Induced mutations are those that increase the rate of mutation above the spontaneous background.
All cells on Earth are exposed to a plethora of agents called mutagens, which have the potential to damage DNA and cause induced mutations.
Some of these agents, such as some fungal toxins, cosmic rays, and ultraviolet light, are natural components of our environment.
Others, including some industrial pollutants, medical X rays, and chemicals within tobacco smoke, can be considered as unnatural or human-made additions to our modern world.
On the positive side, geneticists harness some mutagens for use in analyzing genes and gene functions.
The mechanisms by which some of these natural and unnatural agents lead to mutations are outlined in this section.
1) Role of Base Analog in induced mutation
One category of mutagenic chemicals is base analogs, compounds that can substitute for purines or pyrimidines during nucleic acid biosynthesis.
For example, 5-bromouracil (5-BU), a derivative of uracil, behaves as a thymine analog but is halogenated at the number 5 position of the pyrimidine ring.
If 5-BU is chemically linked to deoxyribose, the nucleoside analog bromodeoxyuridine (BrdU) is formed.
The presence of the bromine atom in place of the methyl group increases the probability that a tautomeric shift will occur.
If 5-BU is incorporated into DNA in place of thymine and a tautomeric shift to the enol form occurs, 5-BU base-pairs with guanine.
After one round of replication, an A = T to G≡C transition results.
Furthermore, the presence of 5-BU within DNA increases the sensitivity of the molecule to ultraviolet (UV) light, which itself is mutagenic.
There are other base analogs that are mutagenic.
For example, 2-amino purine (2-AP) can act as an analog of adenine.
In addition to its base-pairing affinity with thymine, 2-AP can also base-pair with cytosine, leading to possible transitions from A = T to G≡C following replication.
2) Alkylating, Intercalating, and Adduct-Forming Agents cause induced mutation
A number of naturally occurring and human-made chemicals alter the structure of DNA and cause induced mutations.
The sulfur-containing mustard gases, discovered during World War I, were some of the first chemical mutagens identi-fied in chemical warfare studies.
Mustard gases are alkylating agents—that is, they donate an alkyl group, such as CH3 or CH3CH2, to amino or keto groups in nucleotides.
Ethylmethane sulfonate (EMS), for example, alkylates the keto groups in the number 6 position of guanine and in the number 4 position of thymine.
As with base analogs, base-pairing affinities are altered, and transition mutations result. For example, 6-ethylguanine acts as an analog of adenine and pairs with thymines.
Intercalating agents are chemicals that have dimensions and shapes that allow them to wedge between the base pairs of DNA.
When bound between base pairs, intercalating agents cause base pairs to distort and DNA strands to unwind.
These changes in DNA structure affect many functions including transcription, replication, and repair.
Deletions and insertions occur during DNA replication and repair, leading to frameshift mutations.
Some intercalating agents are used as DNA stains.
An example is ethidium bromide, a fluorescent compound.
That is commonly used in molecular biology laboratories to visualize DNA during purifications and gel electrophoresis.
The mutagenic characteristics of both ethidium bromide and the ultraviolet light used to visualize its fluorescence, that mean this chemical must be used with caution.
Other intercalating agents are used for cancer chemotherapy.
Examples are doxorubicin, which is used to treat Hodgkin’s lymphoma and dactinomycin, which is used to treat a variety of sarcomas.
Because cancer cells undergo into DNA replication more frequently than noncancer cells.
They are more sensitive than normal cells to the mutagenic and damaging effects of these chemotherapeutic agents.
Another group of chemicals that cause induced mutations are known as adduct-forming agents.
A DNA adduct is a substance that covalently binds to DNA, altering its conformation and interfering with replication and repair.
Two examples of adduct-forming substances are,
- acetaldehyde (a component of cigarette smoke)
- heterocyclic amines (HCAs).
HCAs are cancer-causing chemicals that are created during the cooking of meats such as beef, chicken, and fish.
HCAs are formed at high temperatures from amino acids and creatine. Many HCAs covalently bind to guanine bases.
At least 17 different HCAs have been linked to the development of cancers, such as those of the stomach, colon, and breast
3) Ultraviolet Light leads induced mutation
All electromagnetic radiation consists of energetic waves that we define by their different wavelengths.
The full range of wavelengths is referred to as the electromagnetic spectrum, and the energy of any radiation in the spectrum varies inversely with its wavelength.
Waves in the range of visible light and longer are benign when they interact with most organic molecules.
However, waves of shorter length than visible light, being inherently more energetic, have the potential to disrupt organic molecules.
As we know, purines and pyrimidines absorb ultraviolet (UV) radiation most intensely at a wavelength of about 260 nm.
Although Earth’s ozone layer absorbs the most dangerous types of UV radiation, suf-ficient UV radiation can induce thousands of DNA lesions per hour in any cell exposed to this radiation.
One major effect of UV radiation on DNA is the creation of pyrimidine dimers—chemical species consisting of two identical pyrimidines—particularly ones consisting of two thymine residues.
The dimers distort the DNA conformation and inhibit normal replication.
As a result, errors can be introduced in the base sequence of DNA during replication.
When UV-induced dimerization is extensive, it is responsible (at least in part) for the killing effects of UV radiation on cells.
4) Ionizing Radiation causes induced mutation
As noted above, the energy of radiation varies inversely with wavelength.
Therefore, X rays, gamma rays, and cosmic rays are more energetic than UV radiation.
As a result, they penetrate deeply into tissues, causing ionization of the molecules encountered along the way.
Hence, this type of radiation is called ionizing radiation.
As ionizing radiation penetrates cells, stable molecules and atoms are transformed into free radicals—chemical species containing one or more unpaired electrons.
Free radicals can directly or indirectly affect the genetic material.
Altering purines and pyrimidines in DNA, breaking phosphodiester bonds, disrupting the integrity of chromosomes, and producing a variety of chromosomal aberrations, such as deletions, translocations, and chromosomal fragmentation.
Given the capacity of ionizing radiation to cause serious genetic damage.
It is important to consider what levels of radiation are mutagenic in humans and what sources of ionizing radiation cause the most damage in everyday life.
There is a linear relationship between X-ray dose and the induction of mutation; for each doubling of the dose, twice as many mutations are induced.
Because the line intersects near the zero axis, this graph suggests that even very small doses of radiation are mutagenic.
Although it is often assumed that radiation from artificial sources such as nuclear power plant waste and medical X rays are the most significant sources of radiation exposure for humans, scientific data indicate otherwise.
Scientists estimate that less than 20 percent of human radiation exposure arises from human-made sources.
The annual radiation exposure for humans residing in the United States.
As these data indicate, the greatest radiation exposure comes from radon gas, cosmic rays, and natural soil radioactivity.
More than half of human-made radiation exposure comes from medical X rays and radioactive pharmaceuticals.