Genetics Chapter 18

What is a mutation?

Sustainer of life and cause of great suffering

What are mutations sources of?

• All genetic variation, which further provides the raw material for evolution

• Source of many diseases and disorders

What are mutations useful for?

They are useful for probing fundamental biological processes

What are the categories of mutations?

Somatic mutations, Germ-line mutations, and Gene vs. Chromosomal Mutations

Where do somatic mutations occur?

In nonreproductive cells and are passed to new cells through mitosis, creating a clone of cells having the mutant genes

Where do germ-line mutations occur?

In cells that give rise to gametes. Mutations are passed to approximately half the members of the next generation, who will carry the mutation in all of their cells

What are the types mutations based on base substitutions?

Transition and Transversion

What are the types of mutations based on insertions and deletions?

Frameshift mutations and in-frame insertions and deletions

What are the three basic types of gene mutations?

Base substitutions, insertions and deletions

What is a base substitution?

Alters a single codon

What is an insertion or deletion?

Alters the reading frame and may change many codons

What is a transition?

Substitution of purine for a purine, or pyrimidine for pyrimidine

What is a transversion?

Substitution of a pyrimidine for a purine, or a purine for a pyrimidine

What are the possible base changes of a transition

Purine to Purine:

• A → G

• G → A

Pyrimidine to Pyrimidine:

• T → C

• C → T

What are the possible base changes for a transversion?

Purine to Pyrimidine:

• A → C

• A → T

• G → C

• G → T

Pyrimidine to Purine:

• C → A

• C → G

• T → A

• T → G

What do expanding nucleotide repeats consist of?

Increase in the number of copies of a set of nucleotides

What is the fragile X-chromosome associated with?

A characteristic constriction (fragile site) on the long arm

What is the repeated sequence, and number of copies of repeat in the normal and disease range of Fragile-X syndrome?

CGG

• Normal: 6-54

• Disease: 50-1500

What is the repeated sequence, and number of copies of repeat in the normal and disease range of Huntington syndrome?

CAG

• Normal: 9-37

• Disease: 37-121

How can nucleotide repeats occur?

In the course of replication, a hairpin can form on the newly synthesized strand, which causes part of the template to be replicated twice, and increase the number of repeats on the newly synthesize strand.

What is a forward mutation?

Wild type → Mutant type

What is a reverse mutation?

Mutant type → wild type

What is a missense mutation?

amino acid → different amino acid

What is a nonsense mutation?

sense codon → nonsense codon

What is a silent mutation?

codon → synonymous codon

What is a neutral mutation?

No change in function

• example: changing a charged AA for a different AA with the same charge

Ex: With WT as Gly-Val-Leu-Lys-Arg, what can occur with a nonsense mutation?

Mutant

Gly → STOP; results in truncated protein

Ex: With WT as Gly-Val-Leu-Lys-Arg, what can occur with a silent mutation?

Mutant

Gly-Val-Leu-Lys-Arg

What can base substitutions cause?

Missense, Nonsense, and Silent mutations

What is an example of a loss-of-function mutation?

REVIEW

What is an example of gain-of-function mutation?

REVIEW

What is an example of a conditional mutation?

Bacteria growing at 37° instead of 25°

What is an example of a lethal mutation?

Homozygous dominant yellow mice will die since the YY mutation is lethal

What is a loss-of-function mutation

Causes a complete or partial loss of function

What is a gain-of-function mutation?

Causes the appearance of a new trait or function or causes the appearance of a trait in inappropriate tissue, or at an inappropriate time

What is a lethal mutation?

Causes premature death

What is a suppressor mutation?

Suppresses the effect of an earlier mutation at a different site

Where does a suppressor mutation occur and what does it produce?

it occurs at a site different from that of the original mutation and produces an individual that has both the original mutation and the suppressor mutation, but has the wild type phenotype

What is an intragenic suppressor mutation?

Suppresses the effect of an earlier mutation within the same gene

What is an intergenic suppressor mutation?

Suppresses the effect of an earlier mutation in another gene

What are factors affecting mutation rates?

• Frequency with which a change takes place in DNA

• The probability that when a change takes place, that change will be repaired

• The probability that a mutation will be detected

What is adaptive mutation?

Genetic variation critical for evolutionary change that brings about adaptation to new environments

What can impact adaptive mutation?

Stressful conditions, where adaptation might be necessary to survive, induce increased mutation in bacteria

What are different factors that mutations are potentially caused by?

Spontaneous replication errors, spontaneous chemical changes, chemically induced mutations, and radiation

What are spontaneous replication errors?

Tautomeric shifts, mispairing due to other structures, incorporation errors and replication errors, and deletions and insertions

What are causes of deletions and insertions?

Strand slippage, unequal crossing over

What are the different forms of purine and pyrimidine bases?

Tautomers

Why can nonstandard base pairing occur?

Due to the flexibility in DNA structure

• Thymine-guanine wobble

• Cytosine-adenine protonated wobble

What can wobble base pairing lead to?

A replication error

What can result from strand slippage?

Insertions and deletions

What does unequal crossing over produce?

Insertions and deletions

What are the types of spontaneous chemical changes?

Depurination and deamination

What is depurination?

loss of purine

What is deamination?

Loss of amino group

What can depurination lead to?

May lead to base substitution

• Depurination is the loss of a purine base from a nucleotide

What does deamination do?

Alters DNA bases

What are some chemically induced mutations?

Mutagen, base analogs

What is an example of a base analog?

5-Bromouracil; resembles thymine, except it has a bromine atom in place of a methyl group on the 5-carbon atom

What can incorporation of 5-bromouracil lead to?

Incorporation of 5-Bromouracil into a DNA strand can lead to a replicated error

What are alkylating agents?

Agents that donate alkyl group

What is an example of an alkylating agent?

ethylmethylsulfonate (EMS)

How can deamination be chemically induced?

Nitrous acid

How can hydroxylamine be chemically induced?

Add hydroxyl group

How can an oxidative reaction be chemically induced?

By superoxide radicals, like hydrogen peroxide

How can intercalating agents be chemically induced?

Proflavin, acridine orange, and ethidium bromide

What do oxidative radicals do?

Convert Guanine into 8-oxy-7,8-dihydrodeoxyguanine, which can mispair with adenine

What do proflavin and acridine orange do as intercalating agents?

Insert themselves between adjacent bases in DNA, distorting the three-dimensional structure of the helix

What happens to mutation rates due to radiation?

Mutation rates greatly increase in all organisms

What is a pyrimidine dimer?

Two thymine bases block replication

What is the SOS system in bacteria?

SOS system allows bacterial cells to bypass the replication block with a mutation-prone pathway

What do pyrimidine dimers result from?

Ultraviolent light

What is the Ames test used for?

To identify chemical mutagens

What are transposable elements?

Sequences that can move about the genome

What is transposition?

Movement of the transposons

What was transposition first studied in?

Corn; jumping genes

What are features of Transposable elements?

Flanking direct repeats, terminal inverted repeats

How are flanking direct repeats generated?

When a transposable element inserts into DNA

What can transposition take place through?

DNA or an RNA intermediate

What is replication transposition?

A new copy of the transposable element inserts in a new location, and the old copy stays behind

What is nonreplicative transposition?

The old copy excises from the old site and moves to a new site

What is RNA intermediate transposition?

requires reverse transcription to integrate into the target site

How do organisms control transposition?

Many organisms limit transposition by methylating the DNA in regions where transposons are common

What is significant about transposition in humans?

About 45% of the human genome comprises sequences that are related to transposable elements, mostly retrotransposons

How do transposons cause mutations?

Inserting into another gene, or promoting DNA rearrangements

What are examples of how transposons were studied?

• Approximately half of spontaneous mutations in Drosophila

• Human genetic diseases

• The color of grapes

How were grape colors related to transposons?

White color resulted from insertion of a retrotransposon

Red color resulted from deletion of a retrotransposon

What are the two major groups of DNA transposons?

Non-replicative and replicative

What are insertion sequences?

carries only the genetic information needed for transposition

What are composite transposons?

Flanked by two copies off an insertion sequence that may itself transpose

What are noncomposite transposons?

Lack insertion sequences; possess a gene for transposase and have terminal inverted repeats

What is IS1?

Insertion sequences that are simple tranposable elements found in bacteria

What is Tn10?

A composite transposon in bacteria

What are the two primary groups of transposable elements in eukaryotes?

Short inverted repeats (similar to transposable elements in bacteria), retrotransposons

What are examples of short inverted repeats?

• P elements in Drosophila

• Ac and Ds elements in corn

What are examples of retrotransposons?

• Ty elements in yeast

• Copia elements in Drosophila

• Alu sequences in humans

What does C⁺ do in corn?

Pigment - dominant trait

What does c do in corn?

colorless

What is the phenotype for C⁺C⁺ and C⁺c?

Pigmented

What is the phenotype for cc?

colorless

What are Ac and Ds?

Transposable elements in maize; different Ds elements have different deletions