Psychology 5137 Topic

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Psychology 5-137Topic 2

• Mendelian Genetics

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Types of Genetic Influence

• Chromosomal
• Monogenic
• (Single-gene, mendelian)
• Multigenic
• (galtonian, multifactorial, polygenic, oligogenic
  disorders with complex genetics)
• Mitochondrial

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Mendels Laws

• Law of Segregation
• Law of Independent Assortment
• Principles
• Inherited characteristics governed by a pair of
  factors (genes)
• One gene inherited from each parent
• Individual genes can come in alternative forms
  (alleles), which can dominate in their expression
  
• In gametogenesis (meiosis) alleles segregate
  independently
• Transmission of alleles affecting different
  characteristics is independent

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Terminology

• Provisional definition of gene - sequence of DNA
  whose primary purpose is the regulation of
  protein synthesis
• Genotype vs Phenotype
• Chromosomes threadlike structures on which
  individual genes are located

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Chromosome 9

• Locus (location) and allele (alternative form)
• Centromere, short (p) and long (q) arms

Centromere
p
q
ABO locus
(9q34.1)
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Karyotype
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Mitosis

• Process of somatic cell duplication in which a
  cell produces two genetically identical daughter
  cells.
• Chromosomes usually visualized during metaphase
• Error nondisjunction of sister chromatids gives
  rise to mosaicism.

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Meiosis

• Process of gametic cell production
  (gametogenesis) in which genetic material is
  reduced by half (from diploid to haploid)
• Error nondisjunction of homologous chromosomes
  (aneuploidy)
• Recombination (we will return to)

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Anueploidy Trisomy 21
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Mendelian Patterns of Inheritance

• Autosomal dominant (Huntington Disease)
• Autosomal recessive (PKU)
• X-linked recessive (Lesch-Nyhan)
• (X-linked dominant)
• (Y-linked holanderic)

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Autosomal Dominant

• A single copy of the deviant gene is sufficient
  to produce the disorder
• AA Aa aa
• Affected Affected Unaffected
• Distinct familial pattern of familial
  transmission.

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Huntington Disease

• Variable age of onset ( anticipation)
• Variable expressivity
• Issues in molecular diagnostics

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Huntington Disease

• Affects 1/20,000 individuals of European ancestry
• Mean age of onset is 35 years, range is neonate
  to 70 years

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Anticipation

• An inherited disorder whose age of onset gets
  earlier and/or severity increases in successive
  generations
• HD unstable mutation (trinucleotide repeat
  expansion but later)

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Kirkwood et al. (2001) Archives of Neurology 58
273-278
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Variable Expressivity

• Choreic Form
• Rigid Form
• Distinct phenotypic manifestations of the
  disorder among individuals with the same genotype
• Distinguish from genetic heterogeneity different
  genotypes give rise to same phenotype

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HD First Success of the Positional Cloning
Strategy?

• In 1983, HD gene locus was mapped to chromosome
  4p (4p16.3) using linkage analysis.
• In 1993, HD gene (proteinhuntingtin) was cloned.
  Mutation is a variable number of CAG repeats
  (trinucleotide repeat). Such that
• lt 35 repeats Unaffected
• 36-39 repeats Possibly affected
• gt 40 repeats Affected
• It is an unstable mutation the number of
  repeats can increase during meiois, especially
  through dads.

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Molecular Diagnostics

• Premobid Diagnosis (Predictive Testing)
• Prior to 1983 50/50 chance
• 1983 to 1993 Risk probability could be refined
• Currently Number of repeats can be quantified

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Penetrance

• HD is completely penetrant because
• Genotype aa Aa AA
• Affected 0 100 100
• Reduced or incomplete penetrance
• Genotype aa Aa AA
• Affected 0 lt100 lt100

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Phenylketonuria

• Nature of gene function
• Pleiotropy
• Genotype-environment interaction

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Phenylketonuria

• 1/10,000 births among Western Northern
  Europeans
• Symptoms
• Severe mental retardation (if untreated)
• Irritable, hyperactive, subject to seizures
• Eczema hypopigmentaion
• Musty odor

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Pleiotropy GxE Interaction

• Pleiotropy one gene can have multiple
  phenotypic effects
• Genotype-Environment Interaction (provisional) -
  PKU phenotype only occurs when the necessary
  genotype is reared in the obligate environment.

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PKU A Public Health Success

• 1934 disorder inheritance pattern
• 1947 metabolic defect determined
• 1954 first successful treatment program
• 1963 Guthrie test developed
• Current All US states and many countries screen
  for PKU

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Treatment Issues

• When should treatment be initiated?
• When should treatment be terminated?
• Maternal PKU

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X-linked Recessive

• Two copies of deviant gene in females but only
  one copy is males is needed to develop the
  disorder.
• Females
  Males
• aa Aa AA a
  A
• Aff Un Un Affect
  Unaff

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Lesch-Nyhan Disease

• 1/380,000 births
• Developmental delay in sitting, crawling
• Low IQ
• Self mutilation

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Summary

• Terminology, mitosis meiosis
• Huntington Disease
• Variable age of onset, anticipation
• Variable expressivity
• Molecular diagnostics
• (genetic heterogeneity, reduced penetrance)
• PKU
• Gene ? behavior
• Pleiotropy
• G x E interaction
• Lesch-Nyhan
• X-linkage
• No effective treatment