7.2 Mendelian & Non-Mendelian Genetics

Gregor Mendel's Classical Laws of Inheritance

Genetics is the study of heredity and variation in living organisms. Modern transmission genetics originated from Gregor Mendel's quantitative experiments on garden peas (Pisum sativum).

1. Mendel's First Law: Law of Segregation

Mendel's Law of Segregation states that an organism possesses two alleles for each gene, which segregate (separate) during gamete formation so that each gamete carries only one allele for each gene.

• Cytological Basis: Occurs during Anaphase I of meiosis, when homologous chromosomes carrying maternal and paternal alleles split and migrate to opposite poles of the cell.
• Monohybrid Cross (Aa x Aa):
  • Genotypic Ratio: $1,AA : 2,Aa : 1,aa$ ($1:2:1$)
  • Phenotypic Ratio: $3\text{ Dominant} : 1\text{ Recessive}$ ($3:1$)

          Parental Gametes: Aa x Aa
               A          a
          +----------+----------+
        A |   AA     |   Aa     |
          +----------+----------+
        a |   Aa     |   aa     |
          +----------+----------+

2. Mendel's Second Law: Law of Independent Assortment

Mendel's Law of Independent Assortment states that the alleles of two or more different genes assort independently of one another during gamete formation, provided the genes are located on different chromosomes or far apart on the same chromosome.

• Cytological Basis: Occurs during Metaphase I and Anaphase I of meiosis, determined by the random orientation of different tetrads on the metaphase plate.
• Dihybrid Cross (AaBb x AaBb):
  • Phenotypic Ratio: $9,A_B_ : 3,A_bb : 3,aaB_ : 1,aabb$ ($9:3:3:1$)

3. The Test Cross (Backcross)

A test cross is used to determine the unknown genotype of an organism displaying a dominant phenotype. The individual with the dominant phenotype ($A_$) is crossed with a homozygous recessive individual ($aa$):

• If the unknown parent is homozygous dominant ($AA$), $100%$ of offspring will display the dominant phenotype ($Aa$).
• If the unknown parent is heterozygous ($Aa$), $50%$ of offspring will display the dominant phenotype ($Aa$) and $50%$ will display the recessive phenotype ($aa$).

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Extensions to Mendelian Genetics

While classical Mendelian traits exhibit simple complete dominance, many eukaryotic traits deviate from strict single-gene dominant/recessive dynamics.

1. Incomplete Dominance

In incomplete dominance, the heterozygous phenotype is a quantitative blend intermediate between the two homozygous phenotypes. Neither allele is completely dominant.

• Example: Crossing true-breeding red snapdragons ($C^R C^R$) with true-breeding white snapdragons ($C^W C^W$) yields $100%$ pink heterozygous offspring ($C^R C^W$).
• Self-cross of Pink Heterozygotes ($C^R C^W \times C^R C^W$):
  • Genotypic and Phenotypic Ratios match: $1\text{ Red } (C^R C^R) : 2\text{ Pink } (C^R C^W) : 1\text{ White } (C^W C^W)$ ($1:2:1$).

2. Codominance

In codominance, both alleles in a heterozygote are fully and simultaneously expressed without blending.

• Example: Human ABO Blood Groups. The gene $I$ encodes a glycosyltransferase enzyme. Alleles $I^A$ and $I^B$ are codominant with each other, while allele $i$ is recessive.
  • Genotype $I^A I^A$ or $I^A i$: Type A blood (expresses A antigen).
  • Genotype $I^B I^B$ or $I^B i$: Type B blood (expresses B antigen).
  • Genotype $I^A I^B$: Type AB blood (simultaneously expresses BOTH A and B antigens on RBC surfaces).
  • Genotype $ii$: Type O blood (expresses neither antigen).

3. Penetrance vs. Expressivity

• Penetrance: A population-level probability defined as the proportion of individuals carrying a specific mutant genotype who actually express the corresponding clinical phenotype. Expressed as a percentage (e.g., $80%$ penetrance means $80%$ of gene carriers display symptoms).
• Expressivity: An individual-level metric describing the intensity or spectrum of phenotypic manifestations among individuals with identical genotypes. Variable expressivity means patients with the exact same genetic mutation experience varying degrees of symptom severity (e.g., Neurofibromatosis type 1).

  Penetrance: Do you show the trait? (Yes/No - Binary Population Metric)
  Expressivity: How severely do you show the trait? (Shades of Gray - Individual Spectrum)

4. Epistasis

Epistasis occurs when the expression of one gene masks or modifies the phenotypic expression of a second, independent gene.

• Example: Labrador Retriever Coat Color. Gene $B$ controls pigment color ($B$ = Black, $b$ = Brown), while Gene $E$ controls pigment deposition in hair follicles ($E$ = Deposition, $e$ = No deposition).
  • If an individual is homozygous recessive $ee$, no pigment is deposited regardless of the $B$ locus, producing a yellow coat.
  • Cross of two double heterozygotes ($BbEe \times BbEe$) yields a modified phenotypic ratio: $9\text{ Black} : 3\text{ Brown} : 4\text{ Yellow}$ ($9:3:4$ recessive epistasis).

5. Pleiotropy vs. Polygenic Traits

• Pleiotropy: A single gene influences multiple, seemingly unrelated phenotypic traits throughout the body. For example, Marfan syndrome results from a single mutation in the fibrillin-1 gene ($FBN1$), causing skeletal elongation, aortic aneurysms, and lens dislocation.
• Polygenic Inheritance: Multiple independent genes exert additive effects to shape a single continuous trait (e.g., human height, skin color, intelligence), generating a bell-shaped Gaussian distribution curve.

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Sex-Linked & Extranuclear Inheritance

1. Sex-Linked (X-Linked Recessive) Inheritance

Sex chromosomes ($X$ and $Y$) determine genetic sex in humans. Genes located on the X chromosome display unique sex-linked inheritance patterns because human males are hemizygous ($X^m Y$), possessing only one X chromosome.

• Males express all X-linked alleles (whether dominant or recessive) because there is no corresponding allele on the Y chromosome.
• Females ($XX$) require two copies of an X-linked recessive allele to express the disease ($X^m X^m$), making X-linked recessive traits far more common in males.
• Carrier Mother ($X^N X^n$) x Unaffected Father ($X^N Y$):
  • $50%$ of sons will be affected ($X^n Y$).
  • $50%$ of daughters will be heterozygous carriers ($X^N X^n$).
  • Key Rule: Affected fathers pass their X chromosome to $100%$ of their daughters and $0%$ of their sons (no male-to-male transmission).

2. Extranuclear (Mitochondrial) Inheritance

Not all genetic material resides in the nucleus. Mitochondria possess their own double-stranded circular DNA (mtDNA) encoding metabolic enzymes, tRNAs, and rRNAs.

• Strict Maternal Inheritance: During fertilization, the sperm contributes only its nuclear genome; its mitochondria are tagged with ubiquitin and destroyed inside the zygote. The zygote inherits all cytoplasm and mitochondria exclusively from the oocyte.
• Pedigree Signature: An affected mother passes a mitochondrial condition to $100%$ of her offspring (both sons and daughters). An affected father passes the condition to $0%$ of his offspring.
• Heteroplasmy: The presence of a mixture of normal and mutant mtDNA within a single cell. Phenotypic severity depends on the proportion of mutant mitochondria partitioned to a given tissue.