Day 9, Lecture 2 (Sept 1.): Genetics XII: Non-Mendelian inheritance

Question 1

Genetic anticipation

Answer 1

• apparent worsening of a disorder in subsequent generations
  
  • The unifying mechanism is triple (less common other than 3) repeats.
  • There is a normal number of repeats, but above a certain cut-off the repeats become unstable, and can expand
  • Expansion occurs in meiosis, and can be parent-specific. The location of the repeats can be 5’UTR, exonic, intronic and 3’UTR. The mechanism of disease can be different as well

Question 2

Digenic inheritance

Answer 2

• Refers to the (rare) observation that disease causation required not 2 alleles in one gene to be dysfunctional, but also one allele in a second gene
• often called tri-allelic inheritance
• Think of as Co-dominance

Question 3

X-inactivation

Answer 3

• Refers to the fact that females typically only hve 1 chrX per cell active. The silencing of the other chrX is initiated through XIST at chrXq13.2, and the mechanism is through methylation.
• Appears to be required in females
  
  • likely related to dosage compensation
• Which of the 2 chrX is inactivated is random event in placental mammals
  
  • but once an X chromosome is inactivated it will remain inactive throughout the lifetime of this cell and its decendents in the organism
  • Since it’s random, it can be randomly skewed

Question 4

Skewed X-inactivation

Answer 4

• Refers to the situation were X-inactivation is different from random.
• Non-random skewed-X inactivation can be due to either positive or negative cell selection mechanisms
• This can modulate expression of disease manifestations of X-linked recessive disorders in females
• may be due to mutated alleles on one of the chrX, or due to a X-autosome translocation
  
  • in a balanced X-autosome translocation the normal ChrX is inactivated preferentially (probably due to a mechanism preventing deleterious monosomy of the translocated autosomal segment)
• For example, if a female is heterozygous for an inactivating mutation in TAZ (assoc. with Barth syndrome)
  
  • most cells express normal tafazzin, possibly due to selective disadvantage of cells with absent tafazzin

Question 5

Heteroplasmy

Answer 5

• Since there are multiple mtDNA copies per cell, the % of abnormal mtDNA may determine severity and timing of onset of disease.

Question 6

Mitochondrial Genetic Bottleneck

Answer 6

The occyte contains only a relatively small number of mtDNA copies

Question 7

Fragile X syndrome

Answer 7

• First example of genetic anticipation
• X-linked disorder (Xq27.3)
  
  • FMR1 gene
  • Series of CGG repeats was identified in the 5’ untranslated region (5’UTR) of this gene
  • the increasing repeat # results in decreased FMR1 production, and leads to disease
  • length correlates to disease severity
  • Repeats can ‘grow’ when passed down the generations
    
    • particulary in maternal meiosis
    • explaining the observation of worsening disease in subsequent generations (anticipation)
• FMR1 protein is critical in the formation and organization of synapses in the brain
• • Characterized
    
    • by intellectual disability associated with autistic features, associated with dysfunction in FMR1
    • minor dysmorphic features
    • hypotonia

Question 8

Mytonic dystrophy

Answer 8

• Expansion disorder
  
  • Associated with expansion of CTG repeats in the 3’ UTR of DMPK
  • Expainsions are more common in maternal meiosis (but can occur in paternal meiosis)
  • exhibits anticipation
• Characterized by:
  
  • Myotonia (inability to relax muscles)
  • intellectual disability
  • Cataracts
  • arrhythmias

Question 9

Pathogeneis in ‘repeat expansion disorder’

Answer 9

• To-date, there are mostly 3 mechanisms:
  
  • Loss of function
    
    • Ex.
      
      • Fragile X syndrome is caused by loss of function of FMR1
      • Friedreich ataxia is caused by loss of frataxin function
  • Gain of function
    
    • Ex.
      
      • Toxicity of excess metabolites, that inhibit other enzymes/metabolites; GADPH binds to stretches of glutamine, and in the case of Huntington disease (HD) excess glutamine may inhibit GADPH
  • Dominant negative
    
    • Sometimes the resulting protein product may interfere with normal physiology, possibly the case in myotonic dystophy

Question 10

What is the only AR expansion repeat disorder

Answer 10

Friedreich’s ataxia

Question 11

Most repeat expansion disorders are due to ___ repeats

Answer 11

• Trinucleotide repeats, but some are due to other repeats.
  
  • Ex.
    
    • ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10 (SCA10)

Question 12

Mitochondrial Inheritance

Answer 12

• Mitochondrial DNA (mtDNA)
  
  • Small (16.569bp)
  • Circular
  • 37 genes (2rRNAs, 22tRNAs and 13 protein-coding)
  • Very gene-dense (no introns)
  • (slightly) different translation code
  • Multiple copies per cell
  • Primitive DNA repair mechanisms (compared to nuclear DNA)
• Inherited from mother

Question 13

the majority of mitochondrial proteins are translated from

Answer 13

• nuclear DNA
• only a small # of proteins in the mitochondria are translated from mtDNA