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A single nucleotide polymorphism or simple nucleotide polymorphism, often abbreviated to just SNP (pronounced snip; plural snips), is a variation in a single nucleotide which may occur at some specific position in the genome, where each variation is present to some appreciable degree within a population (e.g. >1%).
For example, at a specific base position in the human genome, it may be that in most individuals the base C appears there; but in a minority of individuals, the base A appears at that position instead. There is an SNP at this specific base position, and the two possible nucleotide variations - C or A - are said to be alleles for this base position. Although in this example and most SNPs so far discovered there are only two different alleles, there are also triallelic SNPs in which three different base variations may coexist within a population.
SNPs underlie differences in our susceptibility to disease; a wide range of human diseases, e.g. sickle-cell anemia, β-thalassemia and cystic fibrosis result from SNPs. 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's disease.
|Types of SNPs|
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.
Within a genome
The genomic distribution of SNPs is not homogenous; SNPs occur in non-coding regions more frequently than in coding regions or, in general, where natural selection is acting and 'fixing' the allele (eliminating other variants) of the SNP that constitutes the most favorable genetic adaptation. Other factors, like genetic recombination and mutation rate, can also determine SNP density.
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.
Within a population
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. 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.
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.
SNPs' 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. SNPs have been used in genome-wide association studies as high-resolution markers in gene mapping related to diseases or normal traits. SNPs without an observable impact on the phenotype (so called silent mutations) are still useful as genetic markers in genome-wide association studies, because of their quantity and the stable inheritance over generations.
|This section requires expansion. (November 2015)|
The knowledge of SNPs will help in understanding pharmacokinetics (PK) or pharmacodynamics, i.e. how drugs act in individuals with different genetic variants. Diseases with different SNPs may become relevant pharmacogenomic targets for drug therapy. Some SNPs are associated with the metabolism of different drugs.
A single SNP may cause a Mendelian disease, though 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.
All types of SNPs can have an observable phenotype or can result in disease:
- SNPs in non-coding regions can manifest in a higher risk of cancer, and may affect mRNA structure and disease susceptibility.
- SNPs in coding regions:
- synonymous substitutions by definition do not result in a change of amino acid in the protein, but still can affect its function in other ways. An example would be a seemingly silent mutation in the multidrug resistance gene 1 (MDR1), which codes for a cellular membrane pump that expels drugs from the cell, can slow down translation and allow the peptide chain to fold into an unusual conformation, causing the mutant pump to be less functional.
- nonsynonymous substitutions:
- missense - single change in the base results in change in amino acid of protein and its malfunction which leads to disease (e.g. c.1580G>T SNP in LMNA gene - position 1580 (nt) in the DNA sequence (CGT codon) causing the guanine to be replaced with the thymine, yielding CTT codon in the DNA sequence, results at the protein level in the replacement of the arginine by the leucine in the position 527, at the phenotype level this manifests in overlapping mandibuloacral dysplasia and progeria syndrome)
- nonsense - point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product (e.g. Cystic fibrosis caused by the G542X mutation in the cystic fibrosis transmembrane conductance regulator gene).
- rs6311 and rs6313 are SNPs in the Serotonin 5-HT2A receptor gene on human chromosome 13.
- A SNP in the F5 gene causes Factor V Leiden thrombophilia.
- 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.
- rs148649884 and rs138055828 in the FCN1 gene encoding M-ficolin crippled the ligand-binding capability of the recombinant M-ficolin.
As there are for genes, bioinformatics databases exist for SNPs.
- dbSNP is a SNP database from the National Center for Biotechnology Information (NCBI). As of 8 June 2015[update], dbSNP listed 149,735,377 SNPs in humans.
- Kaviar is a compendium of SNPs from multiple data sources including dbSNP.
- 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
- The International HapMap Project, where researchers are identifying Tag SNP to be able to determine the collection of haplotypes present in each subject.
- 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 shown in Table 1.
|Chromosome||Length(bp)||All SNPs||TSC SNPs|
|Total SNPs||kb per SNP||Total SNPs||kb per SNP|
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. SNPs are frequently referred to by their dbSNP rs number, as in the examples above.
SNPs are usually biallelic and thus easily assayed. Analytical methods to discover novel SNPs and detect known SNPs include:
- DNA sequencing;
- capillary electrophoresis;
- mass spectrometry;
- single-strand conformation polymorphism (SSCP);
- single-base extension;
- electrochemical analysis;
- denaturating HPLC and gel electrophoresis;
- restriction fragment length polymorphism;
- hybridization analysis;
Programs for prediction of SNP effects
An important group of SNPs are those that corresponds to missense mutations causing amino acid change on protein level. Point mutation of particular residue can have different effect on protein function (from no effect to complete disruption its function). Usually, change in amino acids with similar size and physico-chemical properties (e.g. substitution from leucine to valine) has mild effect, and opposite. Similarly, if SNP disrupts secondary structure elements (e.g. substitution to proline in alpha helix region) such mutation usually may affect whole protein structure and function. Using those simple and many other machine learning derived rules a group of programs for the prediction of SNP effect was developed:
- International HapMap Project
- SNP array
- SNP genotyping
- SNV calling from NGS data
- Short tandem repeat (STR)
- Single-base extension
- Tag SNP
- SNP Annotation
- "single nucleotide polymorphism / SNP | Learn Science at Scitable". www.nature.com. Retrieved 2015-11-13.
- Hodgkinson, Alan; Eyre-Walker, Adam (November 2, 2009). "Human Triallelic Sites: Evidence for a New Mutational Mechanism?". Genetics. doi:10.4172/2157-7145.1000107.
- Ingram, V. M. (1956). "A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin". Nature 178 (4537): 792–794. doi:10.1038/178792a0. PMID 13369537.
- Chang, J. C.; Kan, Y. W. (1979). "Beta 0 thalassemia, a nonsense mutation in man". Proceedings of the National Academy of Sciences of the United States of America 76 (6): 2886–2889. doi:10.1073/pnas.76.6.2886. PMC 383714. PMID 88735.
- Hamosh, A.; King, T. M.; Rosenstein, B. J.; Corey, M.; Levison, H.; Durie, P.; Tsui, L. C.; McIntosh, I.; Keston, M.; Brock, D. J.; Macek, M.; Zemková, D.; Krásničanová, H.; Vávrová, V.; Macek, M.; Golder, N.; Schwarz, M. J.; Super, M.; Watson, E. K.; Williams, C.; Bush, A.; O'Mahoney, S. M.; Humphries, P.; Dearce, M. A.; Reis, A.; Bürger, J.; Stuhrmann, M.; Schmidtke, J.; Wulbrand, U.; Dörk, T. (1992). "Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus". American journal of human genetics 51 (2): 245–250. PMC 1682672. PMID 1379413.
- Wolf, A. B.; Caselli, R. J.; Reiman, E. M.; Valla, J. (2012). "APOE and neuroenergetics: An emerging paradigm in Alzheimer's disease". Neurobiology of Aging 34 (4): 1007–17. doi:10.1016/j.neurobiolaging.2012.10.011. PMID 23159550.
- Barreiro LB; Laval G; Quach H; Patin E; Quintana-Murci L. (2008). "Natural selection has driven population differentiation in modern humans". Nature Genetics 40 (3): 340–345. doi:10.1038/ng.78. PMID 18246066.
- 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.
- M.A. Varela & W. Amos (2010). "Heterogeneous distribution of SNPs in the human genome: Microsatellites as predictors of nucleotide diversity and divergence". Genomics 95 (3): 151–159. doi:10.1016/j.ygeno.2009.12.003. PMID 20026267.
- 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
- Thomas, P. E.; Klinger, R.; Furlong, L. I.; Hofmann-Apitius, M.; Friedrich, C. M. (2011). "Challenges in the association of human single nucleotide polymorphism mentions with unique database identifiers". BMC Bioinformatics 12: S4. doi:10.1186/1471-2105-12-S4-S4. PMC 3194196. PMID 21992066.
- 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. doi:10.1016/j.ejmhg.2012.08.001.
- Goldstein, J. A. (2001). "Clinical relevance of genetic polymorphisms in the human CYP2C subfamily". British journal of clinical pharmacology 52 (4): 349–355. doi:10.1046/j.0306-5251.2001.01499.x. PMC 2014584. PMID 11678778.
- Lee, C. R. (2004). "CYP2C9 genotype as a predictor of drug disposition in humans". Methods and findings in experimental and clinical pharmacology 26 (6): 463–472. PMID 15349140.
- Yanase, K.; Tsukahara, S.; Mitsuhashi, J.; Sugimoto, Y. (2006). "Functional SNPs of the breast cancer resistance protein ‐ therapeutic effects and inhibitor development". Cancer Letters 234 (1): 73–80. doi:10.1016/j.canlet.2005.04.039. PMID 16303243.
- 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.
- Li, G.; Pan, T.; Guo, D.; Li, L. C. (2014). "Regulatory Variants and Disease: The E-Cadherin -160C/A SNP as an Example". Mol Biol Int 2014: 967565. doi:10.1155/2014/967565. PMC 4167656. PMID 25276428.
- Lu, Yi-Fan; Mauger, David M.; Goldstein, David B.; Urban, Thomas J.; Weeks, Kevin M.; Bradrick, Shelton S. (4 November 2015). "IFNL3 mRNA structure is remodeled by a functional non-coding polymorphism associated with hepatitis C virus clearance". Scientific Reports 5: 16037. doi:10.1038/srep16037.
- Kimchi-Sarfaty, C.; Oh, JM.; Kim, IW.; Sauna, ZE.; Calcagno, AM.; Ambudkar, SV.; Gottesman, MM. (Jan 2007). "A "silent" polymorphism in the MDR1 gene changes substrate specificity". Science 315 (5811): 525–8. doi:10.1126/science.1135308. PMID 17185560.
- Al-Haggar M; Madej-Pilarczyk A; Kozlowski L; Bujnicki JM; Yahia S; Abdel-Hadi D; Shams A; Ahmad N; Hamed S; Puzianowska-Kuznicka M (2012). "A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome". Eur J Hum Genet. 20 (11): 1134–40. doi:10.1038/ejhg.2012.77. PMC 3476705. PMID 22549407.
- Cordovado, SK.; Hendrix, M.; Greene, CN.; Mochal, S.; Earley, MC.; Farrell, PM.; Kharrazi, M.; Hannon, WH.; Mueller, PW. (Feb 2012). "CFTR mutation analysis and haplotype associations in CF patients". Mol Genet Metab 105 (2): 249–54. doi:10.1016/j.ymgme.2011.10.013. PMC 3551260. PMID 22137130.
- Giegling I; Hartmann AM; Möller HJ; Rujescu D (November 2006). "Anger- and aggression-related traits are associated with polymorphisms in the 5-HT-2A gene". Journal of Affective Disorders 96 (1–2): 75–81. doi:10.1016/j.jad.2006.05.016. PMID 16814396.
- Kujovich, J. L. (Jan 2011). "Factor V Leiden thrombophilia". Genet Med 13 (1): 1–16. doi:10.1097/GIM.0b013e3181faa0f2. PMID 21116184.
- 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.
- 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.
- Ammitzbøll, Christian Gytz; Kjær, Troels Rønn; Steffensen, Rudi; Stengaard-Pedersen, Kristian; Nielsen, Hans Jørgen; Thiel, Steffen; Bøgsted, Martin; Jensenius, Jens Christian (28 November 2012). "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.
- National Center for Biotechnology Information, United States National Library of Medicine. 2014. NCBI dbSNP build 142 for human. http://www.ncbi.nlm.nih.gov/mailman/pipermail/dbsnp-announce/2014q4/000147.html
- National Center for Biotechnology Information, United States National Library of Medicine. 2015. NCBI dbSNP build 144 for human. Summary Page. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_summary.cgi?view+summary=view+summary&build_id=144
- Glusman, G; Caballero, J; Mauldin, D. E.; Hood, L; Roach, J. C. (2011). "Kaviar: An accessible system for testing SNV novelty". Bioinformatics 27 (22): 3216–7. doi:10.1093/bioinformatics/btr540. PMC 3208392. PMID 21965822.
- Sachidanandam, R.; Weissman, D.; Schmidt, S. C.; Kakol, J. M.; Stein, L. D.; Marth, G.; Sherry, S.; Mullikin, J. C.; Mortimore, B. J.; Willey, D. L.; Hunt, S. E.; Cole, C. G.; Coggill, P. C.; Rice, C. M.; Ning, Z.; Rogers, J.; Bentley, D. R.; Kwok, P. Y.; Mardis, E. R.; Yeh, R. T.; Schultz, B.; Cook, L.; Davenport, R.; Dante, M.; Fulton, L.; Hillier, L.; Waterston, R. H.; McPherson, J. D.; Gilman, B.; Schaffner, S. (2001). "A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms". Nature 409 (6822): 928–933. doi:10.1038/35057149. PMID 11237013.
- J.T. Den Dunnen (2008-02-20). "Recommendations for the description of sequence variants". Human Genome Variation Society. Retrieved 2008-09-05.
- 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.
- 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.
- Sachidanandam, Ravi; Weissman, David; Schmidt, Steven C.; Kakol, Jerzy M.; Stein, Lincoln D.; Marth, Gabor; Sherry, Steve; Mullikin, James C.; et al. (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.
- 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.
- 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.
- 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.
- Tahira, T.; Kukita, Y.; Higasa, K.; Okazaki, Y.; Yoshinaga, A.; Hayashi, K. (2009). "Estimation of SNP allele frequencies by SSCP analysis of pooled DNA". Methods Mol Biol. Methods in Molecular Biology 578: 193–207. doi:10.1007/978-1-60327-411-1_12. ISBN 978-1-60327-410-4. PMID 19768595.
- Nature Reviews Glossary
- Human Genome Project Information — SNP Fact Sheet
- Relation of SNP's with Cancer
- NCBI resources — Introduction to SNPs from NCBI
- The SNP Consortium LTD — SNP search
- NCBI dbSNP database — "a central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms"
- HGMD — the Human Gene Mutation Database, includes rare mutations and functional SNPs
- SNPedia - a wiki devoted to the medical consequences of DNA variations, including software to analyze personal genomes
- International HapMap Project — "a public resource that will help researchers find genes associated with human disease and response to pharmaceuticals"
- GWAS Central — a central database of summary-level genetic association findings
- 1000 Genomes Project — A Deep Catalog of Human Genetic Variation
- WatCut — an online tool for the design of SNP-RFLP assays
- SNPStats — SNPStats, a web tool for analysis of genetic association studies
- Restriction HomePage — a set of tools for DNA restriction and SNP detection, including design of mutagenic primers
- American Association for Cancer Research Cancer Concepts Factsheet on SNPs
- PharmGKB — The Pharmacogenetics and Pharmacogenomics Knowledge Base, a resource for SNPs associated with drug response and disease outcomes.
- GEN-SNiP — Online tool that identifies polymorphisms in test DNA sequences.
- Rules for Nomenclature of Genes, Genetic Markers, Alleles, and Mutations in Mouse and Rat
- HGNC Guidelines for Human Gene Nomenclature
- SNP effect predictor with galaxy integration
- Human Gene Mutation Database
- GWAS Central
- Open SNP — a portal for sharing own SNP test results
- The HapMap Project