Mutation

Mutations

Mutations are stable heritable changes in DNA sequence of a gene

Alleles: different forms of a gene Þ mutant allele, wild type allele (standard)

Mutations can be good, bad, or indifferent

For some genes, wild type is hard to define (ie blood groups A, B, O)

polymorphic locus Þ different alleles are variants rather than mutants

Genotype: description at the level of the gene

Phenotype: what is observable

Where Do Mutations Come From?

Errors in DNA replication, damage to DNA, non-homologous recombination, inherited mutations (most common source!!!)

Heterozygous once in every 500 bases

Classifications of Mutations

Base substitutions: transitions (pur Þ pur; pyr Þ pyr); transversions (pur Þ pyr; pyr Þ pur)

"Small" deletions and insertions: addition or deletion of a few bases; may occur in "runs" of small repeats Þ "microsatellite instability"

"Large" deletions: deletion of a gene, many genes, even part of a chromosome (ie nonhomologous translocation)

"Large" insertions: caused by mobile genetic elements (ie transposons); major cause of spontaneous mutations

Rearrangements: inversion of a segment of DNA

Missense mutation (base subst): substitution of one amino acid for another

Nonsense mutation (base subst): creates a premature translocation stop codon (not transcription)

Frameshift mutation (small deletion or insertion): addition or subtraction of a few bases (not a multiple of 3), which cause the amino acid sequence to be scrambled

Consequences of Mutations

Missense mutations Þ unpredictable (silent or alteration of function)

Nonsense and frameshift mutations Þ inactive protein

Factors Affecting Phenotype

Complimentation properties: properties of mutations observed in diploid cells

in bacteria or yeast: phenotypes conferred by the same mutation in haploid and diploid are compared
in humans: inferred from patterns of inheritance

Dominant allele: mutant phenotype observed in haploids and diploids (ex: Huntington’s Disease)

Recessive allele: mutant phenotype observed in haploids and homozygous diploids, but not in heterozygous diploids (ex: sickle cell, PKU, Tay-Sacchs)

Codominant alleles: in heterozygous diploid, the observed phenotype is intermediate (ex: blood group antigens)

Interactions With Other Genes

Presence of a 2^nd mutation may enhance or suppress the phenotype of a mutant

Environment

Mental retardation due to PKU can be prevented by a timely diet

Examples

ABO blood group – A and B alleles from altered function of UDP-galactosyl transferase(substrate specificity); O allele from loss of enzyme function

Cystic fibrosis – three nucleotide deletion (codon deletion, NOT leading to frameshift) Þ loss of function

Tay Sachs Disease – insertion of four nucleotides, producing frameshift Þ loss of function