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

Radiation

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

T

A C

T

G

A

C

T

A

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

Insertions

Mutations with Trinucleotide Repeats and Allelic Expansion

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

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

Sperm

Zygote

Imprinting is erased and reprinted in the fetal gonads

Female

Male Germ Cell

Imprint Erased

New Imprints Made

Sperm

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