Gene Mutation

I.  Introduction
a change in the nucleotide sequence that composes a gene.  This is a change or variation from the most common or wildtype sequence.

A mutant allele is an allele that differs from the common allele in the population (also called the wildtype allele).

A mutant phenotype refers to a phenotype that differs from the common or wildtype phenotype.

Mutations are not good or bad, just different from the majority in the population.

Somatic mutations:  are mutations that occur in cells of the body excluding the germline.  Affects subsequent somatic cell descendants. Limited to impact on the individual and not transmitted to offspring.
Germline mutations:  The change occurs during the DNA replication that precedes meiosis.  The resulting gamete and all the cells that descend from it after fertilization have the mutation.

II.  Mutations can alter proteins  -- three examples:

Genotype to disease phenotype

Cystic fibrosis disease                                        CFTR protein        
Duchenne muscular dystrophy                            dystrophin protein
Familial hypercholesterolemia                             LDL receptor protein
Hemophilia A                                                    Factor VIII protein
disease                                            huntingtin protein

III. Causes of Mutation:
    1.  Spontaneous mutation (De novo or new mutations: not caused by exposure to known mutagen)

Errors in DNA replication: DNA bases have slight chemical instability  (exists in alternating forms called tautomers)

 Spontaneous mutation rate: Rate differs for different genes, Size dependence

Sequence dependence, and Hot spots

 On average 1 in 100,000 chance of acquiring a mutation in a gene each round of replication.

 Each individual has multiple new mutations.  Most by chance are not in coding regions of genes.

 Mutation in bacteria can lead to antibiotic resistance. 

Viruses mutate rapidly. 

Influenza vaccines are reassessed each season to accommodate viral changes.

Rapid mutation of HIV virus makes treatment difficult.

     2.    Induced mutations:

Chemicals and radiation can cause mutations. Chemicals causing mutations are called mutagens. Chemicals causing cancer are called carcinogens.

 Alkylating agents:    remove a base

Acridine dyes:   add or remove base

Xrays:                       break chromosomes

                                 delete few nucleotides

UV radiation:            creates thymidine dimers

IV.  Types of Mutations:
Point mutation:

A point mutation is a change of a single nucleotide to one of the other three possible nucleotides


purine replaces purine 

                                                         A -> G   or   G -> A

pyrimidine replaces pyrimidine 

                                                         C  -> T   or   T -> C


purine replaces pyrimidine or

pyrimidine replaces purine

                                                        A or G -> T or C

                                                        T or C ->  A or G

Missense mutation

A point mutation that exchanges one codon for another causing substitution of an amino acid.  Missense mutations may affect protein function severely, mildly or not at all.

 Hemoglobin mutation : glutamic acid -> valine causes sickle cell anemia

Nonsense mutation: A point mutation changing a codon for an amino acid into a stop codon (UAA, UAG or UGA).

Most common cause of factor XI deficiency is a nonsense mutation change glutamic acid to a stop.  Short protein cannot function in clotting.

Insertion or deletion mutations

Addition or subtraction of nucleotides not in multiples of three lead to a change in the reading frame used for translation. Amino acids after that point are different, a phenomenon called a frameshift.

Addition or subtraction of nucleotides in multiples of three leads to addition or subtraction of entire amino acids but not a change in the reading frame.

Two-thirds of Duchenne musular dystrophy cases are large deletions.

Gaucher disease is caused by a single base insertion creating a frameshift.
A tandem duplication is a particular form of insertion in which identical sequences are found side by side. 
Myotonic dystrophy: a triplet repeat disease

    5 -37 copies of CTG repeat      normal  phenotype

    50-1000 repeats                        myotonic dystrophy


A pseudogene is a DNA sequence reminiscent of a gene but which is not translated (may or may not be transcribed).

Not all mutations impact protein function

V.  DNA Repair