Mosaicism

Question 1

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?

Answer 1

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.

Question 2

Types of mosaicism
- General
- Confined

Answer 2

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

Question 3

When does error occur in the event of general mosaicism?

Answer 3

Prior to differentiation

Question 4

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?

Answer 4

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.

Question 5

How are live births from cleavage-stage/blastocyst-stage biopsied aneuploid embryos possible (despite significantly lower LBR than euploid embryos)?

Answer 5

Inaccurate result.

The biopsied cell was the only aneuploid cell.

Mosaicism

Question 6

What is confined placental mosaicism?
How common is it?
What risks is it associated with?

Answer 6

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

Question 7

Which cells does CVS sample?

Answer 7

Cytotrophoblast
Extraembryonic mesoderm

Question 8

What is the outcome of non-disjunction?

Answer 8

Monosomy - 1 cell
Trisomy - 2nd cell

Question 9

When does non-disjunction occur least? Most?

What is the most common meiosis I error?

Answer 9

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

Question 10

Can an oocyte recover a euploid embryo after PSSC?

Answer 10

Yes

Question 11

What is anaphase lagging?
How is it detected?
What is the end result?

Answer 11

When 1 sister chromatid copy fails to be incorporated into the nucleus after division.

Detected by detecting monosomies.

Monosomy - 1 cell
Euploid - 2nd cell

Question 12

Which is more common - monosomy or trisomy?

Answer 12

Monosomy (by 3-5x)

Question 13

What is trisomy rescue?

What occurs 1/3 of the time during trisomy rescue?

Answer 13

When a trisomy line is “rescued” back to euploidy via anaphase lagging

Uniparental disomy occurs 1/3 of the time

Question 14

What is endoreplication?

What is another name for endoreplication?

Answer 14

Chromosome replication without division (impaired cell cycle division: replication without cytokinesis > shutdown of mitosis)

AKA polyploidy

Endoreplication found in skin, blood, gut, brain

Question 15

How is it possible for a cell line to be mosaic despite a normal number of chromosomes?

Answer 15

Uniparental disomy during trisomy rescue

Question 16

What is the incidence of uniparental disomy in the preimplantation embryo?

Answer 16

UPD occurs in 0.06% of blastocysts

Question 17

Angelman syndrome caused by

Answer 17

Uniparental disomy (paternal) of chromosome 15

Question 18

Prader-Willi syndrome caused by

Answer 18

Uniparental disomy (maternal) of chromosome 15

Question 19

What are chaotic mosaics?

Answer 19

Multiple error events taking place on multiple chromosomes during 1 division

Question 20

What is the most common form of mosaicism at the cleavage stage?

Answer 20

Chaotic mosaicism
(As the embryo progresses in stages, chaotic mosaicism becomes less likely)

Question 21

What determines the influence of mosaicism?

Answer 21

• Timing of error
• Ability of error to propagate

Question 22

Where is the centrosome inherited from?

Answer 22

Sperm

Question 23

What is critical to the first mitotic divisions in the embryo?

Answer 23

Centrosome, inherited from sperm

Question 24

What are paternal origins of mosaicism?

Answer 24

• Centrosome
• Sperm aster formation

Question 25

What are maternal origins of mosaicism?

Answer 25

• Mitochondria (affected by maternal age)

Question 26

How does aneuploidy occur more often in advanced maternal age?

Answer 26

• Reactive oxygen species (ROS)
• Environmental factors
• Decrease in cohesion between sister chromatids
• Down-regulation of mitosis genes
• Spindle abnormalities

Question 27

What are some external mechanisms of mosaicism?

Answer 27

IVF - hyperstimulation, stimulation protocols, embryo culture (is 5% O2 better that atmospheric?)

Question 28

What is the first step in embryonic development to consider for mosaicism?

Answer 28

Cleavage stage

Question 29

Incidence of mosaicism in cleavage-stage embryos?

Answer 29

15-90% (mosaicism is routine during pre-implantation development)

(depends on: maternal age, diagnosis, paternal age, what test used to detect abnormalities)

Question 30

Cytotrophoblast is derived from?
Extraembryonic mesoderm is derived from?

Answer 30

Post-implantation embryo development:
- Cytotrophoblast derived from trophoblast
- Extraembryonic mesoderm derived from ICM

Question 31

How is confined placental mosaicism detected? What are the disadvantages of this method?

What is the majority of autosomal abnormalities in CPM?

Answer 31

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