Genetic Principles

Principles

• Codominance
  • both allelic copies are expressed
    • e.g.) blood groups (A, B, AB)
• Variable expression
  • nature and degree of phenotype vary from 1 individual to another with the same mutation
    • e.g.) 2 patients with neurofibromatosis may have varying disease severity
• Incomplete penetrance
  • not all individuals with a mutant genotype have diseased phenotype
    • explanation for a dominant disease “skipping” a generation
  • penetrance can be calculated by ( # with symptoms) / (# with disease genotype)
    • must be figured into recurrance calculations
      • if parents have a 50% chance of giving defective gene but the penetrance is 50%
        • 0.5 x 0.5 x100 = 25% of recurrence
  • observed in recessive and dominant diseases
• Pleiotropy 
  • single mutation has diverse effects upon several organ systems
    • e.g.) PKU
• Anticipation 
  • changes in disease presentation in succeeding generations
    • ↑ severity
    • earlier onset 
  • caused by trinucleotide expansion 
    • region of repeating triplets expands in each generation
    • e.g.) Huntington’s disease, fragile X, myotonic dystrophy, Friedreich ataxia
• Loss of heterozygosity
  • “two-hit model”
  • individual inherits or develops a mutation in one copy of gene
    • disease occurs when the complementary allele is lost
  • e.g. tumor suppressor diseases (Li-Fraumeni, retinoblastoma)
• Dominant negative mutation
  • mutant gene product antagonizes wild-type gene product
    • exerts a dominant effect
    • e.g.) common in multimeric proteins where one mutant subunit can change function of entire enzyme
• De novo mutation
  • genetic disease in an individual with no familial history
  • recurrence risk for offspring of same parents is low
• Locus heterogeneity 
  • different mutations can produce the same phenotype
    • e.g., marfanoid habitus caused by
      • Marfan’s syndrome, MEN 2B, homocystinuria
• Heteroplasmy 
  • presence of both normal and mutated mitochondrial (mt)DNA in the same cell
    • results in variable expression in mitochondrial inherited disease   
• Uniparental disomy 
  • offspring receives both copies of a chromosome from 1 parent
    • no copies from the other parent
    • causes disease if the chromosome is usually imprinted
      • see Epigenetics topic
• Polygenic inheritance 
  • multiple genes are responsible for inheritance of a disease
  • e.g.) androgenic alopecia
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• Heritability
  • can measure the relative effect of genetic vs. environmental factors on a phenotype
    • calculated by phenotypic relationship between dizygotic (DZ) and monozygotic (MZ) twins
    • heritability = (C_MZ-C_DZ) / (1-C_DZ)
      • where C = concordance
        • prevalence of disease in both twins
        • entirely environmental disease should have C_MZ = C_DZ
        • entirely genetic disease should have C_MZ=1.0 and C_DZ=0.5
• siblings share 50% of their genes