Exp 5: Construction & Genetic Analysis of Human Pedigrees: Identifying Modes of Inheritance & Risk Probabilities

Because controlled experimental breeding crosses cannot be conducted in humans, human transmission genetics relies on the retrospective compilation and systematic genealogical analysis of family medical histories recorded as pedigree charts.

Determining the mode of inheritance follows an exclusionary diagnostic algorithm based on five primary Mendelian and non-Mendelian patterns:

• 1. Autosomal Dominant (AD – e.g., Huntington Disease, Marfan Syndrome, Achondroplasia):
  Vertical transmission pattern across every generation (no skipping). Every affected child has at least one affected parent. Unaffected family members do not transmit the trait. Males and females are affected in equal numbers and transmit the trait with equal probability ($50%$ risk to offspring). Male-to-male transmission is observed.
• 2. Autosomal Recessive (AR – e.g., Cystic Fibrosis, Sickle Cell Anemia, Phenylketonuria, Tay-Sachs):
  Horizontal transmission pattern (trait often appears only in siblings of one generation). Trait skips generations; affected individuals typically have phenotypically normal carrier parents ($Aa times Aa$). Males and females are affected in equal numbers. Consanguinity (mating between biological relatives) dramatically increases recurrence risk. Offspring of two carrier parents have a $25%$ ($1/4$) risk of being affected.
• 3. X-Linked Recessive (XLR – e.g., Duchenne Muscular Dystrophy, Hemophilia A/B, Red-Green Color Blindness):
  Marked male predominance (males are hemizygous $X^a Y$ and express the disease from a single mutant allele). Trait skips generations via asymptomatic female obligate carriers ($X^A X^a$). Diagnostic hallmark:NO male-to-male transmission (fathers transmit only their Y chromosome to sons). Carrier mother transmits mutant allele to $50%$ of her sons (affected) and $50%$ of her daughters (carriers). All daughters of an affected male are obligate carriers ($X^A X^a$).
• 4. X-Linked Dominant (XLD – e.g., Hypophosphatemic Rickets, Incontinentia Pigmenti):
  Affected males transmit the condition to $100%$ of their daughters and $0%$ of their sons. Affected females transmit the condition to $50%$ of all offspring regardless of sex. Generally more prevalent in females, but often milder due to random X-inactivation (lyonization).
• 5. Mitochondrial (Maternal) Inheritance (e.g., Leber Hereditary Optic Neuropathy, MELAS):
  Transmitted exclusively through the maternal lineage (sperm mitochondria are tagged with ubiquitin and degraded upon egg fertilization). An affected mother transmits the disease to $100%$ of her children. An affected male never transmits the condition to any of his offspring.