Proteins, phenotypes, mutation, and genetic diversity

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Proteins, phenotypes, mutation, and genetic
diversity
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A quick review of enzymes

• Biological catalysts
• Reactions are connected to form metabolic
  pathways
• Metabolism sum of all biochemical reactions
  (pathways)

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Metabolic pathways
An unbranched pathway
A branched pathway
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Pathways and phenotypes

• Defect in an enzyme can change phenotype and
  cause disease
• Enzyme 1 defect PKU
• Enzyme 5 defect alkaptonuria
• Enzyme 6 albinism
• How?
• Why?

See Fig. 10.5 this is a partial list
enzyme 1 is phenylalanine hydroxylase
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PKU Phenylketonuria (OMIM 261600)

• Body cant convert phenylalanine to tyrosine
• Phenylpyruvic acid accumulates and causes brain
  damage
• Phenylalanine is in all proteins, so strict diet
  must be imposed immediately
• Is inherited as a recessive trait
• more about PKU

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Newborn testing for PKU

• Required by all states in U.S.
• Over 10,000 identified out of 100 million
  screened
• No cure, but brain damage can be avoided with
  immediate treatment
• This is one of many diseases for which screening
  is available
• Not all are performed routinely

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How metabolic disorders cause disease

• Intermediate builds up and causes damage
• A needed substance isnt synthesized

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Enzyme defects are found in other metabolic
pathways

• Carbohydrate metabolism
• Galactosemia
• Glycogen storage disorders
• These are accumulation disorders
• Lactose intolerance
• Enzyme becomes less active over time

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Lipid metabolism disorders

• Many are storage disorders- cant break down
  lipids for energy
• Familial hypercholesterolemia
• (OMIM 144010)
• Transport
• disorder

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Lesch-Nyhan Syndrome (OMIM300322)
Inability to metabolize purines Accumulation of
uric acid instead Gout, liver and kidney
failure Mental retardation Self-mutilation X-linke
d recessive Inability to metabolize vitamins and
minerals also documented
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Structural disorders of proteins

• Hemoglobin
• Sickle cell anemia
• Hemoglobin variant- there are many
• Some have no effect
• Autosomal recessive
• Thalassemias
• Insufficient production of hemoglobin
• Mild or severe anemia
• Autosomal recessive

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Sickle cell anemia Anticancer drugs have been
effective
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Phenotypic variations are not always so drastic

• Allergies
• Sensitivities
• Pharmacogenetics genetic basis for sensitivities
  to drugs
• Resistance
• Toxicity
• Predisposition to cancer
• Tasters, nontasters, supertasters

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Ecogenetics

• What is toxic (or carcinogenic) to whom?
• Some people have resistance genes
• How many (allelic frequency)
• What is the distribution of the allele in the
  population?
• How did these mutations arise in the first place?

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What is a mutation?

• A heritable change in DNA
• Somatic
• Affects all daughter cells of affected cell
• Underlying cause of cancers
• Not transmitted to offspring
• Germline
• Single genes
• Chromosomes

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How are mutations discovered?

• Pedigree analysis (Is the change observed in the
  generations that follow?)
• Recessive mutations are hard to spot!
• Direct genetic analysis
• See Table 11.1 in book for rates- range from lt1
  to over 100 per million gametes
• Some calculated rates are 1 in 1012

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How does mutation occur?

• Spontaneously?
• Its complicated
• Species (viruses mutate very rapidly)
• Some genes mutate more frequently than others
• Size
• Presence of many repeats
• Presence of many G/C pairs

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Types of mutations base substitution
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Frameshift mutations

• Remember the triplet codon
• Adding or removing bases changes the reading
  frame

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Transposable elements

• Discovered in corn studied in bacteria
• 40 of human genome may be transposable elements
  http//www.nature.com/scitable/topicpage/transposo
  ns-or-jumping-genes-not-junk-dna-1211
• Disrupt gene expression
• May play regulatory role

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Induced mutations chemicals and radiation
Modify, substitute, intercalate Used to study
mutation Some are used as drugs Handle with
care!
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Base analogs and intercalating agents
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Multiple repair mechanisms
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Mismatch repair

• Error often occur when DNA is being replicated
• Replicating enzyme has proofreading function
• Studied in bacteria- occurs in humans too, but
  with different mechanism
• DNA repair is critical to survival!

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How do you know if a chemical causes mutations?

• Ames test- developed in 1970s
• Uses bacteria, not animals
• Has been modified to simulate processes in
  animals and find promutagens
• Mutagen chemical that causes mutations in DNA
• Carcinogen chemical that causes cancer
• Many mutagens are carcinogens
• Effect in animals dose levels often difficult
  to assess

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The Ames test
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Mutations, genotypes, and phenotypes

• Diploid individuals have two copies of a gene
• In some disorders, a single mutation is the cause
  (sickle cell anemia)
• In others, many different mutations have been
  found
• Example over 1600 mutations of CTFR (cystic
  fibrosis) gene
• What is the effect of having a different mutation
  on each allele?

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Genomic imprinting

• Generally, male and female alleles are required
  for normal development
• Genes are silenced by methylation (imprinting)
• In humans, a limited number of genes are
  imprinted
• In imprinting, one copy of a gene is silenced
• Implicated in certain diseases

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http//universe-review.ca/I10-46-imprint1.jpg
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Why imprinting?

• Not fully understood
• Implicated in diabetes mellitus, autism,
  schizophrenia, and other disorders
• Is only seen in placental mammals
• There is still much to learn about gene silencing
  and gene regulation

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Summary

• Cell metabolism is a collection of biochemical
  pathways
• Many inherited metabolic disorders have been
  described
• Genetic variation arises through mutation
• Mutations can be spontaneous or induced
• Phenotypes are affected by epigenetic factors as
  well as Mendelian inheritance

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A final word (for now) on the epigenome

• epigenome song