Chapter 18: Human Genetics

What are the three main biological constraints that make studying human genetics difficult compared to model organisms (like fruit flies)?

• Few offspring: Humans don't produce large statistical samples in one generation.

• Long generation time: It takes decades to observe inheritance across generations.

• Ethical constraints: We cannot perform controlled breeding experiments on humans.

Since we cannot experiment on humans, what are the three primary methods used to study human genetics?

• Population studies: Analyzing extended families.

• Pedigree analysis: Tracking "natural experiments" (matings that already occurred) to determine inheritance patterns.

• DNA Sequencing: Molecular analysis of families or population-wide association studies (GWAS).

In the context of gene function, explain the "Central Dogma" logic of a genetic disease. (Flow: Gene → Protein → Function).

Gene (Mutated Allele) → Protein (Non-functional or absent) → Function (Loss of cellular function resulting in disease phenotype)

Mechanistically, why are heterozygotes (carriers) "healthy" in Autosomal Recessive disorders?

The single Dominant allele produces enough functional protein to mask the non-functional protein produced by the recessive allele.

What is the specific molecular defect in Sickle Cell Disease?

A single amino acid substitution in the hemoglobin protein.

What are the two physiological outcomes of the Sickle Cell mutation on red blood cells?

• Destruction of RBCs: Leads to lower oxygen capacity and anemia.

• Clumping: Sickle cells clump together, slowing/blocking blood flow, causing tissue damage and pain.

Explain the Heterozygote Advantage regarding Sickle Cell and Malaria

• Homozygous Recessive: Has Sickle Cell disease (severe).

• Homozygous Dominant: Susceptible to Malaria.

• Heterozygote: Has enough functional hemoglobin to avoid Sickle Cell, but the presence of some sickle traits makes them resistant to the malaria parasite. This preserves the allele in populations where malaria is endemic.

How does Autosomal Dominant inheritance differ from Recessive in terms of allele requirements and onset?

• Allele Requirement: Only one mutated allele is needed to show the phenotype (Heterozygotes have the trait).

• Onset: Often appears late in life (post-reproduction), which allows the allele to be passed on before the carrier knows they have it (e.g., Huntington's).

If a person heterozygous for Polydactyly (Pp) mates with a homozygous recessive individual (pp), what is the probability of their child being polydactyl?

50%. (Polydactyly is dominant. The child only needs one 'P' to have extra digits).

Define Aneuploidy versus Nondisjunction

• Nondisjunction: The process/error where homologous pairs or sister chromatids fail to separate during meiosis.

• Aneuploidy: The result—an atypical number of chromosomes (e.g., 2n+1 or 2n-1).

Why are autosomal monosomies (2n-1) almost always fatal in humans, while sex chromosome aneuploidies are often viable?

Autosomes contain essential genes for life; missing one is lethal. Sex chromosomes (specifically X) have mechanisms for dosage compensation (like X-inactivation), making an imbalance less catastrophic.

Give the Karyotype notation, Chromosomal count, and 3 symptoms

• Notation: 45, X0

• Count: 44 Autosomes + 1 X

• Symptoms: Short stature, webbed neck, sterile, no Barr bodies (because there is only one X).

Klinefelter Syndrome: Give the Karyotype notation, Chromosomal count, and 3 symptoms.

• Notation: 47, XXY

• Count: 44 Autosomes + 2 X + 1 Y

• Symptoms: Tall stature, sterile, learning disabilities, Barr bodies present (due to the extra X).

XYY Syndrome: What is the phenotype, and is the "Supermale" theory accurate?

Phenotype is usually normal and fertile. The "Supermale" theory (aggression/criminality) is discredited.

Differentiate between Inversion and Translocation

• Inversion: A segment of a chromosome is reversed within the same chromosome.

• Translocation: A segment of a chromosome moves to a different (non-homologous) chromosome. (Example: Philadelphia Chromosome).

What is PKU (Phenylketonuria), and what is the specific metabolic pathway failure?

• Defect: Failure to metabolize Phenylalanine into Tyrosine.

• Consequence: Phenylalanine converts to phenylketones (toxic), which accumulate and damage the nervous system.

How is PKU managed clinically?

trictly dietary: Avoiding foods high in phenylalanine (meat, fish, dairy, nuts, diet soda). It cannot be "cured," but symptoms are preventable if caught at birth.

Identify the three main types of fetal testing

1. Amniocentesis (sampling amniotic fluid).

2. CVS (Chorionic Villus Sampling - placenta tissue).

3. NIPT (Non-Invasive Prenatal Testing - blood draw from mother).

When you review the "Non-Mendelian" cards, pay close attention to Barr Bodies.

• Professors love to ask: "How many Barr bodies would you find in a cell of a person with Turner syndrome vs. Klinefelter?"

• Turner (X0): 0 Barr bodies.

• Klinefelter (XXY): 1 Barr body (because $n-1$ X chromosomes are inactivated).

• Normal Female (XX): 1 Barr body.

• Normal Male (XY): 0 Barr bodies.