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Genetics of cell growth and division > mtDNA inheritance > Flashcards

mtDNA inheritance Flashcards

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1
Q

how is mtDNA inherited in humans?

A

maternally

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2
Q

why are yeast good for studying mt?

A

they are faculative anaerobes so can generate energy through glycolysis so can survive loss of mt

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3
Q

how is mtDNA inherited in yeast?

A

by both parents- results in heteroplasmy

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4
Q

how is mtDNA variation generated?

A

10x faster mutation rate due to no protective histones, decreased repair in mtDNA, lack of proofreading activity of polG, high conc of free radicals from respiration

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5
Q

what are the sources of heteroplasmy?

A
  • inheritance of germline mutations
  • age related mutations
  • introduction of foreign mt to reconstructed embyros
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6
Q

what are the 3 theories of how mt bottleneck occurs?

A
  • passive reduction- in oocyte have high copy no. by chance get different segregation that results in reduced copy no.
  • packaging into homoplasmic clusters- segregation of nucleoids
  • selective amplification of certain mtDNA molecules
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7
Q

what is the evidence for selective amplification?

A

during oocytes maturation, in meiosis, certain mtDNA molecules amplified so heteroplasmy levels change between generations. also get random segregation during mitosis after fertilisation. beneficial mt are selected over variants

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8
Q

what is reduced in sperm when compared to spermatogonium?

A

TFAM and mtDNA levels

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9
Q

where is TFAM levels lower than in any other organ?

A

testes

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10
Q

elimination of paternal mDNA in c.elegans

A

paternal mt gradually disappears in oocyte by autophagy. Ubiquitination also involved in degradation. CP5-6 (a homologue of endoG) degrades paternal mtDNA, this degenerates the membrane then allophagy completely destroyed the mtDNA by 4 cell stage

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11
Q

elimination of paternal mDNA in drosophila

A

mostly eliminated during spermatiogenesis- the mt fuse to elongate. EndoG degrades nucleoids. investment cone removes the remaining paternal mtDNA. upon fertilisation vesicles surround sperm derived flaggelum, ATG8a and Rab7 localise to vesicle- endocytosis and autophagy fragment mt. the fragmented mt is engulfed by autophagosomes

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12
Q

how is paternal mtDNA prevented from entering chinese hamsters?

A

sperm tail doesnt enter egg

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13
Q

what is an alternative theory to degeneration of paternal mtDNA in embryos?

A

The paternal mtDNA is eliminated during spermatogesis. uneven distribution to one of the blastomeres

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14
Q

how many people carry a known mtDNA point mutation?

A

1 in200

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15
Q

how many children are born with an inherited mt disease?

A

1 in 4000

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16
Q

what does threshold level mean?

A

% of genomes that must be mutant before disease present

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17
Q

how can a cell return to homoplasmy

A

by chance due to random mitotic segregation

18
Q

why do offspring have different mutant loads?

A

due to random meiotic segregation- will have different amounts of mutant mtDNA so may/may not have disease

19
Q

which tissues have higher oxphos requirements?

A

heart muscle and neurones

20
Q

what mutations can cause mt disease?

A

mutations in mtDNA, nuclear genes encoding OXHOS subunits and proteins required for their translation and assembly

21
Q

why are mt diseases so heterogeneous?

A
  • random segregation during oogenesis and embryogenesis
  • threshold levels of mutant loads
  • tissue specific OXPHOS requirements
  • random segregation causes variable mutant loads in tissues as an individual develops
22
Q

what was the Zhu et al 2014 case study?

A

A to G mutation in 12s rRNA gene of mtDNA that resulted in hearing impairment. age of onset and symptoms varied. risk for deafness increased with mutant load but levels of heteroplasmy did not correlate with disease severity.

23
Q

common mutations in polG

A

94% are missense. majority inherited in an autosomal manner. results in secondary mutations due to defects in polG.

24
Q

why is yeast used as a model for mt disease?

A

mt functions highly conserved between yeast and humans, can undertake large genetic screens faculative anaerobes, become homoplasmic in a few generations, growth phenotype easy to assess- see if can grow on glycerol and therefore do OXPHOS

25
Q

what is an additional contributor to variable disease severity?

A

secondary nuclear mutations that can have an impact on phenotype

26
Q

what happens to growth when the same mtDNA mutations are grown on different nuclear backgrounds?

A

growth is variable

27
Q

how might polymophisms have an effect on diseases?

A

they have no phenotypic effect but may alter mt function, altering the risk of developing common diseases in organs dependent upon mt energy metabolism

28
Q

what do homoplasmic point mutations result in?

A

mild biochemical defects

29
Q

what does level of heteroplasmy correlate with?

A

extent of organ involvement and severity of clinical phenotype

30
Q

example of a multisystem mt disorder

A

MELAS

31
Q

example of an organ specific mt disorder

A

LHON

32
Q

how may mt DNA mutations cause cancer?

A

cause warburg effect- switch from OHPHOS to glycolysis

33
Q

how does relaxed replication influence heteroplasmy levels?

A

turns over mtDNA throughout whole cell cycle- even when cells are not dividing

34
Q

during germline selection, what might happen to milder genetic variants?

A

may not be selected against so passed onto next generation and will accumulate over time due to random genetic drift.

35
Q

what is an alternative view for elimination of paternal mtDNA in drosphila?

A

sperm mtDNA is removed from sperm before fertilisation. by EndoG degradation of nuceloids and sweeping up of nucleoids into waste bag by investment cone

36
Q

what happens to paternal mtDNA in Japanese Medaka fish?

A

eliminated upon fertilisation through gradual decrease of mt nucleoid numbers during spermatogenesis and rapid digestion of sperm mt just after fertilisation

37
Q

what happens to paternal mtDNA in mice?

A

degraded by mitophagy. MUL1 and PARKIN work redundantly to degrade paternal mt by ubiquitination

38
Q

what does a decrease in the number of mt mutations in the 1st and 2nd codon compared to the third show?

A

purifying selection for non-synonymous mutations in protein coding genes during maternal transmission of mtDNA

39
Q

what mutations accumulate at the synonymous third position?

A

mutations in RNA genes

40
Q

what does high levels of heteroplasmy result in in mice?

A

increased stress levels, reduced cognitive capacity meaning they were less physically active, decreased food consumption and lower metabolic rate when compared to homoplasmic mice

41
Q

what happens to heteroplasmic mice over a number of generations?

A

non-random segregation and directional loss of one of the mtDNA populations. heteroplasmy is disadvantageous

Genetics of cell growth and division (9 decks)

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