Mosaicism Flashcards
What is mosaicism?
What causes mosaicism?
Does mosaicism occur in mitosis or meiosis?
Does mosaicism occur pre/post implantation?
Why do we care about mosaicism?
Presence of at least 2 distinct cell lines within an individual
Caused by failure of chromosomes to properly separate
Mosaicism is a product of mitosis, but has its roots in meiosis
Mosaicism occurs BOTH pre and post implantation (post: cancer, aging, T21)
Mosaicism can lead to genetic diseases, miscarriages, and preimplantation embryo wastage.
Types of mosaicism
- General
- Confined
General - 2+ cell lines present throughout the entire individual; mitotic or meiotic origin
Confined - mosaicism confined to a particular area (brain, gonads, placenta); mitotic origin
When does error occur in the event of general mosaicism?
Prior to differentiation
What is the mosaicism rate in the pre-implantation embryo, prior to differentiation?
Why does this rate not dictate the final genotype of the embryo?
Why does mosaicism have potential greater influence in the preimplantation embryo?
65-79%
Euploid cell lines proliferate faster than aneuploid ones
Greater influence in the preimplantation embryo because lower number of total cells at this stage.
How are live births from cleavage-stage/blastocyst-stage biopsied aneuploid embryos possible (despite significantly lower LBR than euploid embryos)?
Inaccurate result.
The biopsied cell was the only aneuploid cell.
Mosaicism
What is confined placental mosaicism?
How common is it?
What risks is it associated with?
Confined placental mosaicism: chromosomal discordance between fetus and placenta
1-2% of all placentas analyzed
Risks of CPM: SAB, intrauterine death, stillbirth, IUGR, abnormal placental function
Which cells does CVS sample?
Cytotrophoblast
Extraembryonic mesoderm
What is the outcome of non-disjunction?
Monosomy - 1 cell
Trisomy - 2nd cell
When does non-disjunction occur least? Most?
What is the most common meiosis I error?
Non-disjunction is least common in - meiosis I and II amongst autosomes
(Most common meiosis I error is PSSC)
Non-disjunction is most common in - 1st cleavage division
Can an oocyte recover a euploid embryo after PSSC?
Yes
What is anaphase lagging?
How is it detected?
What is the end result?
When 1 sister chromatid copy fails to be incorporated into the nucleus after division.
Detected by detecting monosomies.
Monosomy - 1 cell
Euploid - 2nd cell
Which is more common - monosomy or trisomy?
Monosomy (by 3-5x)
What is trisomy rescue?
What occurs 1/3 of the time during trisomy rescue?
When a trisomy line is “rescued” back to euploidy via anaphase lagging
Uniparental disomy occurs 1/3 of the time
What is endoreplication?
What is another name for endoreplication?
Chromosome replication without division (impaired cell cycle division: replication without cytokinesis > shutdown of mitosis)
AKA polyploidy
Endoreplication found in skin, blood, gut, brain
How is it possible for a cell line to be mosaic despite a normal number of chromosomes?
Uniparental disomy during trisomy rescue
What is the incidence of uniparental disomy in the preimplantation embryo?
UPD occurs in 0.06% of blastocysts
Angelman syndrome caused by
Uniparental disomy (paternal) of chromosome 15
Prader-Willi syndrome caused by
Uniparental disomy (maternal) of chromosome 15
What are chaotic mosaics?
Multiple error events taking place on multiple chromosomes during 1 division
What is the most common form of mosaicism at the cleavage stage?
Chaotic mosaicism
(As the embryo progresses in stages, chaotic mosaicism becomes less likely)
What determines the influence of mosaicism?
- Timing of error
- Ability of error to propagate
Where is the centrosome inherited from?
Sperm
What is critical to the first mitotic divisions in the embryo?
Centrosome, inherited from sperm
What are paternal origins of mosaicism?
- Centrosome
- Sperm aster formation
What are maternal origins of mosaicism?
- Mitochondria (affected by maternal age)
How does aneuploidy occur more often in advanced maternal age?
- Reactive oxygen species (ROS)
- Environmental factors
- Decrease in cohesion between sister chromatids
- Down-regulation of mitosis genes
- Spindle abnormalities
What are some external mechanisms of mosaicism?
IVF - hyperstimulation, stimulation protocols, embryo culture (is 5% O2 better that atmospheric?)
What is the first step in embryonic development to consider for mosaicism?
Cleavage stage
Incidence of mosaicism in cleavage-stage embryos?
15-90% (mosaicism is routine during pre-implantation development)
(depends on: maternal age, diagnosis, paternal age, what test used to detect abnormalities)
Cytotrophoblast is derived from?
Extraembryonic mesoderm is derived from?
Post-implantation embryo development:
- Cytotrophoblast derived from trophoblast
- Extraembryonic mesoderm derived from ICM
How is confined placental mosaicism detected? What are the disadvantages of this method?
What is the majority of autosomal abnormalities in CPM?
CVS at 10-12 weeks gestation
Autosomal trisomies
Cons of CVS for CPM detection: maternal contamination (6%), immature placenta at 10-12 weeks may not be representative of the mature placenta
