16. Rare Diseases

• multigenic diseases = less severe mutations in multiple genes, only when combined does the phenotype occur
• monogenic diseases = severe mutations in a single gene, tend to be rare diseases due to selective pressure against deleterious mutations. May be caused by recessive mutations and therefore escape selective pressure
• inheritance of traits is often determined by multiple genes
• autosomal dominant = one copy of mutated gene causes phenotype
• autosomal recessive = one copy of the mutated gene just creates a carrier, two copies needed for the phenotype
• genetic linkage = non-random association of markers as these are passed from parent to offspring
• we can use genetic markers to analyse inherited regions (genetic linkage) to narrow down where a mutated gene is located
• a mutation shared by affected individuals are likely to be surrounded by shared alleles at nearby loci - can use these as markers for the mutated gene
• genetic markers:

  • restriction sites
  • SNPs
  • microsatellites (short tandem repeats)
• single bp mutations can alter the ability of restriction enzymes to cut DNA at specific sequences, this can be used to trace inheritance of an area of DNA by following restriction pattern

  • find out which missing restriction sites are common within the individuals with the mutation
• SNPs = single nucleotide polymorphism, a single nucleotide change in the DNA sequence scattered randomly throughout the genome

  • may give susceptibility to disease
  • act as markers of variation and inheritance
• SNP arrays:

  • give fluorescence comparing patients DNA to known sequence
  • different levels of fluorescence depending on if it matches or not
  • can also give different mutations different colours
• GWAS = genome wide association study, can correlate disease or susceptibility to SNPs

  • shows location of mutations
  • can be done on family or population level
• comparative genome arrays are used to analyse whole genome changes, usually losses or gains of chromosomes

  • add patient and control DNA and add to chip
  • label red and green - yellow = no change at all
  • increase in patient = green
  • decrease = red