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Genetic Variation: Mutation
and Mutagenesis
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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
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Mutations occur in many forms and
arise in different ways and are rich
source of variation (polymorphism)
Nature and origin of mutation
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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
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At different levels:
– Genomic (e.g., aneuploidy)
– Chromosomal (e.g., deletions or translocations)
– Genic (e.g., single base pair changes)
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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
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Mechanical mechanisms:
– Errors of mitosis and meiosis (chromosome
mis-segregation) lead to aneuploidy
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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)
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Human mutation rates can be estimated
Functional Genomics: Mutations
Have Been Informative
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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
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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