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A
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
is said to be polymorphic if more than one
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
occupies that gene's
locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award' ...
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, E
m, E
g, E
h, 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
Cytochrome P450 4A11 is a protein that in humans is codified by the ''CYP4A11'' gene.
Function
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reacti ...
, in which
thymidine
Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. I ...
replaces
cytosine
Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...
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
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
to the blood pressure-regulating
eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-c ...
,
20-hydroxyeicosatetraenoic acid
20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regula ...
. A study has shown that humans bearing this variant in one or both of their CYP4A11 genes have an increased incidence of
hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, ischemic
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
, and
coronary artery disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
.
Most notably, the genes coding for the
major histocompatibility complex
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
(MHC) are in fact the most polymorphic genes known. MHC molecules are involved in the immune system and interact with
T-cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
. There are more than 32,000 different
alleles
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
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 Balancing selection refers to a number of selective processes by which multiple alleles (different versions of a gene) are actively maintained in the gene pool of a population at frequencies larger than expected from genetic drift alone. Balancing ...
.
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
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s rather than polymorphisms. However, since polymorphisms may occur at low allele frequency, this is not a reliable way to tell new mutations from polymorphisms.
Identification
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
DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. Th ...
, either directly or after screening for variation with a method such as
single strand conformation polymorphism analysis.
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
Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, ...
.
*
Small-scale insertions/deletions (Indels) consist of insertions or deletions of bases in DNA.
* Polymorphic repetitive elements. Active
transposable element
A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...
s 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.
*
Microsatellite
A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. ...
s 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
Clinical significance
Lung cancer
Polymorphisms have been discovered in multiple XPD exons. XPD refers to "
xeroderma pigmentosum
Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in sun- ...
group D" and is involved in a
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
mechanism used during
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
. 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
carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
s. 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-year
A pack-year is a clinical Quantification (science), quantification of cigarette smoking used to measure a person's exposure to Tobacco products, tobacco. This is used to assess their risk of developing lung cancer or other pathologies related to t ...
s. 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
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
In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varia ...
(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.
References
{{Reflist, 33em
Genes
Polymorphism (biology)