MUTATIONS IN FAMILIES (Inheritance of genetic conditions)

Mutations: change in DNA sequence that leads to a change in protein expression
Allele: refers to different forms of the same gene

• Wildtype (normal), Mutant (different DNA sequence), and Null (mutation that doesn’t lead to a protein or
  deleted)
  Phenotype: the physical appearance of a trait
  Genotype: the allele associated with a trait
  Classes of Mutations:
• Missense: nucleotide change leads to amino acid change (most common C to T)
• Nonsense: change leads to STOP codon
• Insertions: addition of nucleotide that lead to frameshift
• Deletions: deletion of nucleotides
• Splice site: changes RNA splicing
• Expansion of repeating units
  ins or del
  o 3 bp – ins or del one AA (most common mutation in CF delF508)
  o 2 bp ins or del – frame shift
  o 1 bp ins or del – frame shift
• 1 bp substitution
  o Silent – “wobble”
  o Nonsense – AA to “stop”
  o Missense
   Conservative – changes AA to same or similar AA
   Non-conservative – changes AA by function or charge
   May not change a basepair but may change the RNA splice recognition site
  Changes in more than 3 BP:
• Whole gene deletions or duplications
  o Often due to repeated sequences and mispairing in replications
• Portion of gene deleted or fragment inserted
  o Often due to aberrant splicing
  Normal THE BIG RED DOG RAN OUT.
  Missense THE BIG RAD DOG RAN OUT.
  Nonsense THE BIG RED.
  Frameshift (1 bp deletion) THE BGR EDD OGR ANO….
  Frameshift (1 bp insertion) THE BIG RED DOO GRA NOU
  Frameshift (3bp deletion) THE BIG DOG RAN OUT.
  Triplet repeat expansion THE BIG BIG BIG BIG BIG RED DOG RAN OUT.
  Non-coding mutations that affect gene function
• Promoter/enhancer element Trinucleotide repeats in 5 and 3’UTRs
• Splice sites
  Effects of mutation on gene product
• Null allele (loss of function) – no gene product
• Hypomorph – decreased amt/activity
• Gain of function – increased amt/activity
• Dominant negative – antagonizes normal product
• Neomorph – novel activity of product
  Predicting that a gene product won’t do the job
• Deletion, nonsense, frameshift of sequence are deleterious
• Mutation in a splice site usually bad
• Missense mutations
  – Depends on location in protein
  – Is it non-conservative in terms of AA type?
• Is the AA conserved in evolution?
  Which ones will cause disease?
• All but silent or conservative missense sequence changes are likely to significantly alter product function
• Among frameshifts, location of mutation alters likelihood of severity
• Mutations in coding sequence are identified most frequently…but this may change
  Polymorphism:
• A change in DNA sequence that is not disease causing
• Occurs usually in greater than 1% of population
• Usually does not change an amino acid sequence or produces a significant change (ie: valine for isoleucine)
  Autosomal Dominant:
  Autosomal Dominant Inheritance:
• males and females equally affected
• 1 in 2 chance of affected offspring from an affected parent
• male to male transmission
• structural genes, transcription factors
• only one abnormal copy of the gene (allele) to have the phenotype
  Autosomal Dominant probabilities:
  Daughters 50% normal 50% affected
  Sons 50% normal 50% affected
  Neurofibromatosis
• Café au lait spots In Neurofibromatosis
• A large plexiform neurofibroma
• Caused by a mutation in the NF1 gene on chromosome 17.
• This is one of the largest genes in the genome.
• This is the most common autosomal dominant condition.
• This condition if fully penetrant; every one who had a mutation in this gene will have the condition.
• Expression can be variable; individuals with the same mutation can have different disease severity.
• more than 6 café-au lait spots
• > 5mm (prepubertal) or
• > 15mm (postpubertal)
• 2 or more neurofibromas
• 2 or more Lisch nodules of the iris
• inguinal or axillary freckling
• optic pathway tumor
• osseous lesion: sphenoid wing dysplasia or thinning of long bone cortex
• 1
  st degree relative with NF
• diagnosis by 2 or more of the above findings.
  Variations: Co-dominant expression:
  Definition: alleles that are both expressed when they occur in the heterozygous state.
  Example: ABO blood group antigens
• ABO Blood Groups
  o Defined by the presence or absence of two antigens on the surface of the red cell
  o A and B
  o if you have A, you have anti-B antibodies
  o if you have B you have anti-A antibodies
  o if you have neither (O) you have both anti- A and -B
  o Absence of A or B = O
  o Three allele states: Ia
  I
  b
  I
  null
  ABO blood typing: co-dominant alleles
  Variations: New Mutations
• Occur at a rate of 10-4
  to 10-7
  per locus per cell division
• More easily seen in a very large gene
• Paternal age effects
  Autosomal dominant: new mutation
  Achondroplasia:
• Autosomal dominant
• 100% penetrance
• 1/26000: most common genetic dwarfism