The most common form of human variation is the single nucleotide polymorphism, known as SNPs or sometimes pronounced ‘snips’. An SNP is the alteration of a single nucleotide in the genetic sequence. For example, the presence of an adenosine in a small portion of the population and cytosine in the rest of the population would be a cytosine to adenine transition and considered as an SNP. An SNP may also be the insertion of a nucleotide into the sequence or the deletion of a nucleotide from the sequence. A variant must have a minor allele frequency of at least 1% to be considered polymorphic.
The Effect of Single Nucleotide Polymorphisms
The effect of an SNP varies depending on its location in a gene. When present in the coding region, the alteration may alter the amino acid sequence of the encoded protein, cause a frameshift, truncate the protein, or have no effect at all. These changes may then alter the functionality and/or activation of the protein, the localization of the protein, the stability and lifespan of the protein, or have no effect at all.
If an SNP occurs in the promoter region of a gene, the portion of the genetic sequence where the transcriptional machinery binds by recognizing short nucleotide sequences, the polymorphism can possibly affect the binding of the transcription factors. These types of changes may affect the rate or efficiency of gene transcription, potentially altering mRNA levels, which could consequently alter protein levels.
Alteration of Gene Transcription Regulation
An SNP in the promoter region is the most common type of regulatory polymorphism, which is a DNA element that modifies the level of transcription. However, even this regulation is complex because the actions of transcription factors are context-dependent; the presence or absence of nearby proteins affects the transcriptional activity of a gene. Some transcription factors only bind transiently, regardless of increased amounts of protein. Because human genes respond differently to the same set of factors and stimuli, it is difficult to predict the transcriptional response of a gene just by knowing its sequence.
Gene Variants and Disease
Association studies are performed to determine the allele frequency of variants in populations of patients with a disease and healthy individuals. A higher frequency of a variant in patients, as determined by statistical analyses to determine significance of the association, is evidence that the allele is associated with an increased risk of the disease. A polymorphism may affect risk directly, as mentioned regarding transcriptional regulation, or it may be a marker for a nearby genetic variant that affects risk.
Genetic Disease Research
New technologies developed to study the human genome and newly acquired maps of the human genome have allowed researchers to study SNPs and their possible relationships with disease. The International HapMap Consortium is a project to sequence the human genome and identify SNPs in multiple populations of differing ethnic backgrounds. Other databases and research groups have made their genotyping results for SNPs available online, but some of them are not yet confirmed to occur in the proportion of the population necessary to be deemed polymorphic variants with certainty (i.e. 1%). Understanding the connection between genes and disease is an ongoing struggle.
References:
Kruglyak, L. and Nickerson, D. A. Variation is the spice of life. Nature Genetics 27: 234-236, 2001.
Orphanides, G. and Reinberg, D. A unified theory of gene expression. Cell 108: 439-451, 2002.
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