10.1371/journal.pone.0050585. Unknown parameter |month= ignored (help); Check date values in: |date=, |year= / |date= mismatch (help)
  20. ↑ PMID 11237013 (PMID 11237013)
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  21. ↑ J.T. Den Dunnen (2008-02-20). "Recommendations for the description of sequence variants". Human Genome Variation Society. Retrieved 2008-09-05.
  22. ↑ den Dunnen, Johan T.; Antonarakis, Stylianos E. (2000). "Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion". Human Mutation. 15 (1): 7–12. doi:10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N. PMID 10612815.
  23. ↑ Ogino, Shuji; Gulley, Margaret L.; Den Dunnen, Johan T.; Wilson, Robert B.; Association for Molecular Pathology Training and Education Committee (2007). "Standard Mutation Nomenclature in Molecular DiagnosticsPractical and Educational Challenges". The Journal of Molecular Diagnostics. 9 (1): 1–6. doi:10.2353/jmoldx.2007.060081. PMC 1867422. PMID 17251329.
  24. ↑ Altshuler, D; Pollara, V J; Cowles, C R; Van Etten, W J; Baldwin, J; Linton, L; Lander, E S (2000). "An SNP map of the human genome generated by reduced representation shotgun sequencing". Nature. 407 (6803): 513–6. doi:10.1038/35035083. PMID 11029002.
  25. ↑ Drabovich, A.P.; Krylov, S.N. (2006). "Identification of base pairs in single-nucleotide polymorphisms by MutS protein-mediated capillary electrophoresis". Analytical chemistry. 78 (6): 2035–8. doi:10.1021/ac0520386. PMID 16536443.
  26. ↑ Griffin, T J; Smith, L M (2000). "Genetic identification by mass spectrometric analysis of single-nucleotide polymorphisms: ternary encoding of genotypes". Analytical chemistry. 72 (14): 3298–302. doi:10.1021/ac991390e. PMID 10939403.

References

External links


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