4 ms·

Sounds like mother & father's nuclear DNA, injected into the nucleus of a 3rd party's donor's egg cell, which contains its own mitochondrial DNA. Since mtDNA is

Sounds like mother & father's nuclear DNA, injected into the nucleus of a 3rd party's donor's egg cell, which contains its own mitochondrial DNA. Since mtDNA is normally inherited 100% from the mother (since the mother's egg cell supplies the mitochondria to the embryo), if the mother has a mitochondrial genetic disease, 100% of her children would normally inherit it.

nkrumm 10y ago
Yes-- the inheritance of mtDNA is maternal, but interestingly not 100% of her children will inherit the disease. This is because the mother will have a mix of mutated (diseased) mtDNA and wild-type (healthy) mtDNA in each of her cells, including her eggs. Some of the eggs will have close to all mtDNA mutated, but many will have a relatively low mutational burden. (This variation amongst the mother's cells and eggs is called heteroplasmy). Most mitochondrial genetic diseases have a heteroplasmy threshold (varying by gene/pathway, between 30-90% for many); when the overall burden in a fertilized egg is above this threshold, the disease is manifested in the offspring. Thus, another way to circumvent the transmission of mtDNA diseases is by using regular in vitro fertilization, and checking one of the cells at the 16 or 32 cell stage for their heteroplasmic content. Here are some references: Lightowlers, R. N., Taylor, R. W., & Turnbull, D. M. (2015). Mutations causing mitochondrial disease: What is new and what challenges remain? Science, 349(6255), 1494–1499. http://doi.org/10.1126/science.aac7516 http://doi.org/10.1126/science.aac7516 Taylor, R. W., & Turnbull, D. M. (2005). Mitochondrial DNA mutations in human disease. Nature Reviews Genetics, 6(5), 389–402. http://doi.org/10.1038/nrg1606 http://doi.org/10.1038/nrg1606 Smeets, H. J. M., Sallevelt, S. C. E. H., Dreesen, J. C. F. M., Die Smulders, C. E. M., & Coo, I. F. M. (2015). Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis. Annals of the New York Academy of Sciences, 1350(1), 29–36. http://doi.org/10.1111/nyas.12866 http://doi.org/10.1111/nyas.12866
- rcthompson 10y ago
  Interesting. I wasn't aware of this, but it seems obvious in retrospect. Thanks for the info!
- ralfd 10y ago
  > checking one of the cells at the 16 or 32 cell stage I wonder: How is an embryo dealing with missing a cell at this early? Does this error compound after a few doublings (embryo is smaller)?
  - pmalynin 10y ago
    AFAIK it shouldn't be issue. Some twins (identical twins) are created when a two cell organism detaches into two separate entities.
  - aab0 10y ago
    It doesn't seem to lead to any harms when done as part of preimplantation genetic diagnosis in general, so this specific case shouldn't be too bad.
dnautics 10y ago
There is also the possibility that a sperm mitochondrion can be transmitted to the egg. Normally it's destroyed, but there's always exceptions in biology.

nkrumm 10y ago

Yes-- the inheritance of mtDNA is maternal, but interestingly not 100% of her children will inherit the disease. This is because the mother will have a mix of mutated (diseased) mtDNA and wild-type (healthy) mtDNA in each of her cells, including her eggs. Some of the eggs will have close to all mtDNA mutated, but many will have a relatively low mutational burden. (This variation amongst the mother's cells and eggs is called heteroplasmy). Most mitochondrial genetic diseases have a heteroplasmy threshold (varying by gene/pathway, between 30-90% for many); when the overall burden in a fertilized egg is above this threshold, the disease is manifested in the offspring. Thus, another way to circumvent the transmission of mtDNA diseases is by using regular in vitro fertilization, and checking one of the cells at the 16 or 32 cell stage for their heteroplasmic content. Here are some references: Lightowlers, R. N., Taylor, R. W., & Turnbull, D. M. (2015). Mutations causing mitochondrial disease: What is new and what challenges remain? Science, 349(6255), 1494–1499. http://doi.org/10.1126/science.aac7516 http://doi.org/10.1126/science.aac7516 Taylor, R. W., & Turnbull, D. M. (2005). Mitochondrial DNA mutations in human disease. Nature Reviews Genetics, 6(5), 389–402. http://doi.org/10.1038/nrg1606 http://doi.org/10.1038/nrg1606 Smeets, H. J. M., Sallevelt, S. C. E. H., Dreesen, J. C. F. M., Die Smulders, C. E. M., & Coo, I. F. M. (2015). Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis. Annals of the New York Academy of Sciences, 1350(1), 29–36. http://doi.org/10.1111/nyas.12866 http://doi.org/10.1111/nyas.12866

rcthompson 10y ago
Interesting. I wasn't aware of this, but it seems obvious in retrospect. Thanks for the info!
ralfd 10y ago
> checking one of the cells at the 16 or 32 cell stage I wonder: How is an embryo dealing with missing a cell at this early? Does this error compound after a few doublings (embryo is smaller)?
- pmalynin 10y ago
  AFAIK it shouldn't be issue. Some twins (identical twins) are created when a two cell organism detaches into two separate entities.
- aab0 10y ago
  It doesn't seem to lead to any harms when done as part of preimplantation genetic diagnosis in general, so this specific case shouldn't be too bad.

dnautics 10y ago

There is also the possibility that a sperm mitochondrion can be transmitted to the egg. Normally it's destroyed, but there's always exceptions in biology.