Single nucleotide polymorphisms

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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.SNPs can occur in both coding and non-coding regions of genome.

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 the individuals (particularly in the non-coding parts of genome) are exploited in DNA fingerprinting, which is used in criminology. 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 Alzheimer's disease.

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.

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.

SNPs that are not in protein-coding regions may still affect gene splicing, transcription factor binding, or the sequence of non-coding RNA. Gene expression effected 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. 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. 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.

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, bioinformatics databases exist 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 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.

SNP analysis

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

- DNA sequencing;

- capillary electrophoresis;

- mass spectrometry;

- 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

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 on 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.
• Online tool that predicts on the effects of SNPs on protein function
• 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