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
Mutation has no pre-determined “goal,” any nucleotide of the genome can have a mutation.
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
Substitution, deletion, or insertion of a base pair (point mutation)
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
Uracil-DNA glycosylase
Endonuclease cleavage
DNA Polymerase activity
Ligase activity
Mutations= DNA damage - DNA repair.
DNA Polymerase- direct reversal
Removes mutated base and replaces it with correct one
Uracil-DNA glycosylase: cleaves bond between sugar and base
Endonuclease cleavage: cuts away baseless sugar
DNA polymerase activity: inserts correct base
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
If inserted into a coding gene, can destroy gene’s function (NULL MUTATION)
If inserted into a non-coding region (MAJORITY), has a neutral effect
If inserted into regulatory region, can enhance it or destroy it
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