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Genetic Variation: Mutation
and Mutagenesis
Mutations provide insight to gene
structure and function (key to “functional
genomics”)
History of key concepts revealed by
mutation:
– Colinearity of genes and protein products was
demonstrated by mutation analysis
– The importance of each base in the code was
shown by analysis of mutations
Mutations occur in many forms and
arise in different ways and are rich
source of variation (polymorphism)
Nature and origin of mutation
Spontaneous vs. induced
– Human deleterious mutations are spontaneous, or
environmentally induced
– Mutation induction in mice (and other model
organisms) is a tool of functional genomics
At different levels:
– Genomic (e.g., aneuploidy)
– Chromosomal (e.g., deletions or translocations)
– Genic (e.g., single base pair changes)
Germline (or gametic) vs. somatic
– Germline mutations are inherited
– Somatic mutations are not, but can, nonetheless,
be deleterious (e.g., cancer)
Mechanical and molecular
basis of mutations
Mechanical mechanisms:
– Errors of mitosis and meiosis (chromosome
mis-segregation) lead to aneuploidy
Molecular mechanisms:
– Deletions and insertions
• From small single-gene changes such as frameshifts to
large changes, causing contiguous gene syndromes
– Single base pair mutations include:
• Transition: purine replacing purine or pyrimidine replacing
pyrimidine (e.g., G<-->A or C<-->T)
• Transversion: purine replacing a pyrimidine or pyrimidine
replacing a purine (e.g., A<-->T or A<-->C)
Human mutation rates can be estimated
Functional Genomics: Mutations
Have Been Informative
Ex.: Analysis of patients with cystic fibrosis
led to cloning of the mutated gene and
determination of the cause of the disease
(defective chloride ion channel).
Ex.: Analysis of patients with hereditary
forms of cancer led to the realization that
defects in DNA repair could lead to mutations
that caused cancer.
Ex.: Mutagenesis in the mouse gave rise to
mouse model for human PKU.
Functional Genomics: Mutations
Will Continue To Be Informative
The “post-sequence age”: What are all
those genes doing?
Mutation strategy:
– Induce mutations in model organism (e.g.,
laboratory mouse)
– Screen test-class individuals for phenotype
• Ex: infertility (or aberrant behavior, or abnormal
cardiac function, or … etc.)
– Identify novel genes affecting physiology