• Mutations are heritable changes in the DNA.
• They are essential to the study of genetics and are useful in many
other biological fields.
• Somatic mutations: occur in non reproductive cells.
• Germ-line mutations: occur in cells that give rise to gametes.
Mutations that are a result of natural changes in DNA structure.
1. All types of point mutations can occur spontaneously,
during S, G1 and G2 phases of the cell cycle, or by the
movement of transposons.
2. The spontaneous mutation rate in eukaryotes is between
10-4-to-10-6 per gene per generation, and in bacteria and
a. Genetic constitution of the organism affects its mutation rate.
i. In Drosophila, males and females of the same strain have
similar mutation rates.
ii. Flies of different strains, however, may have different
b. Many spontaneous errors are corrected by the cellular repair
systems, and so do not become fixed in DNA.
• Purine and pyrimidine bases exist in different chemical forms called
• The positions of protons in the DNA bases change.
Wobble base pairing
• Normal, protonated, and other forms of the bases are able to
pair because of flexibility in the DNA helical structure
• Strand slippage may occur when one nucleotide strand forms a small loop .
• If the looped-out nucleotides are on the newly synthesized strand, an
Unequal crossing over
• During normal crossing over, the homologous sequences of the two DNA
molecules align, and crossing over produces no net change in the number
of nucleotides in either molecule.
• Misaligned pairing may cause unequal crossing over
• which results in one DNA molecule with an insertion and the other with a
Spontaneous Chemical Changes
• Depurination: the loss of a purine base from a nucleotide.
• Deamination: the loss of an amino group (NH2) from a base.
• Deamination may occur spontaneously or be induced by mutagenic
• Mutations those that result from changes caused by environmental
chemicals or radiation are called as induced mutations.
• A number of environmental agents are capable of damaging DNA including
certain chemicals and radiation.
• Mutagen: Any environmental agent that significantly increases the rate of
mutation above the spontaneous rate.
• The first discovery of a chemical mutagen was made by Charlotte
• chemicals with structures similar to that of any of the four standard bases
• DNA polymerases cannot distinguish these analogs from the standard
• so, if base analogs are present during replication, they may be
incorporated into newly synthesized DNA molecules.
• Eg. 5-Bromouracil
• chemicals that donate alkyl groups. These agents include methyl (CH3)
and ethyl (CH3–CH2) groups, which are added to nucleotide bases by
• Example, ethylmethanesulfonate (EMS) adds an ethyl group to guanine,
producing 6-ethylguanine, which pairs with thymine.
• In addition to its spontaneous occurrence, deamination can be induced by
• E.g.: nitrous acid deaminates cytosine, creating uracil, which in the next
round of replication pairs with adenine producing a CG:TA transition
• Hydroxylamine is a very specific base modifying mutagen that adds a
hydroxyl group to cytosine.
• It converts cytosine into hydroxylaminocytosine .
• This conversion increases the frequency of a rare tautomer.
• The tautomer pairs with adenine instead of guanine and leads to CG:TA
• Because hydroxylamine acts only on cytosine, it will not generate TA:CG
• Reactive forms of oxygen damage DNA and induce mutations by bringing
about chemical changes to DNA.
• Reactive forms of oxygen includes:
• Superoxide radicals
• Hydrogen peroxide
• Hydroxyl radicals
• They are produced in the course of normal aerobic metabolism, as well as
by radiation, ozone, peroxides, and certain drugs.
• Intercalating agents produce mutations by sandwiching themselves
(intercalating) between adjacent bases in DNA .
• They distorts the three-dimensional structure of the helix and causing
single-nucleotide insertions and deletions in replication.
• These insertions and deletions frequently produce frameshift mutations.
• And so the mutagenic effects of intercalating agents are often severe.
• Because intercalating agents generate both additions and deletions, they
can reverse the effects of their own mutations.
• E.g. : proflavin, acridine orange, ethidium bromide, and dioxin
• Ionizing radiation breaks covalent bonds including those in DNA and is the
leading cause of chromosome mutations.
• Ionizing radiation also frequently results in double-strand breaks in DNA
• Ionizing radiation has a cumulative effect and kills cells at high doses.
• UV (254-260 nm) causes purines and pyrimidines to form abnormal dimer
bonds and bulges in the DNA strands.
• Eg : UV,X-Rays etc.
• Presence of two or more populations of cells with
different genotypes in one individual who has developed from
a single fertilized egg.
• The phenomenon was discovered by Curt Stern.
• Somatic cells of the body are of more than one genotype.
• Different genotypes arise from a single fertilized egg cell, due to
mitotic errors at first or later cleavages.
• In rare cases, Intersex conditions can be caused by mosaicism where some
cells in the body have XX and others XY chromosomes (46, XX/XY).
• Milder forms of Klinefelter syndrome, called 46/47 XY/XXY mosaic where
in some of the patient's cells contain XY chromosomes, and some contain
• Around 30% of Turner's syndrome cases demonstrate mosaicism, while
complete monosomy (45,X) occurs in about 50–60% of cases.
• Gonadal mosaicism or germline mosaicism is a special form of mosaicism,
where some gametes, i.e. either sperm or oocytes, carry a mutation, but
the rest are normal.
• The cause is usually a mutation that occurred in an early stem cell that
gave rise to all or part of the gonadal tissue.
• This can cause only some children to be affected, even for a dominant
Factors inducing mosaicism
• Endogenous factors: Mobile elements, DNA polymerase slippage, and
unbalanced chromosomal segregation.
• Exogenous factors :Nicotine and UV radiation.
• Somatic mosaics have been created in Drosophila using x-ray treatment
and the use of irradiation to induce somatic mutation has been a useful
technique in the study of genetics.
Reference & further reading
• Benjamin A. Pierce Genetics A Conceptual Approach 3rd edition
W.H.Freeman and Company New York.
• Gerald Karp Cell and Molecular biology – Concepts and Experiments 6th
edition John Wiley & Sons Inc.
• Bruce Alberts Molecular biology of the Cell.
• Jeff Hardin Gregory Bertoni Lewis J. Kleinsmith BECKER’S World of the Cell
8th edition Benjamin Cummings.