Genetic disorders

• Mutations

  Mutations in the genome that are present in the germline can be passed on to offspring, which can lead to heritable genetic diseases
• Types of mutations

  • Numerical chromosome abnormalities
  • Splice site mutations
  • Mendelian inheritance
  • Locus heterogeneity
  • Incomplete penetrance
  • X-Mosaicism
• Numerical chromosome abnormalities

  • Polyploidy: extra set of chromosomes. Often leads to lethality.
  • Aneuploidy: extra or missing single chromosome
• Splice site mutations

  • Change in sequence length can reduce the efficiency of the spliceosome recognising the splice acceptor site. Exon is 'skipped' and not expressed.
  • Haploinsufficiency: mutation in 1 gene results in the disorder (dominant) as the amount protein produced isn't sufficient.
  • Dominant negative: mutant protein interferes with the function of the 'normal' protein
• Mendelian inheritance

  • Presence of a mutation in 1 gene is sufficient for disease manifestation
• Locus heterogeneity

  • Several genes influence a phenotype. Mutations in any one of the genes can cause the same phenotype.
  • Phenotypic rescue: because mutations occur in multiple different genes, each offspring inherits at least 1 'normal' allele for each gene
• Incomplete penetrance

  • In theory, a dominant allele should always result in 100% penetrance (disease always manifested).
  • In reality, genetic mutations display a varying degree of penetrance (i.e. may not cause disease when otherwise expected to).
  • Why? Genetic background (i.e. variance in other genes in the genome) + environmental effect
• 1. Mosaicism

  • Females possess two X chromosomes. Randomly, one is inactivated. This can lead to deviations from the Mendelian predictions
• Mitochondrial inheritance

  • Inheritance of mitochondrial disease display their own characteristic patterns.
  • mtDNA inherited from mother.
  • Heteroplasmy complicates the pattern of inheritance. Each offspring can have different phenotypes due to differential mitochondria segregation.
  • Symptoms only manifest in each organ if they contain sufficient mutated mitochondria
• Polygenic disease

  • Several genes contribute additively to the end phenotypic outcome of a trait. No dominant or recessive.
  • Genetic variants can have different effect sizes.
  • Recurrence risks amongst siblings for polygenic disease is typically only 5-10%. Why? Because alleles act in an additive way, offspring must inherit several of the diseased alleles.
  • Threshold theory: once the threshold is reached, the disease is manifested.
  • The Carter effect: Some diseases display sex dimorphism where the different sexes require different thresholds. E.g. males more commonly affected
• Twin studies

  • Used to determine the extend to which a particular disease is determined by genetic and environmental factors.
  • Expected that if the trait is genetically determined, it should show 100% concordance.
  • Dizygotic twins (non-identical) are used as a control to see the effect of the environment.
  • Heritability: proportion of phenotypic variance determined by genetic factors.
  • Narrow-sense heritability: genetic variants contribute to phenotypic outcome in an additive fashion.
  • Broad-sense heritability: twin studies estimate the total combined contribution from all the types of inherited genetic contribution (gene-gene interactions AND additive).
  • Broad-sense heritability = 2 x (CRMZ – CRDZ)
  • CRMZ = concordance rate of monozygotic twins.
  • CRDZ = concordance rate of dizygotic twins
• Somatic mutations in non-cancerous disease

  • Mutations occur continually throughout normal growth. They're difficult to detect because they're only present in a small amount of tissue.
  • The earlier a mutation occurs, the more likely for it to cause disease. Higher proportion of cells that it's present in.
  • The locations of the mutation in the lineage will determine the expressed phenotype.
  • Phenotypic variance = environmental variance + heritable genetic variance + personalised genetic variance as a result of somatic mutations in development
• Cancer genetics


  • Uncontrolled cell growth can be considered a natural Darwinian process where mutations confer a selective growth advantage.
  • In multi-system organisms, mechanisms exist to suppress this.
  • In cancers, genetic defence mechanisms are inactivated, via successive mutations. Cancerous cells display some common features:
  • 1. Replicate indefinitely.
  • 2. Evade apoptosis.
  • Genetic mutation is a central event in tumour formation. Mutations which accelerate mutation rate are early drivers of some cancers.
  • Mutations inactivate DNA repair pathways.
  • Mutations increase the rate of cell division and DNA replication.
  • Cytotoxic drugs kill tumour cells but not cancer stem cells. Because, they have the ability to replicate indefinitely, so evade. Aim is to target the cancer stem cells to prevent the tumour re-growing
• Oncogenes


  • Genes that drive cancerous transformation when activated. Activation usually involves a somatically occurring 'gain of function' mutation, which only needs to occur in 1 copy of the gene.
  • Associated cancers usually occur sporadically with no family history
• Oncogene examples

  • Philadelphia Chromosome & Leukaemia
  • MYCN amplification & neuroblastoma
• Tumour suppressor genes

  • Usually suppress tumour formation. Biallelic inactivation - both alleles must be mutated for tumorigenesis.
  • Associated cancers often display a family history, but can also occur sporadically more rarely.
  • Knudson's 2-hit hypothesis: somatic cell in normal person is mutated and passed to offspring. Offspring inherit a mutation, passed down the germ line. This means that in offspring, only 1 mutation is required for cancerous manifestation in any cell
• Tumour Suppressor Examples

  • Breast Cancer
  • Von Hippel-Lindau Syndrome
• Cytotoxic drugs

  Kill tumour cells but not cancer stem cells. Because, they have the ability to replicate indefinitely, so evade. Aim is to target the cancer stem cells to prevent the tumour re-growing.