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 biological species or 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. 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] Besides natural selection other factors like recombination and mutation rate can also determine SNP density. SNP density can be predicted by the presence of microsatellites as regions of thousands of nucleotides flanking microsatellites have an increased or decreased density of SNPs depending on the microsatellite sequence.[2]
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 as a SNP allele that is common in one geographical or ethnic group may be as much rarer in another.
These genetic variations between the individuals (particularly in the non-coding parts of genome) are exploited in DNA fingerprinting, which is used in forensic science. Also, these genetic variations underlie differences in our susceptibility to, or protection from all kinds of diseases. The severity of illness and the way our body responds to treatments are also manifestations of genetic variations. For example, a single base difference in the Apolipoprotein E is associated with a higher risk for Alzheimer's disease.
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Types
Types of SNPs |
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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.
A SNP in which both alleles produce the same polypeptide sequence is called a synonymous polymorphism (sometimes called a silent mutation). If a different polypeptide sequence is produced the polymorphism is a replacement polymorphism. A replacement polymorphism change may be either missense, which results in a different amino acid, or nonsense, which results in a premature stop codon. Over half of all known disease mutations come from replacement polymorphisms.[3]
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 thought to be key enablers in realizing the concept of personalized medicine.[4] 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 genotyping). See SNP genotyping for details on the various methods used to identify SNPs.
They are usually biallelic and thus easily assayed.[5] 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.[6]
As of October 2011, dbSNP listed 52 million SNPs in humans.[7]
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.[8]
- TAS2R38 codes for PTC tasting ability, and contains 6 annotated SNPs.[9]
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 genetic association studies.
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.[10][11][12] 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;[13]
- capillary electrophoresis;[14]
- mass spectrometry;[15]
- single-strand conformation polymorphism (SSCP);
- electrochemical analysis;
- denaturating HPLC and gel electrophoresis;
- restriction fragment length polymorphism;
- hybridization analysis;
See also
- Single-base extension
- SNP array
- Variome
- TaqMan
- Affymetrix
- International HapMap Project
- tag SNP
- Short tandem repeat (STR)
- Snpstr
Notes
- ^ 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. PMID 18246066.
- ^ 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.
- ^ Stenson, PD; Mort, M, Ball, EV, Howells, K, Phillips, AD, Thomas, NS, Cooper, DN (2009-01-22). "The Human Gene Mutation Database: 2008 update.". Genome medicine 1 (1): 13. PMID 19348700.
- ^ Carlson, Bruce (2008-06-15). "SNPs — A Shortcut to Personalized Medicine". Genetic Engineering & Biotechnology News (Mary Ann Liebert, Inc.) 28 (12). http://www.genengnews.com/gen-articles/snps-a-shortcut-to-personalized-medicine/2507/. Retrieved 2008-07-06. "(subtitle) Medical applications are where the market's growth is expected"
- ^ 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.
- ^ 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.
- ^ NCBI dbSNP build 135 for human.
- ^ 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.
- ^ J.T. Den Dunnen (2008-02-20). "Recommendations for the description of sequence variants". Human Genome Variation Society. http://www.hgvs.org/mutnomen/recs.html. 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 Patholpogy Training and Education Committtee (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1867422.
- ^ 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.
References
- Nature Reviews Glossary
- Human Genome Project Information — SNP Fact Sheet
- Relation of SNP's with Cancer
External links
- 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
- SIFT — "An online tool that predicts the effect of SNPs on protein function"
- PolyPhen-2 - "An online tool that predicts the effect of nonsynonymous SNPs on protein function"
- MutationTaster - "Evaluates disease-causing potential of sequence alterations"
- 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
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