Day 7, Lecture 2 (Aug 30): Genetics XI: Non-Mendelian Inheritance

Question 1

Mono-allelic expression

Answer 1

• about 100 genes are imprinted
• of these 100 genes only one allele is acitve, while the other allele is inacitve (imprinted/silenced)
• Which allele is imprinted/silenced is determined by parent-of-origin
  
  • since only one copy is active:
    
    • there is limited redundancy- if the active copy has a problem, the other allele cannot correct
    • The pedigree in such cases can be quite confusing

Question 2

Silencing/imprinting is an epigeneitc phenomenon, as it is not caused by

Answer 2

changes to the DNA itslef, but due to differential methylation of cytosines

Question 3

Uniparental disomy

Answer 3

• a unique situation, in which an individual has inherited both copies of an allele or (part of) a chromosome from one parent, rahter than the typical situation of receiving one copy from each parent. There may be 2 consequences to this phenomenon:
  
  1. AR disorders with only one parent being a carrier of a ‘mutated’ allele associated with an AR disorder: eg. about 1/500 children with CF have CF due to homozygous mutations in CFTR, both copies inherited from mother- this is called uniparental isodisomy
  2. Disorders of imprinting: an example is Prader-Willi syndrome, in which you need the paternal chr 15 but it is not presnet and the maternal is methylated

Question 4

Imprinting

Answer 4

• Typically, the protein produced via DNA→mRNA→protein is made 50% by one allele, and 50% by other allele
  
  • For example, phenylalanine hydroxylase (PAH) activity is 50% in a parent of a child with severe PKU, as one allele is non-funcitonal
    
    • The activity is enough to not show clincal symptoms, but enzyme level/activity is not normal
• Imprinted genes constitute about 80-100 genes (of the about 20,000 in the human genome)
• of these 80-100 genes, only one allele is active, while the other allele is inactive (aka imprinted or silenced)
  
  • this is named mon-allelic expression
  • • ​Which allele is imprinted/silenced, and which allele is active is determined by ‘parent of origin’
• this silencing is an epigenetic phenomenon, hence is not caused by DNA changes, but due to differential allele methylation
• in some genes
  
  • the silenced copy is paternal in origin
  • in other genes, the silenced copy is maternal
• Since only one copy in imprinted genes is active
  
  • there is limited redundancy
    
    • if the active copy has a problem, the other allele cannot correct it
    • The pedigree in such cases can be quite confusing

Question 5

Which allele is imprinted/silenced, and which allele is active is determined by

Answer 5

• ‘parent of origin’
  
  • during gametogeneiss the parental/maternal imprints are ‘wiped off’, and the paternal/maternal imprint is placed.

Question 6

Question 7

Imprinting diseases may be associated with

Answer 7

• Disorder imprinting
  
  • example:
    
    • Beckwith-Wiedemann syndrome
• Mutation of the active allele
  
  • Examples:
    
    • Prader-Willi syndrome
    • Angelman syndrome

Question 8

Beckwith-Wiedemann syndrome (BWS)

Answer 8

• example of Disordered imprinting
• Recognizable mutli-system with:
  
  • Macrosomia (large infant)
  • Macroglossia (large tongue)
  • Omphalocele
  • Tendency to hypoglycemia
  • Unusual ear-pits
• Genetics:
  
  • 50-60% of BWS are due to a problem in the gene LIT1 in the Beckwith-Wiedemann critical region
    
    • normally, the maternal copy of LIT1 is imprinted (silenced), while paternal copy active)
    • if maternal LIT1 is hypo-methylated, both copies are active, and cause BWS
  • 2-7% of BWS cases are due to a problem in the gene H19, in the BWS critical region
    
    • Normally, the paternal copy of H19 is imprinted (silenced), while maternalcopy is active
    • If maternal H19 is hyper-methylated, both copies are in-active, and cause BWS
  • 10-20% of cases are caused by uniparental disomy
  • 5-10% have a mutation in the gene CDKN1C, another imprinted gnee in the BWS critical region
• Cases of IVF and ICSI (intra-cytoplasmic sperm injection) the risk of BWS is increased
  
  • presumably, ICSI may obtain sperm that hasn’t yet properly been de-methylated and re-methylated in gametogenesis

Question 9

If a mutation is on the allele that is imprinted than

Answer 9

no disease results

Question 10

What was the first disorder described as associated with imprinting

Answer 10

• Prader-Willi Syndrome (PWS)
  
  • 50-60% of pts have a deletion in the 15q11.2 region
    
    • if the deletion is on the paternally inherited chromosome, PWS is the consequence
      
      • This is because the SNRPN gene is active if paternally inherited
  • the other 40% of pts with PWS do not have a deletion
    
    • Some of the pts with PWS who do not have a deletion, have maternal uniparental disomy, resulting in the absence of paternally acitve SNRPN
    • one possible mechanism causing maternal uniparental disomy in PWS is ‘trisomy rescue’

Question 11

Trisomy Rescue

Answer 11

• Uniparental disomy ussually arises due to an error in meiosis. Two chromosomes in either the egg or sperm cell fail to separate and both get passed to the fetus. As a result, the fetus inherits three chromosomes (Trisomy) rather than two. In relatively rare situations, one of the three chromosomes is lost (termed trisomy rescue), resulting in a “normal’ two chromosome state (disomic) after fertilization. one-third of the time, this loss will result in uniparental disomy

Question 12

Angelman syndrome is not usually due to ‘trisomy’ rescue, because non-dysjuntion is typically a _____ problem. However, Angelman may be due to

Answer 12

• non-dysjunction is typically a maternal problem (esp. in Meiosis I)
• However, angelman may be due to ‘monosomy’ rescue

Question 13

What is the most common trisomy

Answer 13

16, but does not get as much attention because it results in miscarriages and not viable births