mtDNA inheritance Flashcards
how is mtDNA inherited in humans?
maternally
why are yeast good for studying mt?
they are faculative anaerobes so can generate energy through glycolysis so can survive loss of mt
how is mtDNA inherited in yeast?
by both parents- results in heteroplasmy
how is mtDNA variation generated?
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
what are the sources of heteroplasmy?
- inheritance of germline mutations
- age related mutations
- introduction of foreign mt to reconstructed embyros
what are the 3 theories of how mt bottleneck occurs?
- 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
what is the evidence for selective amplification?
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
what is reduced in sperm when compared to spermatogonium?
TFAM and mtDNA levels
where is TFAM levels lower than in any other organ?
testes
elimination of paternal mDNA in c.elegans
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
elimination of paternal mDNA in drosophila
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
how is paternal mtDNA prevented from entering chinese hamsters?
sperm tail doesnt enter egg
what is an alternative theory to degeneration of paternal mtDNA in embryos?
The paternal mtDNA is eliminated during spermatogesis. uneven distribution to one of the blastomeres
how many people carry a known mtDNA point mutation?
1 in200
how many children are born with an inherited mt disease?
1 in 4000
what does threshold level mean?
% of genomes that must be mutant before disease present
how can a cell return to homoplasmy
by chance due to random mitotic segregation
why do offspring have different mutant loads?
due to random meiotic segregation- will have different amounts of mutant mtDNA so may/may not have disease
which tissues have higher oxphos requirements?
heart muscle and neurones
what mutations can cause mt disease?
mutations in mtDNA, nuclear genes encoding OXHOS subunits and proteins required for their translation and assembly
why are mt diseases so heterogeneous?
- 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
what was the Zhu et al 2014 case study?
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.
common mutations in polG
94% are missense. majority inherited in an autosomal manner. results in secondary mutations due to defects in polG.
why is yeast used as a model for mt disease?
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