Date:

Assignment:
19-11-2018 Cell and
Molecular Biology
Submitted To:
Dr: Khalid Mahmood Anjum

Sbmitted By:
Azeemullah Tariq (2016-AZ-020)
Farhan Aslam (2016-AZ-007)
Muhammad Tazeem Munawar
(2016-AZ-032)
Muzzammil Hussain (2016-AZ-016)
Muhammad Zohaib (2016-AZ-037)

Topic:

Mutations,their types and

classification.

University of Veterinary
and Animal Sciences
Lahore.
Mutations:
What is Mutation?
“In biology a mutation is the permanent alteration of the nucleotide sequence of genetic material
of an organism,virus,or extrachromosomal DNA or other genetic elements”
The errors during DNA replication (usually during meiosis),and various types of damages in
DNA (may caused by exposure of DNA to radiations or carcinogens),and errors during repairs of
DNA leads to mutations. Mutations can also result from by insertion or deletion of segments of
DNA due to mobile genetic elements.The Observeable characteristics (phenotype) of an
organism may or may not be changed in result of Mutations.
Mutations play a great role in both normal and abnormal biological processes which includes:
evolution, cancer, and the development of the immune system, also including junctional
diversity.RNA virus genomes are based on RNA rather than DNA.It may be double stranded (as
in DNA) or may be single stranded. In some of these viruses (such as the single stranded HIV)
replication occurs quickly and there is no mechanism to check the accuracy of genome. This
error prone process often cause mutations.
Mutation can result in many different types of changes in sequences. Mutations in genes can may
have no effect, or alter the product of a gene, or prevent the gene from functioning properly.
Mutations may also be occur in nongenic regions. The studies on genetic variations in different
species of Drosophila(house fly) suggests that, if mutation change a protein that is produced by
a gene, the result is very harmful, with an estimated 70 percent of amino acid polymorphisms
that have damaging effects, and the remainings are being either neutral or usually beneficial. The
damaging effects can be corrected by reverted the mutated sequence in a processs called DNA
repairing.
Description:
Mutations can also involve the duplications of larger sections of DNA, usually through genetic
recombination. These duplications of DNA act as a major source of raw material for evolving the
new genes, with tens to hundreds of genes duplicated in animal genomes every million years.
The most of genes belong to the large gene families of shared ancestry, which can be detected
by their sequence homology.
There are several methods to produce Novel genes,commonly by duplication and mutation of
ancestral gene,or may be produced by recombining the parts of different genes to form new
combinations of which also have new functions.Each type of protein domain has particular and
independent function,these proteins can be mixed together for producing genes that encoding
new proteins with novel properties.
For Example: The human eye requires four genes to make the structure that can sense the light.
Eye uses three genes for cone cells (color vision) and one gene for rod cells (for night vision);all
these four genes arise from a single ancestral gene.
The advantage of duplicating a gene is that this can increases engineering redundancy. This
engineering redundancy is beneficial that allows the one gene of the pair to perform a new
function while other copy of gene perform the original function.
The changes in the chromosome numbers may leads to even larger mutations, in which
segments of the DNA within the chromosomes breaks and then rearranged. For example in the
Homininae, two chromosomes fused to produce human chromosome 2 this fusion did not takes
place in the families of the other apes and they retain these separate chromosomes.
Nonlethal mutations may accumulate within the gene pool and can increase the amount of
genetic variations. The abundance of some genetic changes in the gene pool can be reduced by
natural selection while other "more favorable" mutations may accumulate and result in adaptive
changes.
For example;offsprings with new mutations are produced by butterfly. The majority of these
mutations usually have no harmful effect but one mutation may change the color of one of the
butterfly's offsprings making them harder (or easier) for predators to see them.If this mutation
(color change) is advantageous then the chances of survival will increase and over a period of
time the small number of these butterflies form a larger population.
Neutral mutations can be defined as mutations whose effect do not fluctuate the fitness of an
organism. They can may be increase in frequency over time due to the genetic drift. The
overwhelming majority of these mutations can not effect the fitness of an organism.The DNA
repair mechanism can correct most changes before they converted to permanent changes.
Beneficial mutations can be improve reproductive success of and organism.
Causes of mutations:
The major causes and explanation of mutations are describe below.
(1) Spontaneous mutations ( also called molecular decay).
(2) Mutations due to error prone replication by pass of naturally occurring DNA damage
(3) Mutations caused due to errors in DNA during repair.
(4) Induced mutations that are caused by mutagens.
Mutant sequences can also used by scientists for different types of scientific experiments and
researches.
(1) Spontaneous mutation
Spontantaneous mutation is a mutation that arise naturally without exposure to mutagens.They
can be characterized by the specific change
(a) Tautomerism:
Change in the position of hydrogen atom results in changing in H_bonding pattern of that base
that cause mutation during replication.
(b) Depurination:
Depurination results in loss of purine bases like Adenine and Guanine which form apurinic site
often called AP site.
(c) Deamination:
Due to hydrolysis replacement of a keto group in place of amine group of a normal base is called
Deamination.Examples include C → U and A → HX
(d) Slipped strand mispairing
During replication, denaturation of the new strand from the template followed by renaturation, in
a different spot (slipping). This may results in insertion or deletion.
(2) Error-prone replication bypass
The evidences shows that the majority of spontaneously arising mutations occur due to error-
prone replication often called translesion synthesis past DNA damage in the template strand.
For example:
The oxidative DNA damages that occur naturally arise at least ten thousand( 10,000) times per
cell in a day in the human beings and fifty thousand (50,000) times or more per cell in a day in
rats. Translesion synthesis is responsible for majority of mutations in mice.
3) Errors introduced during DNA repair
As we know that naturally occurring double strand breaks occur oftenly at a low frequency in
DNA So, their repair usually causes mutations. A major pathway for repairing double-strand
breaks is Non-homologous end joining (NHEJ)
NHEJ do this by removal of some nucleotides to allows inaccurate alignment of the two ends
for rejoining caused by addition of nucleotides to fill these gaps. As a result, NHEJ cause
mutations.
(4) Induced mutation
When genes are exposed to mutagens,the alteration in genes takes place.It may be due
environmental causes.These are called induced mutations.
On molecular level induced mutations can be caused by:
 Chemicals
 Hydroxylamine
 Base analogs
These are chemicals have similar structure as of purines or pyrimidines and can be mix in
nucleotide and act as mutagen. e.g;, 5- bromouracil is a known analogue of thymine and
can be blend in DNA in place of thymine.
 Alkylating agents: like N-ethyl-nitrosorea,(ENU) these are harmful mutagens and have
capacity to mutate replicating and non replicating DNA.
 (e.g., N-ethyl-N-nitrosourea (ENU)).Both replicating and non replicating DNA can be
mutated by these agents. In contrast to ENU, the base analogs can only mutate the DNA
when analog is incorporated in replicating the DNA.The mutagens of these classes have
certain effects that then lead to transitions, transversions(purine is replaced with
pyrimidine), or deletions.
 DNA intercalating agents.for example; ethidium bromide.Have strong capacity to mutate
DNA then other classes of mutagens.
 DNA crosslinkers
 Oxidative damage (oxidative damage of DNA usually occurs at guanine bases due to
high oxidative potential of guanine leads to diseases and cancer)
 Nitrous acid a mutagen that converts amine groups on A and C to the diazo groups that
alter pattern of their hydrogen bonding which consequently leads to incorrect base
pairing during replication.
 Radiations also induced mutations.
 Ultraviolet light (UV) (non-ionizing radiations)
 The two nucleotide bases in DNA the cytosine and thymine are very sensitive
toradiations. The properties of these bases are changed by radiations
 Ionizing radiations:
Ionizing radiations like gamma radiations leads to mutations and cause cancer or death.
Classification of types
(1) By effect on structure
The sequence of a gene (or nucleotide) can be changed in a number of ways. The mutations in
genes have changing effects on health that depends on where they occur and whether they
change the function of essential proteins. The structural mutations can be classified into
following categories:
(1) Small-scale mutations
One or a few nucleotides affected by small-scale mutations.
Point Mutation:
If single nucleotide is affected this type of mutation is called point mutation.
Small scale mutations may includes :
(a) Insertions
Addition of one or more nucleotides into the DNA.. They either caused by jumping genes or in
errors during replication of repeating elements. Addition in the coding region of gene can
change splicing of the mRNA ( so called splice site mutation), or cause a transfer of the reading
frame (frameshift), both of these change the gene product.
These Insertions can be reversed by handling the transposable element.(jumping genes).
(b) Deletions
Removal of one or more nucleotide(s) from the DNA. Like insertion, deletions change the
reading frame of the gene.Generally these are irreversible.
(c) Substitution mutations:
Substitution is a mutation in which one base pair exchange with the other base pair in the
genome.
Like Adenine shifts into Guanine,and Guanine shifts into Adenine.As a result of substitution in a
codon change occur which results in the change in formation of specific amino acids that cause a
change in protein.
For example; Sickle cell anemia , a common genetic disease in which mutations distorts the red
blood cells to sickle shape when these are deoxygenated.These sickle cells accumulate in
capillaries and stop blood circulation.
(2) Large-scale mutations
In large scale mutations the structure of chromosomes changes.
Further classified into following types
(a) Amplifications:
Increase in the dosage of genes located within chromosomes by addition of multiple copies of
chromosomes.Examples include Down’s Syndrome and klinfelter Syndrome.
Down’s Syndrome
In this type of non-disjunction 21st pair of chromosome fail to segregate,that result in gametes
with 24 chromosomes.After fertilization the new individual have 47(2n+1) chromosomes.The
effected organisms have flat and broad face,squint eyes,protruding tongue,mental retardation and
defective development of CNS.
Klinefelter’s Syndrome
The individuals affected with Klinefelter’s Syndrome have additional chomosomes e.g. 47
chromosomes (44 autosomes + XXY).These are phenotypically males but have under developed
secondary sex characters.
There is also possibility of males with 48 chromosomes(44 autosomes+XXXY) and with 49
chromosomes(44 autosomes+XXXXY).
(b) Deletions
In deletions of large chromosomal regions genes in these regions are lost.
Turner’s Syndrome
The individuals affected with Turner’s syndrome have one missing X chromosome with only 45
chromosomes (44 autosomes + X). Organisms with these conditions usually do not survive
pregnancy and are aborted.But if they survive ,have female appearance with short stature,webbed
neck,without ovaries and absence of germ cells.
(c) chromosomal rearrangement
Structural change in the chromosome by large scale mutations called chromosomal
rearrangement, that not only results in decrease of fitness but also to speciation in isolated,
inbred populations.
chromosomal rearrangements include:
Chromosomal translocations:
In which non homologous chromosomes interchange the genetic part.
Chromosomal inversions:
Inverting the orientation in chromosomal segmenents.
(2) By effect on function
Loss-of-function mutations:
It is also called inactivating (non fuctional) mutations, in which resulting gene product having
less or no function (may partially or completely inactivated). When there is complete loss in
allele function(called null allele) this mutation often called an amorph or amorphic mutation.
Gain-of-function mutations:
These are also called activating mutations change the gene product in such a way that effect
stronger (enhanced activation) or even is subtituted by a different and abnormal function.
Dominant negative mutations:
These are also called antimorphic mutations have an altered gene product that acts antagonistic
to the wild-type allele. These mutations often result in change of molecular function.
For example: In humans, these dominant negative mutations results in cancer.
(3) By effect on fitness
Fitness affects may be of following three types
i. Deleterious
ii. Advantageous
iii. Neutral
Harmful Mutations may be harmful(deleterious) or beneficial (advantageous). Theoretical
population genetics uses advantageous and deleterious mostly instead of harmful or beneficial.
Beneficial mutations increases fitness to a organisam by promoting favourable traits.
neutral mutation are neutral neither harm nor benefits to organisam but it might be slightly
beneficial or harmful to the organisam. In most of the cases neutral mutation are with deleterious
affect. It occurs in steady rate and provide base for genetic drift in most variation at molecular
level.
(4) By impact on protein sequence:

(a) Frameshift mutation

 Occurs by deletion or insertion of nucleotides that are not divisible
from three of DNA sequence . Insersion or deletion disrupt reading
frame or grouping of codon resulting in complete different
translation.
(b) Point mutation
Point mutation results due to change in one nucleotide sequence and have its two forms
synonymous and nonsynonmous
i. Synonymous
Neucleotides is changed with codon of same neucleotide so that sequence
of amino acid is not changed. If no phenotypic affect is produced then it is
called silient mutation but all synonymous are not silient .
ii. Non synonymous
Neucleotide is changed with codon of another amino acid ,sequence of amino acid will be
changed .it may be of following two types.

a. Missense mutation
Change neucleotide causes substitution of different amino acid .it
can render resulting protein non functional.
b. Non sense mutation
Mutation in sequence of DNA results in premature stop codon .protein product might be
nonfuctional.

(5) By inheritance:
i. Germline mutation
ii. Somatic mutation
Germline mutation occur in germ cells and transform to next generation while somation
mutations occur in somatic cells and can shift to next generation. Diploid organisam contain two
allel for each trait, on this base we can classify mutation into three classes
a. Heterozygous
Mutation of only one allele
b. Homozygous mutation
Identical mutation of both maternal and paternal alleles
 c. Compound heterozygous mutation
Have two different mutation in paternal and maternal mutation
Mutation rates:
Mutation rates changes across species, evolutionary forces determine mutations are the main
subject of ongoing investigation
(a) Harmful mutations:
Changes in DNA by mutation cause errors in protein sequence, creating completed or
uncompleted non-functional protein.
 When a mutation changes a protein that play a role in body, a medical conditions result.
 Some mutations changes DNA base sequence but do not alter the function of protein
which are made up of protein.
 The study of genes among different species of Drosophila suggests if mutations changes
protein it will be harmful.
 It is estimated that 70 percent of amino acid polymorphisms have damaging effects, the
reminder either natural or weekly beneficial
 DNA damage cause an error when DNA is replicated, this error cause a gene mutation
that could cause a genetic diseases.
 DNA which are damaged are repaired by the DNA repaired system of the cells.
 If DNA damage give rise to mutation than mutation cannot be repaired.
 If mutations occurs in a gene sequence then it has normal DNA structures and cannot be
repaired.
(b) Beneficial mutations:
The mutations which are benefit to organisms are called beneficial mutations.
 Beneficial mutations is sustained in the populations and stored in the form of
adaptions in the evolution.
 Whereas deleterious is not sustained and is removed by the natural selection.
 Neutral mutations are stored by genetic drift.
 The effect of mutations depends upon the environment.
Example:
 Nylonase is an example of beneficial mutations
 Nylonase bacteria eat short molecules of nylon (nylon-6).
  Nylonase are used in wastewater treatment in plants.
 Antibiotics are used for the treatment of diseases which are caused by bacteria.
 But if we use the antibodies again and again bacteria developed a resistance
against the antibodies.
 The bacteria which are resistant do not have the ability to produce as those
without mutation thus slowing down the diseases.
(c) Prions mutation:
Prions are proteins which causes several fatal neurodegenerative diseases in human
and animals.
 These do not contain genetic material.
 The human gene PRNP, it codes for the major prion proteins, PrP, which
causes a mutations that produce the disease causing prions.
(d) Somatic mutation:
A variation in the genetic structures that is not passed through the parents and also
not passed to offspring is called a somatic mutations.
 Somatic mutation is not a inherited because it do not effect the germ line.
 Somatic mutations is promoted by environmental factor i.e ultraviolet radiation and
other chemicals and lead to disease including cancer.
 Human and mice somatic cells have a mutation rate more than ten times higher
than the germ line mutation rate for both species.
 Mice have a high rate of both somatic and germ line m divisions than humans.
 A great difference in mutation between the germ line and somatic tissues reflect
the greater importance of genome maintained in the germ line than in soma
(e) Amorphic mutation:
 An amorph, a term introduced by Muller in 932
 Amorph is a mutated allele lost the ability of parent allele to encode any
functional protein
 Amorph mutation caused by the replacement of an amino acid that deactivates
an enzyme or by the deletion of part of a gene that produce the enzyme.
 Point mutation arise from sponatious mutations that occur during DNA
replication.
  The rate of mutation may increased by mutagens. Mutagens are physical i.e
radiation from UV rays, X rays, or chemicals.
 Mutagens which are associated with cancer are studied to learn about cancer
and its preventation.
(f) Hypomorphic and hypermorphic mutations:
 Hypermorphic is a replacement of amino acids that hide enzymatic activity.
 Usually are recessive but cause some allele to be dominant.
 Hypermprphic change the regulation of gene and causes it to overproduce the
gene produce causing a greater than normal enzyme level
 These are dominant function of alleles.
References:
(1) https://ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutat
ion
(2) https://www.nih.gov/.../most-tumors-body-share-important-
mutations
(3) https://www.ncbi.nlm.nih.gov/books/NBK21578
(4) https://medicalxpress.com
(5) www.mheresearchfoundation.org
(6) https://en.m.wikipedia.org