2. A mutation at the molecular level refers to any
addition, deletion or substitution of the
nucleotide bases in the DNA. DNA is
composed of four different nucleotide bases,
and the order of these bases forms a code for
amino acids, which are the building blocks of
protein.
MUTATIONS
3.
4. TYPES OF MUTATIONS
• The mutation is a process that produces a gene or
chromosome that differs from the wild type (arbitrary
standard for what “normal” is for an organism).
• The mutation may result due to changes either on the
gene or the chromosome itself. Thus, broadly mutation
maybe:
• Gene mutation where the allele of a gene changes.
• Chromosome mutation where segments of
chromosomes, whole chromosomes, or entire sets of
chromosomes change.
5. TYPES OF MUTATIONS
There are various schemes for classification of different
kind of mutations. Depending on:
THE TYPE OF CELL INVOLVED
1. SOMATIC MUTATIONS
• Mutations that are in the somatic tissues of the body.
• Mutations are not transmitted to progeny.
• The extent of the phenotypic effect depends upon
whether the mutation is dominant or recessive
(dominant mutations generally have a greater effect).
• The extent of the phenotypic effect depends upon
whether it occurs early or late in development (early
arising mutations have a greater effect).
6. GERMINAL MUTATIONS
• Mutations that are in the germ tissues of the body.
• Mutations may be transmitted to progeny
• Dominant mutations are seen in first generation
after the mutation occurs
• If a female gamete containing an X-linked
mutation is fertilized, the males will show the
mutant phenotype
• Recessive mutations will only be seen upon the
chance mating with an individual carrying the
recessive allele too; thus, the recessive mutation
may remain hidden for many generations
7.
8.
9. SILENT MUTATION
• A silent mutation, or point mutation, refers to a
change a single nucleotide base. When this
occurs, a different base substitutes for a nucleotide
base yet still codes for the same amino acid. The
nucleotide bases code for amino acids in groups
of three bases, known as codons. Some amino
acids are coded through multiple codons, meaning
that there can be more than one group of three
bases which codes for that amino acid. In a silent
mutation, the substituted base results in a codon
that still codes for the same amino acid. Because
the same amino acid is coded for, there is no effect
on the final protein made from the gene.
10. MISSENSE MUTATION
Missense mutation: This type of
mutation is a change in one DNA base
pair that results in the substitution of one
amino acid for another in the protein
made by a gene.
11. NONSENSE MUTATION
• Nonsense mutation: A nonsense mutation is
also a change in one DNA base pair. Instead
of substituting one amino acid for another,
however, the altered DNA sequence
prematurely signals the cell to stop building
a protein. This type of mutation results in a
shortened protein that may function
improperly or not at all.
12. FRAMESHIFT MUTATION
• Insertion or deletion of nucleotide bases in
multiples other than three causes a frameshift
mutation. Because codons are read in groups of
three bases, insertion or deletion of one or two
bases causes a shift in the reading frame of the
codons. This causes coding of completely
different amino acids and leads to the production
of a completely different protein. This resulting
random coding can also cause a stop codon to be
coded for in the middle of a gene, leading not
only to a completely different protein but also a
truncated one.
13.
14. CONSERVATIVE MUTATIONS
• Conservative mutations result in an amino acid
change. However, the properties of the amino
acid remain the same (e.g., hydrophobic,
hydrophilic, etc.). At times, a change to one
amino acid in the protein is not detrimental to
the organism as a whole. Most proteins can
withstand one or two point mutations before
their function changes.
15. NON-CONSERVATIVE
MUTATIONS
• Non-conservative mutations result in an amino acid change
that has different properties than the wild type. The protein
may lose its function, which can result in a disease in the
organism. For example, sickle-cell disease is caused by a
single point mutation (a missense mutation) in the beta-
hemoglobin gene that converts a GAG codon into GUG,
which encodes the amino acid valine rather than glutamic
acid. The protein may also exhibit a "gain of function" or
become activated, such is the case with the mutation
changing a valine to glutamic acid in the BRAF gene; this
leads to an activation of the RAF protein which causes
unlimited proliferative signalling in cancer cells.[5] These
are both examples of a non-conservative (missense)
mutation.
17. DIRECTION OF MUTATION
• According to their mode of direction following
types of mutations have been recognised:
1. Forward mutations
• In an organism when mutations create a change
from wild type to abnormal phenotype, then that
type of mutations are known as forward
mutations. Most mutations are forward type.
2. Reverse or back mutations
• The forward mutations are often corrected by
error correcting mechanism, so that an abnormal
phenotype changes into wild type phenotype.
18. SIZE AND QUALITY
• According to size following two types of mutations
have been recognized:
• Point mutation
When heritable alterations occur in a very small
segment of DNA molecule, i.e., a single nucleotide
or nucleotide pair, then this type of mutations are
called “point mutations”. The point mutations may
occur due to following types of subnucleotide
change in the DNA and RNA.
• Substitution mutation. A point mutation in which a
nucleotide of a triplet is replaced by another
nucleotide, is called substitution mutation.
19. MULTIPLE MUTATIONS OR GROSS
MUTATIONS
• When changes involving more than one nucleotide pair, or entire gene, then
such mutations are called gross mutations. The gross mutations occur due to
rearrangements of genes within the genome. It may be:
• The rearrangement of genes may occur within a gene. Two mutations within the
same functional gene can produce different effects depending on gene whether
they occur in the cis or trans position.
• The rearrangement of gene may occur in number of genes per chromosome. If
the numbers of gene replicas are non-equivalent on the homologous
chromosomes, they may cause different types of phenotypic effects over the
organisms.
• Due to movement of a gene locus new type of phenotypes may be created,
especially when the gene is relocated near heterochromatin. The movement of
gene loci may take place due to following method:
• (i) Translocation. Movement of a gene may take place to a non-homologous
chromosome and this is known as translocation.
20. • INSERTION OR DELETION: An insertion
changes the number of DNA bases in a gene
by adding a piece of DNA. A deletion removes
a piece of DNA. Insertions or deletions may be
small (one or a few base pairs within a gene)
or large (an entire gene, several genes, or a
large section of a chromosome). In any of
these cases, the protein made by the gene may
not function properly.
21.
22.
23.
24.
25. Duplication: A duplication consists of a piece of DNA
that is abnormally copied one or more times. This type
of mutation may alter the function of the resulting
protein.
26.
27.
28.
29.
30.
31.
32. FRAMESHIFT MUTATION: This type of mutation
occurs when the addition or loss of DNA bases changes a
gene’s reading frame. A reading frame consists of groups
of 3 bases that each code for one amino acid. A frameshift
mutation shifts the grouping of these bases and changes
the code for amino acids. The resulting protein is usually
nonfunctional. Insertions, deletions, and duplications can
all be frameshift mutations.
33. TAUTOMERIC MUTATIONS
• The changed pairing qualities of the bases
(pairing of purine with purine and pyrimidine
with pyrimidine) are due to phenomenon
called tautomerism. Tautomers are the
alternate forms of bases and are produced by
rearrangements of electrons and protons in the
molecules (Fig. 6.46).
34. • Tautomerism is caused by certain chemical mutagens. In
the next replication purines pair with pyrimidines and the
base pair is altered at a particular locus. The uncommon
forms are unstable and at the next replication, cycle revert
back to their normal forms.
• Due to tautomerisation the amino (-NH2) group of
cytosine and adenine is converted into imino (-NH) group
and likewise keto (C=0) of thymine and guanine is
converted to enol group (-OH). Tautomeric thymine pairs
with normal guanine and cytosine with adenine. Such
pairing of nitrogenous bases are known as forbidden base
pairs or unusual base pair.
• Fig. 6.47. Conversion of an A = T pair to G = C and G =
C pair to A = T base by tautomerization (After Burns,
1969).
37. SUPPRESSOR MUTATIONS
• Suppressor mutation (suppressor) In genetics, a
second mutation that masks the phenotypic effects of an earlier
mutation. This second mutation occurs at a different site in
the genome (i.e. it is not a strict reversion). Intragenic
suppression results from a second mutation that corrects the
functioning of the mutant gene (e.g. a mutation of a different
nucleotide in the same triplet, such that the codon then encodes
the original amino acid). Intergenic suppression results from
mutation of a different gene, the product of which
compensates for the dysfunction in the first (e.g. a mutation
that produces a mutant transfer-RNA molecule that inserts
an amino acid in response to a nonsense codon, thus
continuing a protein that would otherwise have been
terminated). If a single suppressor mutation can suppress more
than one existing mutation, it is said to be a supersuppressor.
Compare REVERSE MUTATION.
38.
39. PHENOTYPIC EFFECTS
• Morphological mutations are mutations that affect the
outwardly visible properties of an organism (i.e. curly ears in
cats)
• Lethal mutations are mutations that affect the viability of the
organism (i.e. Manx cat).
• Conditional mutations are mutations in which the mutant allele
causes the mutant phenotype only in certain environments
(called the restrictive condition).
• In the permissive condition, the phenotype is no longer mutant.
• Example. Siamese cat – mutant allele causes albino phenotype
at the restrictive temperature of most of the cat body but not at
the permissive temperature in the extremities where the body
temperatures is lower.
• Biochemical mutations are mutations that may not be visible or
affect a specific morphological characteristic but may have a
general affect on the ability to grow or proliferate.
40. • For example, the bacterium Escherichia coli
does not require the amino acid tryptophan for
growth because they can synthesize
tryptophan. However, there are E. coli mutants
that have mutations in the trp genes. These
mutants are auxotrophic for tryptophan, and
tryptophan must be added to the nutrient
medium for growth.
41. MAGNITUDE OF PHENOTYPIC EFFECT
• According to their phenotypic effects following kinds of mutations may
occur:
• Dominant mutations
The mutations which have dominant phenotypic expression are called
dominant mutations. For example, in man the mutation disease aniridia
(absence of iris of eyes) occurs due to a dominant mutant gene.
• Recessive mutations
Most types of mutations are recessive in nature and so they are not
expressed phenotypically immediately. The phenotypic effects of
mutations of a recessive gene is seen only after one or more
generations, when the mutant gene is able to recombine with another
similar recessive gene.
• Isoalleles
Some mutations alter the phenotype of an organism so slightly that they
can be detected only by special techniques. Mutant genes that give
slightly modified phenotypes are called isoalleles. They produce
identical phenotypes in homozygous or heterozygous combinations.
42. LOSS OF FUNCTION OR
GAIN OF FUNCTION
• Loss of function mutation
Loss of function mutation is also called
inactivating mutations, result in the gene product
having less or no function (being partially or
wholly inactivated).
• Gain of function mutations
The gain of function mutations also called
activating mutations, change the gene product
such that its effect gets stronger (enhanced
activation) or even is superseded by a different
and abnormal function.
43. TYPE OF CHROMOSOME
INVOLVED
• According to the types of chromosomes, the
mutations may be of following two kinds:
• Autosomal mutations. This type of mutation
occurs in autosomal chromosomes.
• Sex chromosomal mutations. This type of
mutation occurs in sex chromosomes.
44. CHROMOSOMAL MUTATION
AND TYPES
• The changes in the genome involving
chromosome parts, whole chromosomes, or whole
chromosome sets are called chromosome
aberrations or chromosome mutations.
• Chromosome mutations have proved to be of
great significance in applied biology—
agriculture (including horticulture), animal
husbandry and medicine.
• Chromosome mutations are inherited once they
occur and are of the following types:
45. STRUCTURAL CHANGES IN CHROMOSOMES
• Changes in number of genes
• (a) Loss: Deletion which involves loss of a broken part of a
chromosome.
• (b) Addition: Duplication which involves addition of a part
of chromosome.
• Changes in gene arrangement:
• (a) Rotation of a group of genes 1800 within one
chromosome: Inversion in which broken segment reattached
to original chromosome in reverse order.
• (b) Exchange of parts between chromosomes of different
pairs: Translocation in which the broken segment becomes
attached to a non- homologous chromosome resulting in new
linkage relations.
46. CHANGES IN NUMBER OF
CHROMOSOMES
Euploidy
• It involves the loss, or gain, of whole chromosome set.
• The term euploidy (Gr., eu = even or true; ploid = unit) designates
genomes containing chromosomes that are multiples of some basic
number (x).
• The euploids are those organisms which contain balanced set or sets
of chromosomes in any number.
• The number of chromosomes in a basic set is called the monoploid
number, x.
• Those euploid types whose number of sets is greater than two are
called polyploid.
• Thus, 1x is monoploid, 2x is diploid; and the polyploid types are 3x
(triploid), 4x (tetraploid), 5x (pentaploid), 6x (hexaploid) and so on.
• Mutation due to Euploidy refers to the state of having a chromosome
number that is an exact multiple of a basic chromosome set. This
means the number of chromosome sets is increased in euploidy.
47. POLYPLOIDY
• Addition of one or more sets of chromosomes.
• They may be further:
• (a) Autopolyploidy. The autopolyploidy
involves polyploidy, in which the same basic
set of chromosomes are multiplied.
• (b) Allopolyploidy. The polyploidy results due
the doubling of chromosome number in a F1
hybrid which is derived from two distinctly
different species. The resultant species is
called an allopolyploid.
48. ANEUPLOIDY
It involves the loss, or gain, of a part of the chromosome set.
It refers to a condition in which one or a few chromosomes are
added or deleted from the normal chromosome number. Hence, the
number of chromosomes in aneuploidy can be greater or smaller
than the number of chromosomes in the wild type.
Various types of aneuploidy can be identified as: nullisomy,
monosomy, and trisomy.
Nullisomy (2n-2) is the loss of both chromosomes of the
homologous pair. This conditions may be lethal in most organisms.
Monosomy (2n-1) is the loss of a single chromosome of the
homologous pair.
Trisomy is the gain of an extra chromosome (2n+1). Klinefelter
syndrome (44+XXY/XYY) and Down syndrome are examples of
trisomy.
49. FACTORS IMPACTING GENOMIC
MUTATION RATES
• Somatic mutation rates vary considerably across regions of
the genome. Understanding the factors that contribute to
this variation is essential for methods for the detection of
driver genes, and is also independently of interest in terms
of understanding cancer biology (Fig. 3). One of the first
genomic features to be associated with genomic mutation
rate is gene expression level. Highly transcribed genes
generally show lower mutation rates compared to weakly
expressed genes. It has also been noted that the transcribed
strand of genes shows lower mutations rates compared to
the nontranscribed strand, which has been interpreted as
suggesting that the impact of gene expression on mutation
rate may be due to transcription-coupled nucleotide excision
repair.
50. Many factors influence mutations rates both within individual cancer genomes and across
individuals. Here we give several examples of factors that influence mutation rates from
three categories: environmental exposures, factors that impact DNA replication and repair,
and features that vary across the genome.
51. DNA repair has emerged as a central factor in mutation rate
variation in cancer genomes. Early efforts to characterize the variability
of mutation rate across the genome identified chromatin markers
associated with chromatin state as being particularly associated with
cancer genome mutation rate. Markers of closed chromatin have
generally been associated with higher mutation rate, while open
chromatin states have been associated with lower mutation rate. This
observed association was given a mechanistic interpretation when
chromatin state was linked to access of DNA repair machinery to the
underlying DNA in the context of mutation rates. It has been observed
that while mismatch repair proficient tumors demonstrate substantial
mutation rate variability across the genome, this variability is
considerably reduced in mismatch repair deficient tumors. Combined
with the observed association of mutation rate with chromatin state,
these results suggest a model in which open chromatin state makes
DNA more available for repair, resulting in lower mutation rates in
these regions when DNA repair is proficient.
52. Other studies have suggested a plausible role for the interaction
of DNA repair and chromatin state in more specific chromatin
interactions. Reduced mutation rates have been observed in DNase I
hypersensitive sites, while this hypomutation is absent in tumors with
deficient nucleotide excision repair, again suggesting easier access of
repair machinery in open chromatin as a factor influencing mutation
rates. While DNase I hypersensitivity sites show reduced mutation rates,
increased mutation rates have been noted at the actual site of protein
binding. Transcription factor binding sites coincide with decreased
excision repair activity as measured by excision repair sequencing, and
the excess mutation rate at these sites relative to flanking regions is
disrupted in XPC-deficient skin cancers, suggesting that this mutation
rate variability is again caused by access to DNA repair factors. In
colorectal cancer, CTCF binding sites have an excess of mutations,
while colorectal tumors harboring mutations that disrupt the
proofreading activity of POLE actually have fewer mutations at these
sites compared to background mutations, again implicating an
interaction between protein binding and DNA repair.
53. Understanding mutation rate variability both within and between cancer
genomes has important implications for the detection of driver genes. The number
of mutations available for driver gene discover influences the power to detect
driver genes. Mutation rate variability can also lead to “false positives” in analyses,
genes that have high mutation rates but are not driver genes. Accounting for factors
that influence mutation rate can help improve the performance of statistical
methods and decrease the likelihood of false positives. Recently, ratiometric
methods which use the ratio of different types of mutations as opposed to raw rates
have been suggest as a method that can improve performance in the presence of un-
modeled variation in mutation rates.
In addition to varying across the genome, mutation rates also vary
substantially across individuals. Environmental exposures such as tobacco smoke,
UV light, and aristolochic acid can result in increased mutation rates in cancer
genomes. Mutation rates across individuals are also impacted by variability in the
activity of certain cellular processes. In the next section we discuss some of the
environmental and endogenous-driven mutational processes that contribute to the
heterogeneity of mutation rates.
54. When mutations occur in the germ cells, they may be passed on to the
next generation. The change in the DNA may be a single nucleotide substitution or
it may involve many nucleotides, such as in the case of an insertion or deletion.
Many hemoglobinopathies are due to point mutations that cause the replacement of
an amino acid (missense) and consequently an abnormal protein product. The most
common mutation causing Tay–Sachs disease is a 4-base-pair (bp) insertion
(frameshift), while the F508del mutation in the cystic fibrosis gene is a 3-bp
deletion.
The source of genetic variation in a population is mutation. Mutation
rates in humans have been estimated to be on the order of 10−4 to 10−6 per gene
per generation. The rate of nucleotide substitutions is estimated to be 1 in 108 per
generation, implying that 30 nucleotide mutations would be expected in each
human gamete.
Most new mutations are lost due to chance. However, new mutations arise
in each generation, and some become established in the population. Suppose μ is
the mutation rate from A1 to A2 per generation. If the frequencies
of A1 and A2 are pt and qt, respectively, in generation t, then in the (t + 1)th
generation the frequency of A2 is
qt+1=qt+μpt=qt+μ(1−qt)=μ+(1−μ)qt.
