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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