Mutation: The Source of Genetic Variation

Pedigree: An X-Linked Recessive Trait Mutation: The Source of Genetic Variation Chapter 11 Pedigree: A Dominant Trait (e.g. Achondroplasia) Mutatio...
Author: Phebe McKinney
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Pedigree: An X-Linked Recessive Trait

Mutation: The Source of Genetic Variation Chapter 11

Pedigree: A Dominant Trait (e.g. Achondroplasia)

Mutation Rates and Dominant Mutations

Measuring Spontaneous Mutation Rates

Mutation Rates for Selected Genes

!  Studies of mutation rates in a variety of dominant and sex-linked recessive traits indicate that mutations in the human genome are rare events; about 1 in 1 million copies of a gene !  Mutation rate •  The number of events that produce mutated alleles per locus per generation

Why Do Genes Have Different Mutation Rates?

Environmental Factors Influence Mutation Rates

!  Several factors influence mutation rate

!  Environmental agents, including radiation and chemicals, can cause mutations

•  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

!  Chernobyl


Types of Radiation

!  Radiation

!  Ionizing radiation

•  Form of electromagnetic energy

!  Radiation causes biological damage •  Ionized molecules can cause mutation in DNA •  Free radicals (H+, OH-) produced by hydrolysis can cause mutations in DNA •  If mutations are not repaired, cancer may occur

•  Radiation that produces ions during interaction with other matter, including molecules in cells

!  Background radiation •  Radiation in the environment that contributes to radiation exposure •  Radiation damage is measured in rem

US Sources of Radiation Exposure !  In the US, the average person is exposed to about 360 mrem/year, 82% of which is natural •  Mutations in somatic cells increase cancer risk

Sources and Doses of Radiation

Chemicals Can Cause Mutations

Thymine and 5!- Bromouracil (Base Analog)

!  Some chemicals cause nucleotide substitutions or change the number of nucleotides in DNA !  Other chemicals structurally change the bases in DNA, causing a base pair change after replication

Conversion of Cytosine to Uracil (chemical modification of bases)

Acridine Orange (intercalating agent) !  Produces frameshift mutations

Ames Test: Test for Mutagenicity

DNA Damage From UV Light: Thymine Dimers

!  Salmonella hisbacteria (mutation in gene for histidine) G

!  Chemical substance to be tested is placed on bacterial plate !  Look for back mutations

Two Types of Mutations









Many Hemoglobin Mutations are Caused by Nucleotide Substitutions

!  Nucleotide substitutions •  Mutations that involve replacing one or more nucleotides in a DNA molecule with other nucleotides

!  Frameshift mutations •  Mutational events in which a number of bases (other than multiples of three) are added to or removed from DNA, causing a shift in the codon reading frame

!  Three types of nucleotide substitutions •  Missense mutations •  Nonsense mutations •  Silent mutations

Missense Mutations (Example: Hemoglobin)

Hemoglobin Composed of: "

!  Missense mutations

• Globular proteins "

•  Mutations that cause the substitution of one amino acid for another in a protein

• Two alpha chains and two beta chains " • They surround an iron-containing heme group"

!  Example: The GAG codon in hemoglobin can mutate to GUG, AAG, or GCG Figure 11.1!

Hemoglobin Variants: Single Nucleotide Substitutions

Mutations Can Cause Cells to Sickle Mutations Can Cause Cells to Sickle

Chapter 12 Opener"

Sickle Cell Disease Results from a Base Change in Beta Globin Gene

Nonsense Mutations

!  Nonsense mutations •  Mutations that change an amino acid specifying a codon to one of three termination codons

!  Example: A UAU codon in beta globin can mutate to a stop codon UAA

Figure 12.1"

Genetic Code

Frameshift Mutations Can Be Caused Nucleotide Deletions and Insertions !  THE FAT CAT ATE THE RAT •  Normal code

!  THE FAA TCA TAT ETH ERA T •  Insertion

!  THE FTC ATA TET HER AT •  Deletion


Mutations with Trinucleotide Repeats and Allelic Expansion

!  Insertions change the reading frame, changing the amino acids in the protein mRNA DNA


Mutations and DNA Damage can be Repaired

Maximum DNA Repair Rates

DNA Polymerase and Mismatch Repair !  Enzymes detect nucleotides that do not base pair in newly replicated DNA ! The incorrect base is excised and replaced

Excision Repair !  UV damage is repaired by excision repair ! Pyrimidine dimers and a few surrounding bases are removed

! Proofreading is the detection of mismatches Figure 12.11"

Genetic Disorders Can Affect DNA Repair Systems !  Several genetic disorders, including xeroderma pigmentosum, are caused by mutations in genes that repair DNA (correlated with cancer)

Mutations in the Cystic Fibrosis Gene

Genomic Imprinting Is a Reversible Alteration of the Genome

Genomic Imprinting Is a Reversible Alteration of the Genome

!  Genomic imprinting alters the expression of normal genes, depending on whether they are inherited maternally or paternally !  Genomic imprinting •  When expression of a gene depends on whether it is inherited from the mother or the father •  Also known as genetic or parental imprinting

Genomic Imprinting and Genetic Disorders

Imprinting Changes With Each Generation Oocyte

!  Disorders of chromosome 15 (80% of cases) •  Prader-Willi syndrome (PWS): deletion on the paternal copy •  Angelman syndrome (AS): deletion on the maternal copy



Imprinting is erased and reprinted in the fetal gonads


Male Germ Cell

Imprint Erased

New Imprints Made


Genomic Imprinting and Genetic Disorders !  Uniparental disomy (UPD) •  A condition in which both copies of a chromosome are inherited from one parent

!  About 20% of PWS and AS cases have no deletions, but UPD has been identified •  PWD: Both copies come from the mother •  AS: Both copies come from the father

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