Mutations
Mutations are changes in the DNA sequence that can affect the structure
and function of proteins, sometimes leading to diseases or altered cellular
functions.
Types of Mutations
Let’s review the types of mutations discussed in our videos:
1. Point Mutations:
A point mutation is a change in a single nucleotide base in the DNA
sequence. These can result in several different outcomes:
Silent Mutation: A change in the nucleotide that does not alter the amino
acid sequence of the protein. For example, changing a codon from GTA to
GTT still codes for the same amino acid, valine, as shown below.
Missense Mutation: A change in the nucleotide that results in a different
amino acid being incorporated into the protein. This can affect protein
function. For example, the mutation CCC (proline) to ACC (threonine) is a
missense mutation.
Nonsense Mutation: A change in the nucleotide that converts a codon
into a stop codon, leading to premature termination of protein synthesis.
This often produces a nonfunctional protein, particularly if it results in
termination far upstream of the regular stop codon.
2. Insertion and Deletion Mutations (Indels): These mutations involve the
addition (insertion) or removal (deletion) of one or more nucleotides in the
DNA sequence.
Frameshift Mutation: If the number of inserted or deleted nucleotides is
not a multiple of three, it causes a shift in the reading frame, altering all
downstream codons. This can result in a completely nonfunctional protein.
In-frame Mutation: If an insertion or deletion occurs in a multiple of
three, the reading frame is not shifted, but an amino acid is added or lost,
potentially affecting protein function.
A frameshift mutation is shown here:
3. Single Chromosome Mutations: Mutations can also affect larger regions
of a chromosome, resulting in structural changes. These types of mutations
involve alterations to a single chromosome's structure without affecting
others:
Duplication: A portion of the DNA sequence is duplicated, leading to
extra copies of a specific gene or segment of the chromosome. This can
increase the dosage of gene products and potentially result in disease if the
increased gene expression disrupts normal cellular function.
Inversion: A chromosome segment is reversed end to end. In an inversion,
the affected segment is flipped in orientation, potentially disrupting the
function of genes in that region. There are two types: a pericentric
inversion involves the centromere; a paracentric inversion: Does not
involve the centromere.
Deletion: A portion of the chromosome is lost or deleted, leading to the
removal of essential genetic material. Depending on the size of the
deletion and the genes affected, this can cause severe developmental or
functional consequences.
Translocation (single-chromosome): While typically associated with
interchromosomal mutations, translocations within a single chromosome
can occur, where one part of the chromosome moves to a different location
on the same chromosome.
The following figure shows a deletion, followed by a duplication, followed
by an inversion.
4. Interchromosomal Mutations: Interchromosomal mutations involve
exchanges or alterations between two or more chromosomes, often
disrupting gene regulation or function:
Translocation: A chromosomal abnormality in which segments from two
different chromosomes are exchanged. There are two main types:
a reciprocal Translocation involves an exchange of material between two
non-homologous chromosomes. This can disrupt gene function if the
breakpoint occurs within a gene or its regulatory regions. A Robertsonian
Translocation involves the fusion of two acrocentric chromosomes,
leading to a single chromosome. This type of translocation is often
associated with genetic disorders such as Down syndrome.
Insertion (interchromosomal): A segment from one chromosome is
inserted into another chromosome. This can disrupt gene function if the
insertion occurs within a critical gene or regulatory region.
Chromosomal Fusion: Two separate chromosomes fuse into one larger
chromosome. This can affect gene expression and regulation.
Here is an example of a reciprocal translocation between chromosomes.
5. Expansions of Repeat Sequences: Some genes contain repeated
sequences of nucleotides (e.g., CAG repeats in the Huntington gene).
Expansion mutations involve an increase in the number of these repeat
units. If the number of repeats exceeds a certain threshold, it can lead to
disease. For example, Huntington's disease results from an excessive
number of CAG repeats, causing abnormal protein aggregation and
neurodegeneration.