This document discusses several types of genetic mutations and variations that can occur, including pseudogenes, transposons, expanding triplet repeats, and copy number variants. It provides examples of how each type can disrupt gene function and cause genetic disorders. The position and severity of a mutation depends on how it affects the protein encoded by the gene. The genetic code and certain mutations help lessen the effects of mutations by resulting in synonymous codons or similar amino acid substitutions. Conditional mutations only cause effects under certain environmental conditions.

1. Ikram Ullah
M.Phil MLSc

2. Pseudogene
 Pseudogene is a DNA sequence that is very similar to
the sequence of a protein-encoding gene
 A pseudogene is not translated into protein, although
it may be transcribed
 The pseudogene may have descended from the
original gene sequence, which was duplicated when
DNA strands misaligned during meiosis
 When this happens, a gene and its copy end up right
next to each other on the chromosome.

3.  The original gene or the copy then mutates to such an extent that
it is no longer functional and becomes a pseudogene
 Its duplicate lives on as the functional gene.
 Although a pseudogene is not translated, its presence can
interfere with the expression of the functional gene and cause a
mutation
 For example, some cases of Gaucher disease result from a
crossover between the working gene and its pseudogene,
 Which has 96 percent of the same sequence and is located
16,000 bases away.
 The result is a fusion gene, which is a DNA sequence containing
part of the functional gene and part of the pseudogene

5. Transposons, or jumping genes
 Transposons can alter gene function in several ways
 They can disrupt the site they jump from, shut off
transcription of the gene they jump into,
 or alter the reading frame of their destination if they
are not a multiple of three bases.
 For example, a boy with X-linked hemophilia A had a
transposon in his factor VIII gene

7. Expanding Repeats
 Myotonic dystrophy is an inherited disease that begins
at an earlier age and causes more severe symptoms
from one generation to the next
 A grandfather might experience only mild weakness in
his forearms, and cataracts
 His daughter might have more noticeable arm and leg
weakness, and a flat facial expression
 Her affected children might experience severe muscle
weakness

8.  For many years, the “anticipation”—the worsening of
symptoms over generations—was thought to be
psychological.
 Myotonic dystrophy is caused by a type of mutation
called an expanding triplet repeat
 The gene, on chromosome 19, has an area rich in
repeats of the DNA triplet CTG
 A person who does not have myotonic dystrophy
usually has from 5 to 37 copies of the repeat;
 A person with the disorder has from 50 to thousands
of copies

9.  The mechanism behind triplet repeat disorders lies in the
DNA sequence
 The bases of the repeated triplets implicated in the
expansion diseases, unlike others, bond to each other in
ways that bend the DNA strand into shapes, such as
hairpins
 These shapes then interfere with replication, which causes
the expansion
 The triplet repeat disorders are said to cause a “dominant
toxic gain of function.”
 This means that they cause something novel to happen,
rather than removing a function

11. Copy Number Variants
 In addition to differing, if only slightly, in our DNA
sequences,
 We also differ in the numbers of copies of particular DNA
sequences
 These sequences that vary in number from person to
person are called copy number variants (CNVs)
 Our genomes have hundreds to thousands of them, and
they account for about a quarter of the genome
 Copy number is a different form of information than DNA
sequence differences

12.  If a wild type short sequence and a variant with two
SNPs are written as:
The fat rat sat on a red cat (wild type)
The fat rat sat in a red hat (two SNPs)
 Then the sequence with two CNVs might be:
The fat fat rat sat on a red red red cat

13.  A CNV can range in size from a few DNA bases to
millions, and copies may lie next to each other on a
chromosome (“tandem”) or might be far away—even
parts of other chromosomes.
 CNVs may have no effect on the phenotype, or they
can disrupt a gene’s function and harm health.
 A CNV may have a direct effect by inserting into a
protein-encoding gene
 And offsetting its reading frame, or have an indirect
effect by destabilizing surrounding sequences

16. The Importance of Position
 The degree to which a mutation alters the phenotype
depends upon where in the gene the change occurs,
 And how the mutation affects the conformation, activity, or
abundance of an encoded protein
 A mutation that replaces an amino acid with a very similar
one would probably not affect the phenotype greatly,
 because it wouldn’t substantially change the conformation
of the protein.
 Even substituting a very different amino acid would not
have much effect if the change is in part of the protein not
crucial to its function

17. Globin Variants
 Mutations in globin genes can cause anemia with or
without sickling, or cause cyanosis (a blue pallor due
to poor oxygen binding)
 Rarely, a mutation boosts the molecule’s affinity for
oxygen
 Some globin gene variants exert no effect and are thus
considered “clinically silent”
 Hemoglobin S and hemoglobin C are variants that
result from mutations that change the sixth amino
acid in the beta globin polypeptide

18. Factors That Lessen the Effects of Mutation
 The genetic code protects against mutation
 Synonymous codons specify the same amino acid.
 Mutation in the third codon position is effectively
“silent” because the two condons are synonymous.
 For example, a change from RNA codon CAA to CAG
does not alter the designated amino acid, glutamine

19.  Other genetic code prevent synthesis of very altered
proteins.
 For example, mutations in the second codon position
sometimes replace one amino acid with another that
has a similar conformation, minimizing disruption of
the protein’s conformation.
 GCC mutated to GGC, for instance, replaces alanine
with equally small glycine

21.  A conditional mutation affects the phenotype only under
certain conditions.
 This can be protective if an individual avoids the exposures
that trigger symptoms.
 Consider a common variant of the X-linked gene that
encodes glucose 6-phosphate dehydrogenase (G6PD),
 An enzyme that immature red blood cells use to extract
energy from glucose
 This mutation can cause life-threatening hemolytic
anemia, but only under rather unusual conditions—eating
fava beans or taking certain antimalarial drugs