Types of DNA Mutations: Point, Chromosomal and Genomic Mutations, Causes and Consequences

Gene or Molecular Mutations (Point Mutations)

Point mutations are punctual mutations that affect one or more of the nucleotides of DNA. They are observed only with the electron microscope and can be of two types:

Substitution Mutations

Substitution mutations produce the change of one base for another in a given position. Depending on which bases are exchanged, these mutations are classified as:

• Transition mutations: a purine base changes to another purine (A → G), or a pyrimidine changes to another pyrimidine (T → C).
• Transversion mutations: a purine base changes to a pyrimidine (A, G → T, C), or a pyrimidine changes to a purine (T, C → A, G).

Frameshift Mutations

Frameshift mutations occur when base pairs are added or deleted, altering the length of the cDNA. They are classified as:

• Deletion mutations: when one or more nucleotides are lost from the cDNA.
• Insertion mutations: when, on the contrary, additional nucleotides are inserted into the cDNA, and the rest of the nucleotides of the DNA are displaced.

Consequences of Point Mutations on Proteins

Point mutations can have four consequences for the PROTEIN:

• Silent mutation: it does not alter the sequence of the PROTEIN, does not change the amino acid, or occurs in introns, or involves synonymous codons that encode the same amino acid, for example: AGA (Arg) → AGG (Arg).
• Missense mutation: a new triplet is produced that encodes a different amino acid, so the PROTEIN has one amino acid changed. This is what happens in the hemoglobin of sickle cell anemia, where the sixth amino acid, glutamic acid, is replaced by valine: GAG (Glu) → GUG (Val).
• Nonsense mutation: it produces a termination codon, for example CAG (Gln) → UAG (Stop), so the PROTEIN is shorter.
• Frameshift mutation: occurs when the reading frame changes due to the addition or deletion of a number of nucleotides that is not a multiple of 3. The displacement of the reading frame produces a completely different PROTEIN from that of the point mutation.

Chromosomal Mutations

Chromosomal mutations are changes in the structure of the chromosome and, therefore, are visible under the microscope. They alter the normal frequency of recombination of chromosomes during meiosis, which reduces fertility. They can be of four types:

• Inversion: a mutation in which a chromosome fragment is reversed. The gene sequence of the fragment is reversed relative to its original chromosome.
• Deletion: a mutation involving the loss of a chromosome fragment.
• Duplication: a mutation in which a chromosome fragment is repeated.
• Translocation: a mutation that changes the chromosomal position of a fragment. It may be reciprocal if fragments are exchanged between two chromosomes, and non-reciprocal, in which case it is called transposition.

Karyotype or Genomic Mutations

These mutations affect the number of chromosomes, which are visible under the microscope. They can be of two types:

Euploidy

Euploidy mutations affect the number of complete haploid sets of chromosomes. They can be:

• Polyploidy: when there are more than two complete haploid sets of chromosomes. Thus, triploid (3n), tetraploid (4n) individuals, etc. are obtained. In plants, polyploidy is often accompanied by an increase in the size of the specimens. In humans, triploidy is responsible for numerous spontaneous abortions; in this case the karyotype is 69 or 69,XXX, 69,XXY.
• Monoploidy (haploidy): when there is only one set of chromosomes.

Aneuploidy

Aneuploidy mutations affect only the number of one particular chromosome pair. They can be:

• Nullisomy: the complete pair is absent.
• Monosomy: one chromosome of a pair is missing. In humans, the most frequent monosomy is Turner syndrome (XO), a sexual monosomy.
• Trisomy: there is an extra chromosome in a pair. In humans, the most frequent trisomies are Trisomy 21 (Down syndrome), Trisomy 18 (Edwards syndrome), Trisomy 13 (Patau syndrome), triple X syndrome (XXX), Klinefelter syndrome (XXY), and XYY syndrome (double Y).
• Tetrasomy: there are two extra pairs of a chromosome in the set.

Causes of Mutations

Depending on the mutagenic agent that originates them, mutations can be of two types: spontaneous and induced.

Spontaneous Mutations

They are mainly due to:

• Replication errors: the most common are due to tautomerism, a type of isomerism.
• Random DNA lesions: they can be caused by depurination, which is the breakage of the glycosidic bond between the purine base and deoxyribose; by deamination, which is the loss of amino groups; or by oxidative damage to DNA caused by free radicals such as oxygen (O₂), hydrogen peroxide (H₂O₂) or hydroxyl (OH−), originating from metabolism.
• Transposable genetic elements or transposons: DNA sequences that can change position within the genome. As they move, they generate deletions and insertions in the genes where they are inserted.

Induced Mutations

Induced mutations arise as a consequence of exposure to mutagenic radiations, chemicals or other agents:

• Base analogue mutagens replace a normal base in DNA, being analogues of the known bases.
• Mutagens that alter base pairing cause incorrect pairings.
• Intercalating mutagens insert themselves between the nitrogenous bases of DNA and cause insertions or deletions.
• Mutagens that cause specific loss of base pairing produce major damage, causing nitrogenous bases to be lost during DNA replication.
• Ultraviolet light causes the formation of pyrimidine dimers through covalent bonds between adjacent pyrimidines.
• Ionizing radiation, such as X-rays or gamma rays, can break bonds and fragment the phosphodiester backbone of DNA.