2- Mutations at the molecular level to phenotypes

• One gene one polypeptide ‘

• Assume one gene is a coding sequence of DNA that encodes a single polypeptide 

Central Dogma: 

• DNA → RNA → proteins 

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

• mRNA is transcribed in proteins 

Exceptions: 

• Prions proteins which propagate via proteins and not nucleic acids

• Retroviruses which have RNA as the genetic material. The RNA is converted into DNA via reverse transcriptase

Colinearity of gene and polypeptide:  

• Changes in amino acid sequence result from changes in DNA sequence (mutations) 

Spontaneous mutations: 

Replication errors 

• Base substitutions 

• Small amplifications 

Errors during DNA repair 

Base substitutions 

Recombinational errors 

• Large deletions 

• Large amplifications 

• Rearrangements 

Nondisjunction 

• Changes in chromosome number 

• Chromosomes don't segregate properly 

Spontaneous depurination 

• Base substitution 

• Base pairs with the wrong base 

Deamination of cytosine 

• Base substitution 

Transposable elements 

• Insertion 

• Can jump around the genome and sometimes insert where they are not wanted 

Induced mutations & consequences  

Physical agents 

• Ionising radiation 

• UV radiation 

Chemical agents 

• Base analogues 

• Nucleotide analogues 

• Mutagens eg. anticancer agents 

Consequences of above 

• Cell cycle arrest or cell death 

• Base changes 

• Deletions 

Major types of mutations 

• Point mutations

• High frequency of reversion 

• Base pair substitutions 

• Small deletions

• Small insertions / duplications 

• Larger mutations

• Low frequency of reversion 

• Large deletions 

• Large insertions / duplications 

• Rearrangements 

• Chromosome abnormalities 

Classes of mutations 

• Germinal mutations 

• Occur in germline 

• Somatic mutations 

• Will not be inherited; affects only the individual eg. cancer 

• Missense mutations 

• A single nucleotide change leads to a single amino acid change 

• Nonsense mutations 

• A single nucleotide change that ;eads to a stop code and a truncated protein 

• Null mutations 

• Completely knockout function of a gene 

Consequences of mutations dependent on: 

• Location (coding or non coding region)

• Type of mutation (large or small, missense, nonsense, frameshift etc.)

Eg. CFTR gene (cystic fibrosis) 

• Contains 27 exons 

• 250 kb of chromosome 7 

DF508 mutation 

• Most frequent mutation 

• Deletion of the nucleotides deleting phenylalanine at position 508 

Spectrum of CFTR gene mutations 

• More than 1200 mutations are known 

Different levels of what can occur as a result of the mutation: 

• No protein produced 

• Protein not matured 

• Receptor does not regulate properly 

Definitions: 

Mutations 

1. Process which produces a mutant gene set 

2. An alteration in the DNA of a gene or set of genes

Mutant - organism or cell carrying a mutation 

Allele - one of two or more form of the same gene 

Types of mutations 

• Resistance - can grow in presence of eg. antibiotics 

• Lethal - so drastic that organism cannot survive 

• Conditional mutation - eg. siamese cat coat colour 

• Conditional lethal - eg. dead and 25 degrees but alive at 37 degrees - a temperature sensitive mutation