Human Genome & Disease

Mutations

  • Mutations are permanent changes to DNA sequence, can be inherited (germline - passed via gametes) or acquired (somatic - not passed to next generation).
  • Most mutations have no effect, but can be beneficial or deleterious, influenced by environment and other genes.

Classifying Mutations

  • Dominant vs. Recessive: Based on whether a phenotype appears in heterozygotes or only in homozygotes, respectively.
  • Loss of function vs. Gain of function: Whether a mutation disrupts or enhances gene function; loss-of-function often recessive, gain-of-function often dominant.

Inheritance Patterns

  • Pedigree analysis helps determine if an allele is dominant/recessive, autosomal, or sex-linked.

Monogenic Diseases

  • Examples: Haemophilia A/B (X-linked recessive), Huntington disease (autosomal dominant), Cystic fibrosis (autosomal recessive).

Haemophilia A & B

  • Disorders of blood clotting, mostly affects males.
  • Haemophilia A: Impaired factor VIII, Haemophilia B: Impaired factor XI.
  • X-linked recessive: Sons of carrier women have 0.5 probability of inheriting.

Huntington Disease

  • Progressive tremor, involuntary movements, neurodegeneration, mid-life onset.
  • Autosomal dominant inheritance.
  • Caused by expansion of CAG triplet repeat in HTT gene, leading to unstable protein.
  • Genetic testing can determine disease development risk using PCR to measure CAG repeat length.

Cystic Fibrosis

  • Lung infections, pancreatic insufficiency, salty skin.
  • Autosomal recessive inheritance.
  • Caused by mutations in CFTR gene (chloride ion transporter).
  • deltaF508 is common mutation; new treatments aim to rescue mis-addressed proteins.

Finding Disease Genes

  • Sequence genomes, map to reference, identify common/novel variants, predict harmfulness, validate and test.

Polygenic Disorders

  • Involve multiple genes and environmental factors.
  • Examples: Obesity, diabetes, rheumatoid arthritis, bipolar disorder.

Finding Polygenic Disease Genes

  • Identify variations, compare cases vs. controls, look for shared variants in cases, validate and test.

Genetic Determinism

  • Most diseases are probabilistic, arising from a combination of genetic variations and environment; genes do not guarantee destiny.