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

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Flashcards in Day 9, Lecture 2 (Sept 1.): Genetics XII: Non-Mendelian inheritance Deck (13)
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1
Q

Genetic anticipation

A
  • 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
2
Q

Digenic inheritance

A
  • 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
3
Q

X-inactivation

A
  • 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
4
Q

Skewed X-inactivation

A
  • 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
5
Q

Heteroplasmy

A
  • Since there are multiple mtDNA copies per cell, the % of abnormal mtDNA may determine severity and timing of onset of disease.
6
Q

Mitochondrial Genetic Bottleneck

A

The occyte contains only a relatively small number of mtDNA copies

7
Q

Fragile X syndrome

A
  • 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
8
Q

Mytonic dystrophy

A
  • 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
9
Q

Pathogeneis in ‘repeat expansion disorder’

A
  • 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
10
Q

What is the only AR expansion repeat disorder

A

Friedreich’s ataxia

11
Q

Most repeat expansion disorders are due to ___ repeats

A
  • Trinucleotide repeats, but some are due to other repeats.
    • Ex.
      • ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10 (SCA10)
12
Q

Mitochondrial Inheritance

A
  • 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
13
Q

the majority of mitochondrial proteins are translated from

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

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