Gene polymorphism

A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population.^[1] 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.^[2]

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.^[3] Some polymorphisms are visible. For example, in dogs the E locus can have any of five different alleles, known as E, E^m, E^g, E^h, and e.^[4] Varying combinations of these alleles contribute to the pigmentation and patterns seen in dog coats.^[5]

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

Some polymorphism may be maintained by balancing selection.

Differences between gene polymorphism and mutation

A rule of thumb that is sometimes used is to classify genetic variants that occur below 1% allele frequency as mutations rather than polymorphisms.^[8] However, since polymorphisms may occur at low allele frequency, this is not a reliable way to tell new mutations from polymorphisms.^[9] A mutation is a change to an inherited genetic sequence.

• In unicellular organisms, there isn't a distinction.
• In multi-cellular organisms which replicate via sexual reproduction nearly all mutations are not passed on to subsequent generations. A mutation may, or may not, be passed on to off-spring (e.g. if is a mutation that happens in some replicating cells that are not part of the germline, none of the off-spring will bear the mutation.
  • For example, a mutation may occur in a skin cell as a result of
    ultraviolet light resulting in a thiamine dimer which is not properly repaired before the skin cell undergoes mitosis
    and divides.
  • This is quite distinct from a mutation which occurs during meiosis, which can be subsequently passed on to future generations, and it is very helpful to be clear when discussing mutations whether it is a somatic mutation or gemline mutation.^[10]

In the case of

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.^[14]

Types

A polymorphism can be any sequence difference. Examples include:

• Single nucleotide polymorphisms (SNPs) are a single nucleotide changes that happen in the genome in a particular location. The single nucleotide polymorphism is the most common form of genetic variation.^[15]
• Small-scale insertions/deletions (Indels) consist of insertions or deletions of bases in DNA.^[16]
• Polymorphic repetitive elements. Active transposable elements can also cause polymorphism by inserting themselves in new locations. For example, repetitive elements of the Alu and LINE1 families cause polymorphisms in human genome.^[17]
• Microsatellites are repeats of 1-6 base pairs of DNA sequence. Microsatellites are commonly used as a molecular markers especially for identifying the relationship between alleles^[18]

Clinical significance

Many different human disease result from polymorphisms. Polymorphisms also play significant role as risk factors for development of disease.

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.^[23] Asp312Asn and Lys751Gln are the two common polymorphisms of XPD that result in a change in a single amino acid.^[24] This variation in Asn and Gln alleles has been related to individuals having a reduced DNA repair efficiency.^[25] 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,^[26] to finding no statistical significance between smokers who have either allele polymorphism and their susceptibility to lung cancer.^[27] Research continues to be conducted to determine the relationship between XPD polymorphisms and lung cancer risk.

As a cornerstone of

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.[29] 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.^[30] 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.^[31] 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.^[31] Continued research into gene-environment interactions may lead to more specialized treatment plans based on an individual's surroundings.

References