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 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 = (CMZ-CDZ) / (1-CDZ) where C = concordance prevalence of disease in both twins entirely environmental disease should have CMZ = CDZ entirely genetic disease should have CMZ=1.0 and CDZ=0.5 siblings share 50% of their genes