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Michael Cummings
David Reisman • University of South Carolina
Mutation: The Source of Genetic Variation
Chapter 11
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
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
Fig. 11-9, p. 256
mRNA transcribed from the DNA
DNA TEMPLATE STRAND
Resulting amino acid sequence Arginine Glycine Tyrosine Tryptophan Asparagine
Altered message in mRNA
A BASE INSERTION (RED) IN DNA
The altered amino acid sequence Arginine Glycine Leucine Leucine Glutamic acid
Genomic analysis has revealed that deletions and insertions account for 5-10% of known mutations
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