Mutations

Mutations, and what do they affect

The process of alteration of a gene or chromosome, or the end-product of this process.

Can affect genes from one allele to another, and thus produce a “mutant” phenotype.

Haplotype

A particular DNA sequence that differs by one or more mutations from homologous sequences

Genotype

Unique genetic makeup of an individual, usually in relation to a specific gene.

Richard Goldschmidt (1878-1958)

Mutationist Theories

Hopeful Monster

Geneticist- one of the first scientists to integrate genetics, development and evolution.

Mutationist Theories: Proposed new species can arise by mutations (sudden changes in genetic makeup of an organism).

Hopeful Monster: A sudden drastic change in the entire genome can sometimes create an entirely new higher taxon (any Linnaean rank above species).

All these theories refuted by Modern Synthesis of Biological Thought in 1930’s and 1940s.

Limits of Mutation

Even dramatic mutations are limited to alteration of pre-existing traits or development pathways.

Hopeful Monster: NOT VALID

Polygeny

Many loci affect the same trait.

Loci (Plural of locus)

Exact position for a gene on a chromosome.

Mutations are random in two areas

1. Mutation has no pre-determined “goal,” any nucleotide of the genome can have a mutation.

2. The environment does not induce advantageous mutations- this is Lamarckian-inheritance of acquired characteristics.

Jean-Baptiste Lamarck (1744-1829)

Organisms altered their behavior in response to environmental change.

Adaptation theory

Mutations occur when phage is introduced in 4th generation, but in reality we see it is random.

Charles Darwin (1809-1882)

Natural selection

Heritable variation- Due to random mutations

Human mutation rate data

1 in 30 million base pairs (very low)

Diploid genome: 6.6 X 10^9 bp, average zygote has 220 new mutations

Mutation rate: genome

2.5 of genome has functional, transcribed genes, so average human zygote carries about 6 mutations that are potentially harmful.

Mutational events

1. Substitution, deletion, or insertion of a base pair (point mutation)

2. Chromosomal deletion, insertion, or rearrangement (chromosomal mutation).

Point mutations

Result in gene mutations only if they occur in coding region of gene or regulating sequences

Somatic mutations

Occur in somatic cells and only affect the individual in which the mutation arises

Germ-line mutations

Alter gametes and passed to the next generation

Transition mutations

Occur at a higher frequency than transversions

Base pair substitution

Mutation at one nucleotide- can result in synonymous or silent mutations (no effect on amino acid translation) or nonsynonymous mutations (change amino acid translation).

Missense mutation

Change from one amino acid to another; here, a transition mutation from AT to GC changes the codon from lysine to glutamic acid.

Nonsense mutation

Change from an amino acid to a stop codon; here, a transversion mutation from AT to TA changes the codon from lysine to UAA stop codon.

Neutral mutation

A type of missense mutation in that a different amino acid results, but the function of the amino acid doesn’t change

Change from an amino acid to another amino acid with similar chemical properties; here, an AT-to-GC transition mutation changes the codon from lysine to arginine

Silent mutation

Do not result in an amino acid change- remember wobble

Change in codon such that the same amino acid is specified; here, an AT-to-GC transition in the third position of the codon gives a codon that still encodes lysine.

Suppressor mutation

Mutation at a different site from original mutation that compensates for the negative effects of the original mutation

Tautomers

Different chemical states of nitrogenous bases

Normal state: Keto form

Enol form tautomers

Hydroxyl group (OH) affixed to a carbon with a double bond

Enol and imino forms are rare- but they can cause unusual base pairing, leading to mutations.

Imino form tautomers

Double bond migrates and moves position of hydrogen bonds

Enol and imino forms are rare- but they can cause unusual base pairing, leading to mutations.

Spontaneous Mutation

No special agent

• DNA replication errors

  • Base substitution: tautomers to specific transitions

  • Deletions/additions: looping out to frameshifts in genes

• Molecular changes

  • Depurination

  • Deamination

Induced mutations

Carcinogens: mutagens that cause cancer

Site-specific mutagenesis

Specific mutation within a gene to mutant gene introduced into normal cell to observe effects on phenotype

Thymine Dimers

UV light: Causes mutations because DNA bases absorb light in ultraviolet range

Absorbed light causes photochemical (light induced) changes

Commonly causes thymine dimers (T^T) to form, which disrupts A-T pairing, causes a bulge in DNA, disrupts DNA replication at bulge, and can lead to cell death (skin cancer)

Effects of ionizing radiation is cumulative- gets worse over one’s lifetime

Intercalating agents

Ethidium bromide is used to stain DNA during electrophoresis

• Inserts into DNA multiple times, and chemical glows under UV light.

Base excision repair

1. Uracil-DNA glycosylase

2. Endonuclease cleavage

3. DNA Polymerase activity

4. Ligase activity

Mutations= DNA damage - DNA repair.

DNA Polymerase- direct reversal

Removes mutated base and replaces it with correct one

1. Uracil-DNA glycosylase: cleaves bond between sugar and base

2. Endonuclease cleavage: cuts away baseless sugar

3. DNA polymerase activity: inserts correct base

4. Ligase activity: bonds new base to others in DNA strand

Methyl-Directed Mismatch Repair

Newly synthesized prokaryotic DNA has unmethylated bases- old DNA is methylated to protect from its own restriction enzymes

Xeroderma pigmentosum

Homozygosity for recessive mutation in a DNA repair gene

Intense freckles and lesions when exposed to light, an eventually die of malignant cancer.

Transposable elements overview

Prokaryote and eukaryote genomes

Encode proteins that allow them to “jump” to another part of the genome, or copy the gene and then insert it elsewhere- NONHOMOLOGOUS RECOMBINATION

Eukaryotes have a second type of TE that uses reverse transcriptase to make DNA copies of mRNA transcripts and insert into genome

RARE: activity would likely kill cell

Transposable elements function effects

1. If inserted into a coding gene, can destroy gene’s function (NULL MUTATION)

2. If inserted into a non-coding region (MAJORITY), has a neutral effect

3. If inserted into regulatory region, can enhance it or destroy it

4. Can cause chromosome mutations- deletions, inversion, breakage

Barbara McClintock (1902-1992)

Discovered transposons (complex TE’s) in corn.

1983 Nobel

AC

Autonomous TE

independent

Ds

Nonautonomous

Needs autonomous TE to activate