Gene Mutations and DNA Repair Mechanisms

Mutations

Sustainer of life and cause of great suffering; source of all genetic variation, which further provides the raw material for evolution.

Somatic mutations

Mutations that occur in somatic cells.

Germ-line mutations

Mutations that occur in germ cells and can be passed on to offspring.

Base substitutions

A type of gene mutation where one base is replaced by another.

Transition

Base substitution in which a purine replaces a purine or a pyrimidine replaces a pyrimidine.

Transversion

Base substitution in which a purine replaces a pyrimidine or a pyrimidine replaces a purine.

Insertions

Addition of one or more nucleotides.

Deletions

Deletion of one or more nucleotides.

Frameshift mutations

Insertion or deletion that alters the reading frame of a gene.

In-frame insertions and deletions

Deletion or insertion of a multiple of three nucleotides that does not alter the reading frame.

Expanding nucleotide repeats

Increases the number of copies of a set of nucleotides.

Forward mutation

Changes the wild-type phenotype to a mutant phenotype.

Reverse mutation

Changes a mutant phenotype back to the wild-type phenotype.

Missense mutation

Changes a sense codon into a different sense codon, resulting in the incorporation of a different amino acid in the protein.

Nonsense mutation

Changes a sense codon into a nonsense (stop) codon, causing premature termination of translation.

Silent mutation

Changes a sense codon into a synonymous codon, leaving the amino acid sequence of the protein unchanged.

Neutral mutation

Changes the amino acid sequence of a protein without altering its ability to function.

Loss-of-function mutation

Causes a complete or partial loss of function.

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.

Lethal mutation

Causes premature death.

Suppressor mutation

A mutation that hides or suppresses the effect of another mutation.

Intragenic suppressor mutation

Suppresses the effect of an earlier mutation within the same gene.

Intergenic suppressor mutation

Suppresses the effect of an earlier mutation in another gene.

Mutation rates

Factors affecting mutation rates include frequency of change in DNA and probability of repair.

Adaptive mutation

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

Spontaneous replication errors

Errors that occur during DNA replication.

Depurination

Loss of a purine base from a nucleotide.

Deamination

Loss of an amino group from a DNA base.

Mutagen

An agent that causes mutations.

Base analogs

Compounds that resemble DNA bases and can be incorporated into DNA.

Alkylating agents

Chemicals that donate alkyl groups to DNA bases.

Intercalating agents

Proflavin, acridine orange, and ethidium bromide that insert themselves between adjacent bases in DNA, distorting the three-dimensional structure of the helix.

Radiation

Greatly increases mutation rates in all organisms.

Pyrimidine dimer

Two thymine bases block replication.

SOS system in bacteria

Allows bacterial cells to bypass the replication block with a mutation-prone pathway.

Ames test

Used to identify chemical mutagens.

Transposable elements

Sequences that can move about the genome.

Transposition

Movement of the transposons.

Flanking direct repeats

Generated when a transposable element inserts into DNA.

Terminal inverted repeats

Common characteristic of many transposable elements.

DNA transposition

Transposition may take place through DNA or an RNA intermediate.

Replicative transposition

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

Nonreplicative transposition

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

RNA intermediate transposition

Requires reverse transcription to integrate into the target site.

Control of transposition

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

Transposition in humans

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

Mutagenic effects of transposition

Transposons cause mutations by inserting into another gene and promoting DNA rearrangements.

Examples of transposons

Approximately half of spontaneous mutations in Drosophila, human genetic diseases, and the color of grapes.

Insertion sequences

Carries only the genetic information needed for transposition.

Composite transposons

Flanked by two copies of an insertion sequence that may itself transpose.

Noncomposite transposons

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

Transposable elements in eukaryotes

Two primary groups similar to transposable elements in bacteria: short inverted repeats and retrotransposons.

Mismatch repair

Mismatched bases and other DNA lesions are corrected by enzymes that cut out a section of the newly synthesized strand of DNA and replace it with new nucleotides.

Direct repair

Restores the correct structures of altered nucleotides.

Base-excision repair

Glycosylase enzymes recognize and remove specific types of modified bases.

Nucleotide-excision repair

Removes and replaces many types of damaged DNA that distort the DNA structure.

Repair of double-strand breaks

Two major pathways: Homology directed repair and Nonhomologous end joining.

Translesion DNA polymerases

Allow replication to proceed past bulky distortions in the DNA but often introduce errors as they bypass the distorted region.

Genetic diseases and faulty DNA repair

Defects in DNA repair are the underlying cause of several genetic diseases, many characterized by a predisposition to cancer.

Xeroderma pigmentosum

Characterized by freckle-like spots on skin, sensitivity to sunlight, predisposition to skin cancer due to defects in nucleotide-excision repair.

Cockayne syndrome

Dwarfism, sensitivity to sunlight, premature aging, deafness, intellectual disability due to defects in nucleotide-excision repair.

Trichothiodystrophy

Brittle hair, skin abnormalities, short stature, immature sexual development, characteristic facial features possibly due to defects in the repair of interstrand crosslinks.

Li-Fraumeni syndrome

Predisposition to cancer in many different tissues due to defects in DNA damage response.

Werner syndrome

Premature aging, predisposition to cancer due to defect in homologous recombination.