Download Mutation: The Source of Genetic Variation

Michael Cummings
Chapter 11
Mutation:
The Source of Genetic Variation
David Reisman • University of South Carolina
 What comes to mind when you hear the word
mutation?
 Often this word has a negative connotation, but
mutation has made the immense variety of life on
earth possible.
11.1 Mutations Are Heritable Changes in
DNA
 Mutations are the ultimate source of all genetic
variation in humans and other organisms
 Mutation can occur spontaneously as a result of
errors in DNA replication or is induced by exposure
to radiation or chemicals
 An agent that causes a mutation is called a
mutagen
Two Categories of Mutations
 Somatic Mutations
• Occur in cells of the body that do not form gametes
• Occurs in mitosis
• Is not transmitted to future generations
 Germ-line Mutations
• Occur in cells that produce gametes
• Occurs during meiosis
• Transmitted to future generations - inherited
11.2 Mutations Can
Be Detected in Several Ways
 How do we know that a mutation in a gene has
occurred?
• Change in a phenotype that is passed on
 Mutations that do not cause a change in phenotype
would most likely only be detected by sequencing
an individual’s DNA
Identification of Dominant Mutation
 Dominant mutations are easiest to detect; they are
expressed in the heterozygous condition
 Sudden appearance of a dominant mutation in a
family can be observed in a single generation
 Accurate pedigree information can be used to
identify the individual in whom a mutation arose
Pedigree Analysis: Sudden Appearance of a
Dominant Trait
Fig. 11-1, p. 246
Recessive and Sex-Linked Recessive
Mutations
 It is more difficult to detect a recessive mutation
• Can be detected only in the homozygous condition
 It is extremely difficult to identify the origin of a
recessive mutation
 It is even more difficult to determine the origin of a
sex-linked recessive mutation
• Generally will only appear in males in a family tree
Pedigree: An X-Linked Recessive Trait
 Queen Victoria and hemophilia
11.3 Measuring
Spontaneous Mutation Rates
 Mutation rate
• ranges from approx 1 in 10,000 to 1 in 1,000,000
copies of a gene
 Several factors influence mutation rate
• Size of the gene: Larger genes have higher mutation
rates
• Nucleotide sequence: Presence of nucleotide repeats
are associated with higher mutation rates
• Spontaneous chemical changes: C/G base pairs are
more likely to mutate than A/T pairs
Mutation Rates for Selected Genes
Table 11-1, p. 249
Known Mutagens: Radiation
 Radiation
• The process by which electromagnetic energy travels
through air
 In the US, the average person is exposed to about
360 mrem/year, 81% of which is from natural
background sources (cosmic rays, sunlight, dirt and
rocks)
 A dose of 5,000 mrem is need to cause somatic cell
mutations and increase susceptibility to cancer
Known Mutagens: Chemicals
 Base analogs structurally resemble nucleotides and are
incorporated into DNA or RNA during synthesis (causes
insertion of G rather than A so that an A/T base pair is
converted to a G/C in the helix
 Chemical modifiers directly change the bases in DNA,
Nitrous acid changes cytosine into uracil, resulting in a
G/C to A/T mutation
 Intercalating agents generally distort the double helix,
addition or deletion of a base pairs during DNA
replication
Exposure to Chemical Mutagens
Not in text, not included on exam questions
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Aflatoxin – in peanuts
Nitrophenols, anisoles, toluene – hair dyes
Furylfofuramide – food additive
Nitrosamines – pesticides, herbicides cigarette smoke
Sodium nitrite – smoked meats
PBDEs – flame retardant
Types of Mutations
 Point Mutations or Nucleotide substitutions
• Missense mutation – replaces one amino acid with another
• Nonsense mutations – an amino acid codon is changed to
a stop codon
• Sense mutation – a termination codon is changed into a
one that codes for an amino acid, producing elongated
proteins
• Silent mutation – no effect on phenotype
 Frameshift mutations
• Bases are added to or removed from DNA, causing a shift in
the codon reading frame (nucleotide changes in multiples of 3 will
NOT cause a frame-shift, but very likely alter the phenotype)
Hemoglobin Variants: Missense Mutations
Fig. 11-8, p. 254
Sense mutations in Alpha Globin Proteins
Table 11-3, p. 255
Genomic analysis has revealed that deletions and insertions
account for 5-10% of known mutations
mRNA transcribed from the DNA
DNA TEMPLATE STRAND
Resulting amino acid sequence
Arginine
Glycine
Tyrosine
Tryptophan
Asparagine
Arginine
Glycine
Leucine
Leucine
Glutamic acid
Altered message in mRNA
A BASE INSERTION (RED) IN DNA
The altered amino acid sequence
Fig. 11-9, p. 256
Trinucleotide Repeats
and Gene Expansions
 Trinucleotide repeats
• A three base-pair repeating sequence (example:
CGGCGGCGGCGG)
 Allelic expansion
• Increase in gene size caused by an increase in the
number of trinucleotide sequences
• Potential for expansion is a characteristic of a specific
allele
Diseases due to Expanded Tri-Nucleotide
Repeats
Table 11-4, p. 257
Gene Expansion
is Related to Anticipation
 Anticipation
• Onset of a genetic disorder at earlier ages and with
increasing severity in successive generations
• Due to increasing number of repeats with successive
generations
Anticipation of Myotonic Dystrophy
11.6 Mutations and
DNA Damage Can Be Repaired
 Not all mutations cause permanent genetic damage
 Cells have enzyme systems that repair DNA
• Mismatch repair – enzymes detect nucleotides that do
not base pair in newly replicated DNA; the incorrect base
is excised and replaced
• Excision repair - enzymes cut out the 1-30 bases of
DNA with the mistake and resynthesize the small
fragment
• End-joining – when both strands of the DNA molecule
are cut, proteins simply take the ends and stick them back
together
Rates of DNA Damage
Table 11-5, p. 258
Maximum DNA Repair Rates
Table 11-6, p. 258
Genetic Disorders
Can Affect DNA Repair Systems
 Several genetic disorders,
including xeroderma
pigmentosum, are caused
by mutations in genes that
repair DNA
Fig. 11-15, p. 259