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Mutants and Disease. MUPGRET Workshop . Mutation. Heritable change in the DNA sequence. Naturally occurring Induced. Types of mutations. Chromosomal Point Insertion/Deletion DNA repair. Mutagens. Environmental Chemical. Mutations as a tool. Associating a phenotype with a gene.

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mutants and disease

Mutants and Disease

MUPGRET Workshop

mutation
Mutation
  • Heritable change in the DNA sequence.
    • Naturally occurring
    • Induced
types of mutations
Types of mutations
  • Chromosomal
  • Point
  • Insertion/Deletion
  • DNA repair
mutagens
Mutagens
  • Environmental
  • Chemical
mutations as a tool
Mutations as a tool
  • Associating a phenotype with a gene.
  • Understanding gene function.
  • Studying protein interactions.
  • Understanding cell lineage and organ development.
associating a phenotype with a gene
Associating a phenotype with a gene
  • Changes in the DNA sequence that non-functional or reduced function proteins often cause a visible change in the appearance of the organism.
  • Some changes do not give visible phenotypes.
  • Often identified as an “off-type” in plant species.
misspelled genes 3 possible outcomes

Cell may not be able to follow damaged instruction

OR

Damaged protein is made

OR

Spelling error may be harmless

X

X

Damaged protein may or may not be able to function in the cell.

Cell does not make the protein

Functional protein made by the cell

Misspelled Genes: 3 Possible Outcomes

DNA

A misspelled gene

dwarfing
Dwarfing
  • Gibberellic acid (GA) is a plant hormone.
  • GA levels influence growth.
  • Mutants in genes for GA synthesis, reduce plant height.
associating a phenotype 2
Associating a phenotype #2
  • This is often the first step towards understanding the function of a gene or to dissecting a biochemical pathway.
  • The mutation can be either a naturally occurring one or an induced one.
  • Can be targeted or random.
understanding gene function
Understanding gene function
  • “You don’t know how something really works until you have to fix it.”
  • Disruptions of the gene can be either non-functional or “leaky”.
  • Often the “leaky” phenotypes will really help you understand how to gene works.
understanding gene function1
Understanding gene function
  • In the case of targeted mutagenesis where you know what the other genes in that would/could be co-regulated with the mutant are you can understand the pathway better by looking at expression of the co-regulated genes.
understanding gene function2
Understanding gene function
  • In the case of site directed mutagenesis where you can target particular sequences, you can dissect the part of the protein that is important for function.
  • Can help to ID the catalytic site or a site involved in protein-protein interactions or a site involved in transport, etc.
protein explorer
Protein Explorer
  • Protein Explorer http://molvis.sdsc.edu/protexpl/frntdoor.htm
  • Also available at Biology Workbenchhttp://workbench.sdsc.edu/
  • Tutorials at http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/pdb.shtml
  • Troubleshooting http://molvis.sdsc.edu/protexpl/troubles.htm
studying protein protein interaction
Studying protein-protein interaction
  • Often use a series of alleles that have defects in different parts of the gene to identify the site that is required for protein-protein interaction.
  • The series can be insertions, deletions, or point mutations and may come from nature or be induced or a combination of the two.
interaction maps
Interaction Maps
  • Molecular Interaction Maps http://discover.nci.nih.gov/mim/index.jsp
understanding cell lineage
Understanding cell lineage
  • Usually used with transposon mutagenesis.
  • Transposons are mobile pieces of DNA that can insert into a gene and disrupt its function.
  • Insertion can happen throughout development and can be used to track where cells came from with visible marker.
methods for detection mutations
Methods for detection mutations
  • Alteration in electrophoretic mobility
  • Sequencing
  • Protein trunctation test
blazing a genetic trail
Blazing a Genetic Trail
  • It tells the story of how mutations are involved in several different diseases.
  • http://www.hhmi.org/genetictrail/
association genetics
Association Genetics
  • Usually used for medical genetics.
  • Recently applied to plant genetics.
    • Which genes were involved in domestication?
    • Is this gene responsible for part of the difference we see in a particular trait such as plant height?
dwarf 8
Dwarf 8
  • Mutagenesis and trait analysis suggested that d8 might influence flowering time and plant height.
d8 study
D8 study
  • Sequenced D8 in many ~100 maize lines.
  • Measured flowering time and plant height in the same material.
  • Compare DNA sequence to flowering time and plant height.
d8 summary
D8 summary
  • Found several polymorphisms that are associated with changes in flowering time.
  • Data also indicate that D8 has undergone selection.
    • Compare synonymous vs. nonsynonymous substitutions.
plants as a model for disease
Plants as a Model for Disease
  • Sometimes mutations in the same gene in different organisms have similar phenotype.
  • This allows researchers to choose the organism with the best genetic resources to study the normal function of that gene.
  • This also allows researchers to identify prospective genes for a phenotype in one species, based on another.
xeroderma pigmentosa
Xeroderma pigmentosa
  • Autosomal recessive.
  • UV exposure damages DNA.
  • Defect in DNA damage repair.
  • Risks include cancer, telangiectasia, disfigurement.
  • Can be diagnosed before birth.
  • Take total protection measures from sun/fluorescent light.
mechanisms of uv damage
Mechanisms of UV damage
  • Low penetration into tissues.
  • Molecular fragmentation—proteins, enzymes, and nucleic acids contain double bonds that can be ruptured by UV.
  • Free radical generation—molecules of susceptible tissues absorb UV and eject an electron, which is taken up by oxygen, then termed superoxide, a free radical.
free radicals
Free radicals
  • Are scavenged by superoxide dismutase, vitamin C, vitamin E, glutathione peroxidase, carotene.
prions and disease
Prions and Disease
  • Proteins that can change shape.
  • And make other proteins change their shape!
  • As number of changed proteins increases a phenotype is observed.
  • Causal agent of mad cow disease, scrapie in sheep and Creutzfeldt-Jakob disease in humans.
prions ii
Prions II
  • Previously thought only nucleic acid encoded changes caused disease.
  • Stanley Prusiner discovered prion’s ability to change other protein’s structure and won the Nobel Prize.
  • Sup35 is a prion-like protein in yeast.
sup35
Sup35
  • Translation termination factor
  • Carboxyl end binds to the ribosomal complex to terminate translation.
  • If Sup35 is converted to an alternate conformation (infectious prion conformation) the shape change spreads throughout the cell and is passed to daughter cells.
sup351
Sup35
  • In prion conformation causes ribosomes to read through stop codons altering shape and function of proteins.
  • Not adaptively advantageous so why is it maintained?
slide37
Why?
  • True et al. 2000. Nature 407: 477-483.
  • Reduced translation fidelity, extends proteins.
  • Some of these are antibiotic resistant.
  • Could lead to stabilization of new phenotype under correct environment.
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