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Single-nucleotide polymorphism

Single nucleotide in genomic DNA at which different sequence alternatives exist

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For example, a G nucleotide present at a specific location in a reference genome may be replaced by an A in a minority of individuals. The two possible nucleotide variations of this SNP – G or A – are called alleles.

SNPs can help explain differences in susceptibility to a wide range of diseases across a population. For example, a common SNP in the CFH gene is associated with increased risk of age-related macular degeneration. Differences in the severity of an illness or response to treatments may also be manifestations of genetic variations caused by SNPs. For example, two common SNPs in the APOE gene, rs429358 and rs7412, lead to three major APO-E alleles with different associated risks for development of Alzheimer's disease and age at onset of the disease.

Single nucleotide substitutions with an allele frequency of less than 1% are sometimes called single-nucleotide variants. "Variant" may also be used as a general term for any single nucleotide change in a DNA sequence, encompassing both common SNPs and rare mutations, whether germline or somatic. The term single-nucleotide variant has therefore been used to refer to point mutations found in cancer cells. DNA variants must also commonly be taken into consideration in molecular diagnostics applications such as designing PCR primers to detect viruses, in which the viral RNA or DNA sample may contain single-nucleotide variants. However, this nomenclature uses arbitrary distinctions (such as an allele frequency of 1%) and is not used consistently across all fields; the resulting disagreement has prompted calls for a more consistent framework for naming differences in DNA sequences between two samples.

Types

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 SNPs and nonsynonymous SNPs. Synonymous SNPs do not affect the protein sequence, while nonsynonymous SNPs change the amino acid sequence of protein.

  • SNPs in non-coding regions can manifest in a higher risk of cancer, and may affect mRNA structure and disease susceptibility. Non-coding SNPs can also alter the level of expression of a gene, as an eQTL (expression quantitative trait locus).
  • 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 (in MDR1 protein e.g. C1236T polymorphism changes a GGC codon to GGT at amino acid position 412 of the polypeptide (both encode glycine) and the C3435T polymorphism changes ATC to ATT at position 1145 (both encode isoleucine)).
    • 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).

SNPs that are not in protein-coding regions may still affect gene splicing, transcription factor binding, messenger RNA degradation, or the sequence of noncoding 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.

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