DEFINITION

A mutation is a heritable change in the DNA sequence of an organism. These changes can
arise spontaneously due to errors in DNA replication or be induced by external agents
called mutagens, such as radiation, chemicals, or viruses. Mutations can affect single DNA
base pairs (point mutations), larger segments of chromosomes (chromosomal mutations),
or even entire sets of chromosomes (genome mutations). The consequences of a mutation
can range from no observable effect (silent mutations) to significant alterations in protein
function or gene expression, potentially leading to genetic disorders, increased disease
susceptibility, or, in rare cases, beneficial adaptations that contribute to evolution.
Mutations occurring in germline cells (sperm or egg) can be passed on to the offspring,
while those in somatic cells are confined to the individual.

HISTORY
The idea of "mutation" didn't just pop up overnight. For a long time, people noticed weird
variations in living things, like sudden, dramatic changes.
The concept of genetic mutation has evolved through significant scientific milestones. In
1791, farmer Seth Wright observed an unusually short-legged lamb, marking an early
record of a point mutation. However, he couldn't explain the underlying cause. The term
"mutation" was later introduced by Dutch botanist Hugo de Vries in 1900, following his
studies on the evening primrose (Oenothera lamarckiana), where he noted sudden heritable
changes. Building on this foundation, Thomas Hunt Morgan, in 1910, identified a white-
eyed mutation in fruit flies (Drosophila melanogaster), advancing the understanding of
mutations in heredity. Further progress was made by Hermann Joseph Muller in 1927,
who demonstrated that X-rays could induce mutations in Drosophila, earning him the
Nobel Prize in 1946.
In Hugo de Vries' experiments with the evening primrose, he observed that the
variations in the offspring were due to sudden and significant genetic changes, which he
called "mutations." These mutations would lead to the appearance of new traits in the
offspring that were not present in the parent plants. For example, the offspring might have
different leaf shapes, flower colors, or growth patterns. Studied 54343 plants for 8 years &
classified into 8 varieties with distinct characteristics.

CAUSES
Based on Origin:
● Spontaneous Mutations: Occur naturally due to errors in cellular processes or
background environmental factors.
● Induced Mutations: Caused by external agents called mutagens (like radiation
or chemicals).

Mutations arise from a diverse array of causes, broadly categorized as spontaneous and
induced. Spontaneous mutations occur naturally as a result of inherent biological
processes. These can be due to errors during DNA replication, where mismatched base
pairings can slip past proofreading mechanisms, or from spontaneous chemical changes to
DNA bases like deamination or depurination. Induced mutations, on the other hand, are
caused by external environmental agents known as mutagens. These mutagens can be
physical, such as UV radiation from the sun or X-rays, which can damage DNA structure
directly. They can also be chemical, including various natural and synthetic compounds
that can react with DNA and alter its sequence. Examples of chemical mutagens include
certain pesticides, industrial chemicals, and even some compounds found in cigarette
smoke. In essence, mutations can arise from the intrinsic imperfections of biological
systems and from exposure to external environmental factors.

Based on the Scale of DNA Change

GENE(point) MUTATION

A gene mutation is a change in the DNA sequence that occurs within a single gene.
These are localized, small-scale alterations at the level of individual nucleotides (the
building blocks of DNA). They are often also called point mutations because they affect
a specific point or location within a gene. They are smaller in scale compared to
chromosome and genome mutations, focusing on alterations within the boundaries of a
single gene, rather than affecting entire chromosomes or sets of chromosomes.
Types of Gene Mutations (Point Mutations):
We can classify gene mutations into these main types based on the nature of the DNA
sequence change:
a) Substitutions:
Description: One nucleotide base is replaced by a different nucleotide base at a specific
position in the DNA sequence. It's like swapping one letter for another in a word.
Subtypes (based on consequence):
● Missense Mutation: The substitution changes a codon in the mRNA, resulting in a
different amino acid being incorporated into the protein.
Example: Changing a codon for Glycine (GGA) to a codon for Valine (GUA).
Consequence: Can alter protein function, ranging from minor to severe effects,
depending on the importance of the changed amino acid in the protein's structure
and activity.
● Nonsense Mutation: The substitution changes a codon that codes for an amino acid
into a stop codon.
Consequence: Leads to premature termination of protein synthesis. The resulting
protein is often truncated (shorter than normal) and usually non-functional.
● Silent Mutation: The substitution changes a codon, but due to the redundancy of the
genetic code, the new codon still codes for the same amino acid.
Example: Changing a codon GGU to GGC, both code for Glycine.
Consequence: Usually no change in the amino acid sequence of the protein, and
therefore, typically no effect on protein function.

b) Insertions:
Description: One or more extra nucleotides are added into the DNA sequence of a gene.
It's like inserting extra letters into a word.
Consequence: Can cause frameshift mutations if the number of inserted nucleotides is not
a multiple of three. This shifts the reading frame, altering all codons downstream of the
insertion, leading to a completely different (and often non-functional) protein sequence
from that point onwards. If the insertion is a multiple of three, it might insert extra amino
acids into the protein, which could still disrupt function.
c) Deletions:

Description: One or more nucleotides are removed from the DNA sequence of a gene. It's
like deleting letters from a word.
Consequence: Similar to insertions, deletions can also cause frameshift mutations if the
number of deleted nucleotides is not a multiple of three, leading to a shifted reading frame
and a drastically altered protein sequence. Deletions of multiples of three might remove
amino acids from the protein, potentially affecting function depending on the location and
importance of the deleted amino acids.

CHROMOSOME MUTATION
Chromosome mutations are large-scale alterations that affect the structure or number of
chromosomes within a cell. These mutations are significantly larger in scope than gene
mutations, impacting entire chromosomes or substantial segments of chromosomes, rather
than just individual genes. They are larger-scale mutations compared to gene mutations.
They involve changes visible at the level of a karyotype (a visual display of an organism's
chromosomes).
We can classify chromosome mutations into two main categories: changes in
chromosome structure and changes in chromosome number.

a) Changes in Chromosome Structure:

Description: These mutations alter the physical arrangement of genes on a chromosome.
● Deletion (Chromosomal Deletion):
Description: A segment of a chromosome is lost or removed. This can range in size
from a small piece to a large portion of the chromosome.
Consequence: Loss of genetic material. If essential genes are deleted, it can lead to
serious problems.

● Duplication (Chromosomal Duplication):

Description: A segment of a chromosome is repeated, resulting in extra copies of
genes in that region.
Consequence: Overdosage of genes in the duplicated region. This can disrupt the
normal balance of gene products and cellular processes.

● Inversion (Chromosomal Inversion):

Description: A segment of a chromosome is broken, flipped 180 degrees, and then
 re-inserted into the same chromosome. This reverses the order of genes in that
segment.
Consequence: The gene sequence is altered in that region. Can disrupt gene
regulation if the inversion breakpoint occurs within a gene or regulatory region.
Sometimes, inversions can be "position effect" variegation, where
gene expression changes depending on its new position in the chromosome.

● Translocation (Chromosomal Translocation):

Description: A segment of one chromosome breaks off and becomes attached to a
non-homologous chromosome (a different chromosome type). There are two main
types:
Consequence: Can disrupt gene function if breakpoints occur within genes. Can
also alter gene regulation due to the new chromosomal environment. Some
translocations can create fusion genes, where parts of two different genes combine,
sometimes leading to cancer (like in Chronic Myelogenous Leukemia).

b) Changes in Chromosome Number : These mutations involve deviations from the

normal number of chromosomes.

● Aneuploidy:
Description: A cell or organism has an abnormal number of individual
chromosomes. This means there's an extra copy of one chromosome (trisomy) or
missing one chromosome (monosomy), but not a whole extra set of chromosomes.
Aneuploidy usually arises from nondisjunction during meiosis (or mitosis).
● Polyploidy:
Description: A cell or organism has one or more extra complete sets of
chromosomes. Instead of being diploid (2n, two sets), they might be triploid (3n,
three sets), etc.

Down Syndrome (Trisomy 21): Three copies of chromosome 21. Characterized by

intellectual disability, distinctive facial features, heart defects, and other health
issues. The most common autosomal trisomy in live births.
Turner Syndrome (Monosomy X): Females have only one X chromosome (XO).
Characterized by short stature, infertility, heart defects, and other features. Only
viable monosomy in humans.
Klinefelter Syndrome (XXY): Males have an extra X chromosome (XXY).
Characterized by infertility, tall stature, reduced muscle mass, and other features.

GENOME MUTATION
Genome mutations are changes that affect the entire genome of a cell or organism,
primarily by altering the number of chromosomes. While "chromosome mutations" often
refers to structural changes within chromosomes, "genome mutations" typically refers to
changes in the quantity of chromosomes, thus affecting the entire set of genetic
instructions. These are the largest scale of genetic change we've discussed, affecting the
overall chromosomal complement, rather than just individual genes or chromosome
segments.

The main types of genome mutations fall under the categories of aneuploidy and
polyploidy. Here we view them as genome-level changes:

a) Aneuploidy:
Definition: Aneuploidy is a condition in which a cell or organism has an abnormal
number of individual chromosomes. This means there is an imbalance in chromosome
number, with some chromosomes present in extra copies or missing copies, but not an
entire extra set of chromosomes. The genome is not a multiple of the haploid set.

Types of Aneuploidy

● Monosomy (2n-1): Loss of a single chromosome from a diploid set (only one copy
of a chromosome instead of two).
● Trisomy (2n+1): Gain of a single chromosome (three copies of a chromosome
instead of two).
● Nullisomy (2n-2): Loss of a homologous pair of chromosomes (no copies of a
particular chromosome).
● Tetrasomy (2n+2): Gain of a homologous pair of chromosomes (four copies of a
particular chromosome).

b) Polyploidy:

Definition: Polyploidy is a condition where a cell or organism has one or more extra
complete sets of chromosomes. The genome is a multiple of the haploid set (greater than
diploid). Instead of just having two sets (diploid, 2n), a polyploid organism has three sets
(triploid, 3n), four sets (tetraploid, 4n).

Key Feature: Entire sets of chromosomes are duplicated, resulting in a genome that is a
multiple of the haploid number.

Types of Polyploidy:

● Triploidy (3n): Three complete sets of chromosomes.

● Tetraploidy (4n): Four complete sets of chromosomes.

Turner Syndrome (Monosomy X): The only viable monosomy in humans. Caused
by monosomy of the X chromosome (XO) in females, usually due to nondisjunction in
sperm or egg formation.

Klinefelter Syndrome (XXY): A common sex chromosome aneuploidy in males,

caused by having an extra X chromosome (XXY), usually due to nondisjunction in
maternal or paternal meiosis.
Trisomy 18 (Edwards Syndrome) and Trisomy 13 (Patau Syndrome): More
severe autosomal trisomies (trisomy 18 and 13 respectively) caused by nondisjunction.
These conditions are associated with multiple severe birth defects, and infants often
have very short lifespans.

Other Sex Chromosome Aneuploidies: XXX (Trisomy X), XYY (Jacobs

Syndrome). These often have milder phenotypes compared to autosomal aneuploidies.

Causes of Genome Mutations:

a) Nondisjunction (Primary Cause of Aneuploidy):
Nondisjunction is the failure of homologous chromosomes (in meiosis I) or sister
chromatids (in meiosis II or mitosis) to separate properly during cell division.

Result: This results in some gametes (or somatic cells if nondisjunction occurs in
mitosis) having extra chromosomes, and others missing chromosomes. When these
abnormal gametes participate in fertilization, they lead to aneuploid offspring.

Occurrence: Nondisjunction can happen in either maternal or paternal meiosis and

can occur in meiosis I or meiosis II. Maternal nondisjunction is a more frequent
cause of certain aneuploidies like Down Syndrome, and the risk of nondisjunction
increases with maternal age.

b) Errors in Cell Division (Causes of Polyploidy):

Failure of Meiosis I or II: If all chromosomes in a diploid cell fail to separate

during meiosis I or II, it can result in diploid gametes (2n) instead of haploid gametes
(n). Fertilization of a diploid egg by a haploid sperm (or vice versa) leads to a triploid
zygote (3n). Fertilization of a diploid egg by a diploid sperm leads to a tetraploid
zygote (4n), etc.

Polyspermy: Fertilization of an egg by more than one sperm (dispermy, trispermy,

etc.) can directly introduce extra sets of paternal chromosomes, leading to polyploidy
(triploidy from dispermy is common).

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