SF06 Molecular Genetics Disease mechanisms

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SF06 Molecular GeneticsDisease mechanisms

• R.Daniel Gietz Ph.D.
• Department of Biochemistry and Medical Genetics

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Learning Objectives
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Human Genetic Variation

• Humans display a remarkable amount of variation
  in phenotype.
• Height, hair colour, and skin colour
• Variation can be more dramatic the presentation
  of various disease states such as cystic
  fibrosis, Tay Sach disease etc..

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Human genetic Variation

• Mutation can change the DNA sequence in both
  germline cells and somatic cells.
• Somatic mutations can give rise to cancer
• Germline mutations are passed on to subsequent
  generations.

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Variation Lingo

• Alternate forms of the same gene are Alleles.
• If you have the same allele at a locus you are
  homozygous.
• If you have two different alleles at a locus you
  are heterozygous.
• If a gene has more than two alleles at a locus
  the locus is considered polymorphic.

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Human Genetic Variation

• Main Causes
• single base changes changing a single A to a T
  in a gene can change a protein to be non
  functional and give rise to a change in phenotype
  usually deleterious.
• small base deletions or additions the loss or
  addition of one or a few bases from a gene can
  have drastic effects on the function of gene
  product.
• large deletions or insertions of DNA these types
  of changes can occasionally be viewed at the
  chromosomal level
• chromosomal aberrations translocations,
  inversions, deletions. Changes in chromosome
  number Trisomy or monosomy, cause specific
  genetic syndromes such as Down Syndrome.

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Human Genetic Variation

• Single Base changes
• Transitions
• Purine to purine or pyrimidine to pyrimidine
• A to G or G to A T to C or C to T
• Transversions
• Purine to pyrimidine or pyrimidine to purine
• 4 different types.

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Human Genetic Variation

• Single base changes
• Synonymous changes
• Silent mutation (DNA polymorphism)
• Nonsynonymous changes (changes in protein)
• Missense mutations
• Nonsense mutations
• Frameshift mutations

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Human Genetic Variation

• Location of base substitutions in coding DNA is
  nonrandom.
• Non degenerate sites (all 3 sub are
  nonsynonymous)
• 2 fold degenerate sites
• 4 fold degenerate sites

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Genetic Code degeneracy
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Rates of nonsynonymous substitution

• Protein coding genes show a tremendous amount of
  variation in amount of non-synonymous
  substitution.
• Due to natural selection at the level of protein
  function.

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Nonsynonymous base changes

• Changes at the protein level
• Missense mutations
• Nonsense mutations
• Frameshift

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Frameshift Mutation
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Parts of a Gene susceptible to mutation

• Promoter
• Exons
• Intron (splicing involvement)
• Terminator
• Example ? globin gene and ? thalassemia mutations

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? globin gene mutations
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Figure 11-13
B-globin mutations causing b-thalassemia
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Human Genetic Variation

• Main Causes
• single base changes changing a single A to a T
  in a gene can change a protein to be non
  functional and give rise to a change in phenotype
  usually deleterious.
• small base deletions or additions the loss or
  addition of one or a few bases from a gene can
  have drastic effects on the function of gene
  product.
• large deletions or insertions of DNA these types
  of changes can occasionally be viewed at the
  chromosomal level
• chromosomal aberrations translocations,
  inversions, deletions. Changes in chromosome
  number Trisomy or monosomy, cause specific
  genetic syndromes such as Down Syndrome.

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Human Genome and repeat DNA

• Single copy DNA makes up only a small portion of
  DNA in the human genome.
• Cloning and Sequencing and has shown many
  different types of repeat DNA

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Repetitive DNA
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Interspersed human repeat DNA
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Recombination and Repeat DNA

• Recombination can give rise to deletion and
  duplication causing genetic disease.
• Small repeat elements can expand or contract by
  slip strand misspairing

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Recombination contributes to pathology
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Slip strand Mispairing Causing deletion or
duplication
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Recombination can cause gene deletion
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Recombination can cause gene deletion
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Triplet repeat expansion
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Triplet repeat expansion

• Huntington disease CAG 9-35 37-100
• Kennedy disease CAG 17-24 40-55
• Spino-cerebellar Ataxia CAG 19-36 43-81
• Machado Joseph D CAG 12-36 67-75
• Myotonic dystrophy CTG 5-35 50-400
• Fragile X CGG CCG GCC 6-50 200-1000

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Human Genetic Variation

• Main Causes
• single base changes changing a single A to a T
  in a gene can change a protein to be non
  functional and give rise to a change in phenotype
  usually deleterious.
• small base deletions or additions the loss or
  addition of one or a few bases from a gene can
  have drastic effects on the function of gene
  product.
• large deletions or insertions of DNA these types
  of changes can occasionally be viewed at the
  chromosomal level
• chromosomal aberrations translocations,
  inversions, deletions. Changes in chromosome
  number Trisomy or monosomy, cause specific
  genetic syndromes such as Down Syndrome.

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Chromosomal Aberations

• Numerous types of deletions, inversions,
  translocations are caused by problems with
  recombination processes.

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Summary

• Human Variation can occur at various level
• Single base substitution
• Small deletions or additions
• Large deletions or additions
• Chromosomal abberations

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Summary

• Many parts of a gene can affect phenotype
• A variety of mechanisms give rise to the
  variation
• Mutation
• Recombination
• Slipstrand misspairing