2- Mutations at the molecular level to phenotypes

Central Dogma

DNA is transcribed into mRNA, tRNA, rRNA and other small RNAs

mRNA is transcribed into protein

Exceptions to the central dogma

Prions proteins

Retroviruses which have RNA as the genetic material

Collinearity of gene and polypeptide

Changes in AA sequence result from changes in DNA sequence (mutations)

Replication errors leads to:

Base substitutions

Small amplifications

Errors during DNA repair leads to:

Base substitutions

Recombinational errors lead to:

Large deletions

Large amplifications

Rearrangements

Nondisjunction leads to:

Base substitution

Base pairs with the wrong base

Transposable elements

Insertion

Can jump around the genome

Sometimes insert where they are not wanted

Physical agents that induce mutations:

Ionising radiation

UV radiation

Chemical elements that induce mutations:

Base analogues

Nucleotide analogues

Mutagens

Consequences of physical and chemical mutation inducing agents

Cell arrest or cell death

Base changes

Deletions

Point mutations

High frequency of reversion

Base pair substitutions

Small deletions

Small insertions / duplications

Larger mutations

Low frequency of reversion

Large deletions

Large insertions / deletions

Rearrangements

Chromosome abnormalities

Germinal mutations

Occur in germline

Can be inherited

Somatic mutations

Will not be inherited

Only affect the individual

Missense mutation

Single nucleotide change leads to a single amino acid change

Nonsense mutation

Single nucleotide change that leads to a stop codon and a truncated protein

Null mutations

Complete knockout function of a gene

Effect of mutation in promoter region

Increased or decreased gene expression

Effect of mutation in regulatory sequence of gene

Altered regulation of gene expression

Effect of mutation in 3’ of protein coding region

Defective transcription termination or alteration of mRNA stability

Effect of mutation within intron

Defective mRNA splicing

Effect of mutation in the origin of replication

Defect in initiation of DNA replication

Cystic fibrosis mutation

DF508 most frequent

Deletion of phenylalanine at position 508

Class 1 mutation in CF

Alter production of protein

Class 2 mutation in CF

Alter the maturation and transport of the protein to the plasma membrane

Class 3 mutation in CF

Disturb the regulation of Cl channel

Class 4 mutation in CF

Cause modified ability or selectivity

Class 5 mutation in CF

Affect mRNA stability

Class 6 mutation in CF

Alter stability of mature CFTR protein

Conditional mutation

Mutational phenotype only expressed under certain environmental conditions

Conditional lethal mutation

Environmental conditions etc. can make it lethal

Eg. temperature