The Human Genome and Disease: Monogenic and Polygenic Inheritance

Apply pedigree analysis to explain different methods by which mutations can be inherited.
Explain the process of finding disease-causing genes using Next-Generation Sequencing (NGS).
Outline specific examples of monogenic and polygenic diseases.
Describe the concept of genetic determinism and the role of gene-environment interactions.

Definition: Mutations are permanent changes to the DNA sequence and serve as the primary driving force for evolution.
Classification by Origin:
- Germline Mutations: These occur in the gametes (eggs and sperm). They are inherited and passed on to the next generation.
- Somatic Mutations: These are acquired by somatic cells through DNA damage or incorrect copying. They are not passed to the next generation.
Impact of Mutations:
- Mutations can have beneficial, neutral, or deleterious (harmful) effects.
- The vast majority of mutations have no effect on the organism.
- The outcome of a mutation is influenced by environmental effects (e.g., diet, exposure to toxins) and the "genetic background" (interaction with other genes).

Dominant vs. Recessive Alleles:
- Humans are diploid, possessing two copies of each gene (maternal and paternal).
- Heterozygous: One mutant allele and one wildtype allele.
- Homozygous: Both alleles are mutant.
- Dominant Mutation: One that causes a phenotype even when heterozygous.
- Recessive Mutation: One that causes a phenotype only when homozygous.
Loss of Function vs. Gain of Function:
- Loss of Function: The mutation causes the gene to break, work poorly, or not work at all. These are often recessive because a normal copy on the other chromosome can usually compensate for the lost function.
- Gain of Function: The mutation causes a gene to work "too well" or perform a novel, unexpected function. These are often dominant because the normal copy cannot mask the overactive or novel activity of the mutant allele.

Autosomal Recessive:
- Characteristics: Typically skip generations. Affected individuals are often offspring of two asymptomatic carriers. Males and females are equally likely to inherit the trait.
- Examples: Inability to taste phenylthiocarbamide (PTC), Cystic Fibrosis.
Autosomal Dominant:
- Characteristics: Occurs commonly in the pedigree. Affected individuals must have at least one affected parent. Males and females are equally likely to inherit the trait.
- Examples: Widow’s peak, Huntington disease.
X-linked Recessive:
- Characteristics: Primarily affects males. Fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
- Examples: Haemophilia A, Haemophilia B.
Identification Strategy:
- Rule out X-linked inheritance if male-to-male transmission is observed.
- If carriers (individuals who do not show the condition but pass it on) are absent, the condition may be dominant.
- Find the pattern that explains every instance of the disease in the pedigree.

Clinical Presentation: Disorders of blood clotting involving high risk of death from uncontrolled bleeding and tissue damage from internal bleeding.
Haemophilia A (Classic): Most common form ( $1/5000$ males). Caused by impaired or absent clotting factor VIII.
Haemophilia B: Clinically indistinguishable from A, but affects factor IX.
Genetics: X-linked recessive disorders. Often caused by an inversion in the Factor VIII gene on the X-chromosome. These are "loss of function" mutations.
Inheritance: Sons of carrier women have a probability of $0.5$ for inheriting the disease. Approximately $30\%$ of cases are sporadic (no family history).
Treatment: Intravenous infusion of the missing protein.
Historical Note: Queen Victoria was a known carrier of Haemophilia (likely B).

Clinical Presentation: Progressive tremors, involuntary movements, and neurodegeneration with mid-life onset (ages $30-50$ ).
Genetics: Autosomal dominant inheritance on Chromosome 4 (HTT gene).
Molecular Basis: Expansion of a CAG triplet repeat. CAG codes for glutamine, leading to a long polyglutamine tract. The resulting unstable protein fragments and clumps in nerve cells, causing damage.
Testing and CAG Repeat Thresholds:
- $10-26$ copies: Normal.
- $27-35$ copies: Risk of descendants developing HD.
- $36-40$ copies: Risk of developing the disease personally.
- $40+$ copies: Disease develops.
Pedigree Probabilities: If a parent is heterozygous ( $Hh$ ) and the other is $hh$ , the probability an individual contracts HD is $0.5$ . For a grandchild where the parent's status is unknown but has a $0.5$ chance of being a carrier, the probability is $0.5 \times 0.5 = 0.25$ .
Ethical Considerations: Testing allows detection before symptoms, but some family members (e.g., Amy and Beth) may have conflicting views on wanting to know results that reveal their own status.

Historical Background: Folklore noted that children whose foreheads tasted salty were "bewitched" and would die. In 1606, Alonso y de los Ruyzes de Fonteca described this salty sweat phenomenon.
Clinical Presentation: Lung infections, pancreatic insufficiency, salty skin, and congenital absence of the vas deferens in males.
Genetics: Autosomal recessive. The gene (CFTR - Cystic Fibrosis Transmembrane Regulator) was identified in 1979 and located at $7q31.2$ .
Molecular Basis: CFTR is a chloride ion transporter. Reduced function causes thickened cell secretions.
Common Mutation: DeltaF508 (a $3bp$ deletion) is the most common, resulting in protein degradation. It is carried by $1 \text{ in } 25$ Northern Europeans.
Theory: The high frequency of DeltaF508 might be due to a selective advantage for heterozygotes.
Treatment: New therapies attempt to rescue miss-addressed proteins.

Whole Genome Sequencing (WGS): Used to identify genetic variations present in affected individuals but absent in unaffected individuals within a pedigree.
The Workflow:
1. Sequence Genome(s).
2. Map to Human Reference.
3. Filter out Common variants to find Novel variants.
4. Distinguish between variants predicted to be Harmful vs. Benign.
5. Validate and Test.

Polygenic/Complex Disorders: These involve multiple genes acting together or interacting with environmental factors. They do not follow simple Mendelian inheritance patterns.
Examples: Obesity, Diabetes, Rheumatoid arthritis, Gout, Bipolar disorder.
Identification: Requires comparing large cohorts (Cases: $10-100K$ vs. Controls: $10-100K$ ) to find shared variants in cases that are absent in controls.
Genetic Determinism: Most genetic disorders are probabilistic rather than deterministic. Having a disease-related variation does not guarantee the disease will develop. Diseases occur through a combination of variants and environment; different sufferers may have different underlying disease mechanisms.