4.3 Pedigree Analysis

Pedigree analysis is a powerful tool in Mendelian genetics, helping us track inheritance patterns of traits and disorders across generations. By studying family histories visually represented in pedigree charts, we can identify modes of inheritance and predict the likelihood of genetic conditions.

Understanding pedigrees is crucial for genetic counseling and risk assessment. It allows us to infer genotypes, calculate probabilities, and consider complexities like incomplete penetrance and variable expressivity. This knowledge helps in making informed decisions about family planning and genetic testing.

Pedigree charts for inheritance

Understanding pedigree charts

• Pedigree charts visually represent family histories displaying inheritance patterns of specific traits or genetic disorders across multiple generations
• Five main modes of inheritance identified through pedigree analysis
  • Autosomal dominant
  • Autosomal recessive
  • X-linked dominant
  • X-linked recessive
  • Mitochondrial inheritance
• Autosomal dominant inheritance appears in every generation and affects both males and females equally
• Autosomal recessive inheritance typically skips generations and appears more frequently in offspring of consanguineous marriages
• X-linked inheritance patterns display differences between male and female affected individuals, with males typically more affected in recessive conditions
• Mitochondrial inheritance characterized by maternal transmission to all offspring, with no paternal contribution

Complexities in pedigree interpretation

• Presence of de novo mutations complicates interpretation of inheritance patterns in pedigrees
• Incomplete penetrance affects expression of genetic traits in individuals carrying the associated genotype
• Variable expressivity causes differences in the degree or severity of trait expression among individuals with the same genotype
• Genetic heterogeneity occurs when multiple genes can cause the same phenotype (Cystic fibrosis)
• Phenocopies mimic genetic conditions but result from environmental factors (Fetal alcohol syndrome)

Key symbols in pedigree charts

Basic symbols and conventions

• Squares represent males in pedigree charts
• Circles represent females in pedigree charts
• Horizontal lines connecting individuals indicate marriages or matings
• Vertical lines descending from a couple represent their offspring
• Siblings typically arranged from left to right in birth order
• Shaded symbols indicate affected individuals
• Unshaded symbols represent unaffected individuals
• Diagonal line through a symbol indicates the individual is deceased
• Carriers of recessive traits often represented by half-shaded symbols or dots within symbols

Additional pedigree notation

• Roman numerals denote generations (I, II, III)
• Arabic numerals identify individuals within each generation (1, 2, 3)
• Consanguineous marriages indicated by double lines connecting partners
• Proband, individual through whom family history is ascertained, typically indicated by an arrow
• Brackets indicate twins, with vertical line for fraternal and horizontal line for identical twins
• Pregnancy represented by a diamond symbol
• Spontaneous abortion or miscarriage indicated by a small triangle
• Adoption shown by brackets around the symbol

Genotypes from pedigree analysis

Inferring genotypes

• Genotypes inferred by analyzing distribution of affected and unaffected individuals across generations and within sibships
• Autosomal dominant traits
  • Affected individuals typically heterozygous (Aa)
  • Unaffected individuals homozygous recessive (aa)
• Autosomal recessive inheritance
  • Affected individuals homozygous recessive (aa)
  • Carriers heterozygous (Aa)
• X-linked inheritance requires consideration of hemizygosity in males, who have only one X chromosome
• Presence of affected offspring from unaffected parents indicates carrier status in recessive conditions
• Punnett squares used to predict possible genotypes and their frequencies in offspring
  • Example: Crossing two carriers (Aa x Aa) for autosomal recessive trait $$\begin{array}{c|cc} & A & a \\ \hline A & AA & Aa \\ a & Aa & aa \end{array}$$
• Hardy-Weinberg equilibrium applied to estimate allele frequencies in populations based on observed phenotype frequencies
  • Formula: $p^2 + 2pq + q^2 = 1$, where p and q are allele frequencies

Advanced genotype analysis

• Linkage analysis used to track inheritance of genetic markers near disease-causing genes
• Haplotype analysis examines patterns of alleles on a single chromosome to infer inheritance
• Genomic imprinting affects gene expression based on parental origin of alleles (Prader-Willi syndrome)
• Mosaicism results in different genotypes within the same individual, complicating pedigree interpretation

Probability from pedigree analysis

Calculating genetic probabilities

• Carrier probability calculated by considering genotypes of parents and inheritance pattern of trait
• Autosomal recessive disorders
  • Offspring of two carriers have:
    • 25% chance of being affected
    • 50% chance of being carriers
    • 25% chance of being unaffected non-carriers
• X-linked recessive disorders
  • All daughters of affected male will be carriers
  • Sons will be unaffected
• Bayesian analysis updates probability estimates based on new information (genetic test results, status of additional family members)
• Penetrance affects accuracy of probability assessments
  • Complete penetrance: all individuals with genotype express phenotype
  • Incomplete penetrance: some individuals with genotype do not express phenotype

Advanced probability considerations

• Genetic counselors use pedigree analysis with molecular testing to provide risk assessments for individuals and families
• Population genetics principles influence probability of carrier status in certain populations
  • Founder effects increase frequency of specific alleles in isolated populations (Tay-Sachs disease in Ashkenazi Jewish population)
  • Consanguinity rates affect probability of recessive disorders
• Conditional probability used to assess risk given specific family history
• Age-dependent penetrance considered for late-onset disorders (Huntington's disease)
• Anticipation phenomenon where genetic disorders become more severe or appear earlier in subsequent generations (Myotonic dystrophy)