Structural Biochemistry/Genome Analysis/Single Nucleotide Polymorphisms (SNPs)

Identification of Single Nucleotide Polymorphisms (SNPs)Edit

Major efforts have been made in recent years to identify the SNPs in the Human Genome. While previously known as base substitutions, the term SNP has become more common, indicating the importance of this frequent type of base substitution in molecular genetics. An SNP refers to an abundant base substitution, which differs from a rare substitution in that the population has a frequency of greater than 1% of the least abundant allele. Due to the high density of SNPs in genomes, several can usually be located within a few hundred base pairs. Thus, they are a rich source of information for population studies, and the association of genetic factors with disease states.

SNPs are used constantly in the field of disease study. For instance, they are used to identify the multiple genes that are involved in such common diseases such as cancer, diabetes, and certain versions of mental illness.

Polymorphisms and DiseaseEdit

Approximately five hundred human methyltransferase polymorphisms have been identified and have been linked to disease. A polymorphic hotspot was identified at approximately 20 angstrom from the active site in four out of seven protein studied in the research performed by Karen Rutherford and Valerie Daggett. Simulations outlining the molecular dynamics of proteins demonstrated a mutual mechanism of destabilization. The common mechanism is the fact that the mutations change the side chain contacts within the polymorphic site that are sent throughout the protein causing a distortion to the active site. One theory is that these hot spots may have evolved to modulate enzymatic activity.

Single nucleotide polymorphisms occur at a frequency of 1 in every 1000 nucleotide bases of the 3 billion base human genome. SNPs can affect mRNA transcription, structure, enzymatic activity, and stability. Catechol O-methyltransferase (COMT) is a protein displayed to have ample inter-individual differences in enzymatic activity. Restriction fragment length polymorphism mapping acknowledged that the alterations in activity are accredited to a valine to methionine substitution. The alternative consequently decreased the levels in vivo. This substitution has been linked with an increased risk of breast cancer and neuropsychiatric diseases.

Thiopurine S-methyltransferase (TMPT) is at fault for the metabolism of cytotoxic thioputine drugs employed to medicate multiple conditions like leukemia and inflammatory bowel disease. In eleven percent of the population there has been more than twenty TPMT polymorphisms. NMR is important to understanding how the polymorphism affects protein structure and dynamics because structure dictates function. Molecular dynamic (MD) studies are of peak interest when understanding the effects of polymorphism because aggregation or stability issues do not bother them. MD allows one to notice how the mutations affect protein structure at an atomic level. MD demonstrates how COMT and TMPT polymorphisms affect structural detail. Research has demonstrated that polymorphisms contain destabilizing effects. TPMT was found to decrease the levels of immunological protein. Researchers now contain much epidemiological data for the wild type and variant COMT and TMPT proteins that make them more likely to be studied through MD simulations. The data known can be applied to molecule development for the stabilization of protein structure and activators for the treatments of diseases.

SNP Study ExamplesEdit

The effect of genetic variability on drug response in conventional breast cancer treatment. [1]

Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction [2]

Genetic polymorphisms of infectious diseases in case-control studies [3]

Bayesian statistical methods for genetic association studies [4]

Conjuring SNPs to detect associations [5]


1. Vignal, Alain, Denis Milan, Magali SanCristobal, and Andre Eggen. "A Review on SNP and Other Types of Molecular Markers and Their Use in Animal Genetics." Genetics Selection Evolution 34.3 (2002): 275-305. Print.

2. Rutherford, Karen, and Valerie Daggett. "Polymorphisms and Disease: Hotspots of Inactivation in Methyltransferases." Trends in Biochemical Sciences 35.10 (2010): 531-38. Print.