BISC 471879 200203

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BISC 471/879 2002-03

• Molecular Genetics
• Dr. Esther Verheyen
• SSB 8111
• everheye_at_sfu.ca
• TA Kristi Charish
• SSB 7152

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General information

• Lecture notes will be on reserve and can be
  purchased as a package at Quad books
• Lectures will be Wednesdays for 2 hours in AQ3005
  and Fridays for 1 hour in C9000 (Note- this is a
  room change!)
• 3 tutorial sections (used for going over class
  material and for presentations)
• Office hours - Fridays at 1130 or by appointment

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Course Overview

• Topics
• Grading
• Presentations
• Exams
• Tutorials

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Topics

• 1. Human genetic disease
• 2. Structure of the human genome
• 3. Mapping the genome
• 4. Molecular analysis of single gene disorders
• 5. Genetic analysis of complex disease

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Topics (cont)

• 6. Gene therapy
• 7. Gene testing
• 8. DNA fingerprinting
• 9. Ethical considerations of human genetics

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Grading for Undergrads

• One midterm exam (40) on October 16th
• Final Exam (40) on November 29th
• Presentation in tutorial section (15)
• Attendance at tutorials (5)

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Presentations

• Will be starting in 4 weeks (October 2)
• Will be 10-15 minutes long (3 per class)
• To be based on a recent research paper
  (2001-2002) on a gene discussed in a chapter of
  Genome
• Sign up sheet will be on the door of SSB 8111

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Exams

• Primarily short answer
• Based on material in text (I expect you to do the
  assigned reading) and additional materials
  presented in class
• Will incorporate some direct recall and some
  experimental design and thought provoking
  questions

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The study of human genetic disease

• Inheritance patterns in single-gene defects and
  complex traits
• factors influencing expression of certain
  diseases
• chromosomal mutations
• mitochondrial mutations

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Inheritance patterns of human genetic diseases

• autosomal recessive
• homozygous individuals usually born to unaffected
  parents
• parents are unaffected carriers
• affects either sex
• requires inheritance of 2 defective alleles
• usually due to loss of gene function

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Autosomal recessive diseases

• cystic fibrosis 1/2000
• recurrent lung infections, infertility in males
• phenylketonurea (PKU) 1/2,000-5,000 in Europeans
• mental retardation
• b-thalassemia 1/20,000 in general population
  1/100 in areas where malaria is endemic
• severe anemia (depletion of rbc)
• Tay-Sachs disease 1/3000 in Ashkenazi Jews
• neurological degeneration, blindness, paralysis

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Autosomal Dominant Inheritance

• affected person has an affected parent
• transmitted by either sex
• affected person has 50 chance of passing on
  disease to offspring
• Usually due to gain of function or novel
  function of gene (neomorphic mutation)

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Autosomal dominant diseases

• Huntington Disease 1/10,000
• late onset, involuntary movements, dementia
• Myotonic Dystrophy 1/8,500
• prolonged muscle contraction (myotonia), muscle
  atrophy, cataracts
• Neurofibramomatosis, type I 1/4,000-5,000
• tumours on the peripheral nerves of the head,
  neck and body pigmented café-au-lait spots

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X-linked recessive inheritance

• affects mainly males
• often find affected uncles and nephews
• males are usually born to carrier mothers
• carrier females can show symptoms resulting from
  X-inactivation
• never get male to male transmission

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X-linked recessive diseases

• Duchenne muscular dystrophy males 1/3,500
• early onset, progressive muscle weakness, severe
  skeletal muscle degeneration
• Haemophilia A males 1/5,000
• deficiency of clotting factor VIII, excessive
  bleeding from minor traumas, internal bleeding
• Fragile X syndrome males 1/1,500, females 1/2,500
• mental retardation
• mildly affects 1/3 of female carriers- appears
  partially dominant

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X-linked dominant inheritance

• affected fathers pass disorder to daughters,
  never to sons
• vitamin D-independent rickets
• quite rare

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Factors affecting the expression of a disease

• Genetic heterogeneity
• non-allelic loci that produce the same phenotype
• Deafness, polycystic kidney disease
• mutations in same gene cause different phenotypes
• Muscular dystrophy- Becker, Duchenne

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Complementation

• Heterogeneity is often seen in syndromes that
  result from failure of a complex pathway - eg.
  profound congenital hearing loss
• if two affected individuals marry, often their
  children are unaffected ? complementation
• parental cross a1a1 x a2a2 aaBB x Aabb
  ? ? a1a2 mutant offspring AaBb
  wildtype one locus two loci failure to
  complement complementation

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Factors affecting the expression of a disease

• Penetrance
• measure of the frequency of a phenotype when a
  given genotype is present
• usually refers to incomplete penetrance
• some individuals with a mutant genotype show no
  symptoms
• Variable expressivity
• some aspect of the phenotype is always observed
  but the degree varies among individuals

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Variations in penetrance and expressivity
Non-penetrance appears to skip a generation,
looks recessive
Variable expression each quandrant refers to a
specific phenotype often due to influence of
other genetic factors or the environment
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Other factors affecting expression

• Mosaicism
• when all the cells in the body do not have the
  same genotype
• can affect either germline or somatic tissues
• in germline can cause a spontaneous mutation in
  offspring
• human mutation rates 1/107per gene per cell
  generation- bodies contain 1013 cells.
• only if a somatic clone occurs in relevant tissue
  or causes a substantially sized clone will a
  disease manifest
• if mutation confers growth advantage (cancer)
• if mutation occurs in early embryo
• Chimeras
• a fusion of two genetically distinct zygotes

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Other factors affecting expression

• Phenocopy
• an environmental factor triggers an illness that
  resembles a genetic disease
• eg. deafness due to rubella infection in
  pregnancy
• Environmental effects
• an illness may be exacerbated by the environment,
  or can be treated by controlling the environment
• eg. Severity of PKU due to amount of
  phenylalanine in diet
• Anticipation
• severity increases with each successive
  generation
• often can be confused with random variations in
  severity

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Other factors affecting expression

• Anticipation
• A special type of variable expression
• Tendency of some dominant disorders to become
  more severe with successive generations
• Found to be caused by expansion of tri-nucleotide
  repeats
• Repeat length increases with each generation
• Severity of disease increases with increased
  repeat length
• Found in Fragile X syndrome, myotonic dystrophy
  and Huntingtons disease
• Imprinting
• Expression of an allele depends on which parent
  it was inherited from - allele is somehow
  marked
• One particular case- a deletion of 15q12 results
  in 2 different syndromes depending on which
  parent it was inherited from (Prader-Willi
  syndrom from dad, Angelman syndrome from mom)

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Multifactorial or complex disorders

• Genetic component is influenced by environment
• Often due to the interaction of several genes
• Genotype does not necessarily predict phenotypic
  outcome
• Studies
• Family studies- increased risk within families as
  compared to general population
• Adoption studies
• Twin studies- reared together or apart

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Molecular Genetics on the Internet

• OMIM (On-line Mendelian Inheritance in Man)
• catalog of human genes and genetic disorders
  organized by Victor McKusick
• www.ncbi.nlm.nih.gov/Omim
• NCBI (National Center for Biotechnology Info)
• Links to Medline, GenBank, Omim
• Great starting out point
• www.ncbi.nlm.nih.gov/
• www.ncbi.nlm.nih.gov/PubMed/ (for Medline- main
  way to locate papers)

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Molecular Genetics on the Internet

• Genome projects
• US Human Genome Mapping Project
• www.ornl.gov/hgmis/
• UK Human Mapping Project Resource Centre
• www.hgmp.mrc.ac.uk/ (select Genome web sites)
• Genome Database
• www.gdb.org
• Model organisms
• Drosophila (www.fruitfly.org/annot/)
• C. elegans (www.sanger.ac.uk/Projects/C_elegans/ )