A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to generally be considered polymorphic.
Gene polymorphisms can occur in any region of the genome. The majority of polymorphisms are silent, meaning they do not alter the function or expression of a gene. Some polymorphisms are visible. For example, in dogs the E locus can have any of five different alleles, known as E, Em, Eg, Eh, and e. Varying combinations of these alleles contribute to the pigmentation and patterns seen in dog coats.
A polymorphic variant of a gene can lead to the abnormal expression or to the production of an abnormal form of the protein; this abnormality may cause or be associated with disease. For example, a polymorphic variant of the gene encoding the enzyme CYP4A11, in which thymidine replaces cytosine at the gene's nucleotide 8590 position encodes a CYP4A11 protein that substitutes phenylalanine with serine at the protein's amino acid position 434. This variant protein has reduced enzyme activity in metabolizing arachidonic acid to the blood pressure-regulating eicosanoid, 20-hydroxyeicosatetraenoic acid. A study has shown that humans bearing this variant in one or both of their CYP4A11 genes have an increased incidence of hypertension, ischemic stroke, and coronary artery disease.
Most notably, the genes coding for the major histocompatibility complex (MHC) are in fact the most polymorphic genes known. MHC molecules are involved in the immune system and interact with T-cells. There are more than 32,000 different alleles of human MHC class I and II genes, and it has been estimated that there are 200 variants at the HLA-B HLA-DRB1 loci alone.
Some polymorphism may be maintained by balancing selection.
A rule of thumb that is sometimes used is to classify genetic variants that occur below 1% allele frequency as mutations rather than polymorphisms. However, since polymorphisms may occur at low allele frequency, this is not a reliable way to tell new mutations from polymorphisms.
Polymorphisms can be identified in the laboratory using a variety of methods. Many methods employ PCR to amplify the sequence of a gene. Once amplified, polymorphisms and mutations in the sequence can be detected by DNA sequencing, either directly or after screening for variation with a method such as single strand conformation polymorphism analysis.
A polymorphism can be any sequence difference. Examples include:
Polymorphisms have been discovered in multiple XPD exons. XPD refers to "xeroderma pigmentosum group D" and is involved in a DNA repair mechanism used during DNA replication. XPD works by cutting and removing segments of DNA that have been damaged due to things such as cigarette smoking and inhalation of other environmental carcinogens. Asp312Asn and Lys751Gln are the two common polymorphisms of XPD that result in a change in a single amino acid. This variation in Asn and Gln alleles has been related to individuals having a reduced DNA repair efficiency. Several studies have been conducted to see if this diminished capacity to repair DNA is related to an increased risk of lung cancer. These studies examined the XPD gene in lung cancer patients of varying age, gender, race, and pack-years. The studies provided mixed results, from concluding individuals who are homozygous for the Asn allele or homozygous for the Gln allele had an increased risk of developing lung cancer, to finding no statistical significance between smokers who have either allele polymorphism and their susceptibility to lung cancer. Research continues to be conducted to determine the relationship between XPD polymorphisms and lung cancer risk.
Asthma is an inflammatory disease of the lungs and more than 100 loci have been identified as contributing to the development and severity of the condition. By using the traditional linkage analysis, these asthma correlated genes were able to be identified in small quantities using genome-wide association studies (GWAS). There have been a number of studies looking into various polymorphisms of asthma-associated genes and how those polymorphisms interact with the carrier's environment. One example is the gene CD14, which is known to have a polymorphism that is associated with increased amounts of CD14 protein as well as reduced levels of IgE serum. A study was conducted on 624 children looking at their IgE serum levels as it related to the polymorphism in CD14. The study found that IgE serum levels differed in children with the C allele in the CD14/-260 gene based on the type of allergens they regularly exposed to. Children who were in regular contact with house pets showed higher serum levels of IgE while children who were regularly exposed to stable animals showed lower serum levels of IgE. Continued research into gene-environment interactions may lead to more specialized treatment plans based on an individual's surroundings.