18.01.15 Origin of anueploidy

Question 1

What is anueploidy?

Answer 1

Presence or absence of chromosome(s) on a diploid background -> unbalanced chromosome complement, monosomy, trisomy. Not triploidy (extra set of chromosomes)

Question 2

What is synapsis?

Answer 2

Synapsis: Pairing of chromosome homologues during prophase I (zygotene) and the formation of the synaptonemal complex, which is a protein assembly that holds together homologous chromosomes during prophase of the first meiotic division

Question 3

What is recombination/crossing over?

Answer 3

DNA exchange between non-sister chromatids generating genetic variation

Question 4

What is the function of chiasmata?

Answer 4

Join bivalents together.

Question 5

What is the function of cohensin?

Answer 5

Join bivalents together.

Question 6

What is segregation?

Answer 6

How the chromosomes are distributed in the cell/which pole they go to.

Question 7

What is non-disjunction?

Answer 7

How the chromosomes are distributed in the cell/which pole they go to.

Question 8

What is pachytene?

Answer 8

Third stage of prophase of meiosis I during which recombination (crossover) occurs

Question 9

What errors at meiosis I can lead to aneuploidy?

Answer 9

MI error during gametogenesis (Meiosis) – affects entire chromosomes

a) Recombination failure
b) Premature homologue separation
c) True non-disjunction
d) Premature sister chromatid separation

Question 10

What errors at meiosis II can lead to aneuploidy?

Answer 10

MII error during gametogenesis (Meiosis) – affects sister chromatids

a) non-disjunction
b) premature sister chromatid separation

Question 11

How does recombination failure lead to aneuploidy? Give an example.

Answer 11

Recombination failure / Achiasmatic non-disjunction.

Achiamastic: the failure to establish recombination points (chiasmata) between homolog pairs.

Failure to form chiasmata, or premature resolution of chiasmata can result in homologs segregating to the same pole at MI, leading to non-disjunction.

Examples:

paternal X-Y non-disjunction (50% of XXY cases).

maternal T21 (40% of cases)

maternal UPD 15 (20% of cases)

Question 12

How does premature homologue separation lead to aneuploidy? -

Answer 12

Premature homologue separation

Loss of cohesion between homologous chromosomes.

Bivalents segregate in MI largely under the influence of the Spindle Assembly Checkpoint (SAC).

Question 13

What is true non-disjunction?

Answer 13

Failure of chiasmata between homologous chromosomes to resolve at anaphase I, both homologues therefore segregate to the same pole. In males this would produce 2 nullisomic and 2 disomic sperm.

Question 14

What is PCS?

Answer 14

Premature sister chromatid separation (PSCS)

Deterioration of sister chromatid cohesion.

MI: Cohesion along chromosome arms keeps bivalents intact. MII: Cohesion along centromeres holds sister chromatids together.

Advancing maternal age may cause decreased cohesion of sister chromatids ⇨Sister chromatids separate early and travel to separate poles during MI

For segregation of chromosomes 16, 18, 21 and the X chromosome both non-disjunctional (75%) and PSCS errors (25%) have been observed. The presence of a pericentromeric exchange might increase the likelihood of chromosome ‘entanglement’ or PSCS at MI. Subsequent segregation at MII would result in a disomic gamete having identical centromeres — so the case would be scored as originating at MII even though the precipitating event occurred at MI. Therefore, MII non-disjunction may actually originate from an event in MI.

Question 15

What is anaphase lag?

Answer 15

A chromosome fails to attach to the spindle apparatus, or is slowly pulled to its pole, and therefore fails to be included in the reforming nuclear membrane. In the cytoplasm it will form its own micronucleus and eventually be lost.

Question 16

Describe non-disjunction in meiosis II.

Answer 16

result from the failure of sister chromatid separation. Can lead to mosaic aneuploidy (if it is viable), or uniparental disomy (if the extra chromosome from the one parent is retained but the chromosome from the other parent is lost when the cell attempts to correct the aneuploidy).

Question 17

What are the mechanisms and result of postzygotic mitotic error?

Answer 17

Less frequent than meiotic errors

Two mechanisms:

1. Anaphase lagging: Most frequent. Results in monosomy as a consequence of loss of one chromosome.
2. Mitotic non-disjunction. Results in an embryo containing monosomic and trisomic cells for the same chromosome due to reciprocal loss and gain of one chromosome.

Embryos usually mosaic for euploid and aneuploid cells

Question 18

What is parental gonadal mosaicism? How can this give rise to aneuploidy?

Answer 18

Gonadal mosaicism accounts for recurrent homotrisomy.

It affects 6.5% of young couple with a Down Syndrome child.

Molecular cytogenetic analysis of oocytes has proved germinal or gonadal mosaicism for trisomies of chromosomes 13 and 21 in several studies involving both oocytes and first polar bodies.

Question 19

What is simultaneous non-disjunction?

Answer 19

Simultaneous non-disjunction: non-disjunction happens twice in the same meiosis leading to double aneuploidy, two cell lines eg 47,XXY,+21 + 45,X

Question 20

What is sequential non-disjunction?

Answer 20

Sequential non disjunction: Non-disjunction happens in MI and then again in MII leading to four copies of a chromosome present in a gamete (tetrasomy), e.g. Cat eye syndrome tetrasomy 22.

Question 21

What is the incidence of anueploidy in sperm/oocytes?

Answer 21

Sperm: 1-2%
Oocytes: ~20%
Pre-implantation embryos = 25%

Question 22

What % of spontaenous abortions have aneuploidy?

Answer 22

35%

Commonly 45,X, +16, +21, +22

Question 23

What % of stillbirths have aneuploidy?

Answer 23

4%

Most common +13, +18, +21

Question 24

What % of livebirths have aneuploidy?

Answer 24

0.3%

+13, +18, +21, XXX, XXY, XYY

Question 25

What is the mechanism for trisomy 16?

Answer 25

All trisomy 16 cases appear to be true maternal MI non-disjunction. A shift in the exchange position in chiasmata is thought to play a role.

Question 26

What are the mechanisms underlying trisomy 21?

Answer 26

Maternal MI (70% of which 40-50% achiasmate), 
Maternal MII (24%), 
Paternal MI (<2%), 
Paternal MII (<2%)
Post-zygotic (<3%)

Question 27

What is the oocyte selection model?

Answer 27

Oocyte mosaicism selection model: Mitotic errors occur before entry into meiosis, leading to aneuploidy oocytes in primordial follicles that are preferentially recruited in with increased maternal age.

The oocyte mosaicism selection model suggests that mitotic errors occur before entry into meiosis leading to aneuploid oocytes in primordial follicles that are preferentially recruited with increased maternal age.

Question 28

What is the maternal age effect in relation to aneuploidy?

Answer 28

It is well established that aneuploidy dramatically increases as women age: the incidence of trisomy in clinically recognised pregnancies in a woman in her early 20s is approx. 2%–3%, but increases to approx 35% in a woman in her 40s.

Question 29

Why are more aneuploidies thought to arise from the egg than the sperm?

Answer 29

Most human aneuploidies found in embryos originate from the egg and not sperm, likely because of the critical difference in the meiotic process between males and females. In females meiosis initiates during fetal development, arrests at prophase I before birth, and does not resume until just prior to monthly ovulation in adulthood, which can be up to 50 yr later in humans. In males this process continues throughout their lifetime after puberty.

The long time interval between meiotic arrest in the fetus and each ovulation cycle in the adult allows the maternal age to affect aneuploidy incidence.

The “limited oocyte pool” hypothesis suggests that the age effect might be due to the relative scarcity of oocytes at optimal stages of maturation.

Question 30

Which stage of meiosis is associated with maternal age effect non-disjunction?

Answer 30

Meiotic stage MI is the origin of trisomy associated with maternal age but it is unknown if this occurs at fetal MI (pairing and recombination occur; in the prolonged diplotene stage, during which time the oocyte is meiotically ‘arrested’) or in peri-ovulatory stage (at which time MI is resumed and completed).

It has been hypothesised that may be a combination of the two. The first involves the establishment in the fetal ovary of a susceptible bivalent; this component would be age independent. The second hit involves abnormal processing of the susceptible bivalent at metaphase I, in the adult ovary; this would be the age-dependent component of the process. Therefore, the age effect would occur because the older ovary is less efficient at segregating susceptible bivalents.

Deterioration of sister chromatid cohesion with age or in the spindle assembly checkpoint (SAC) make it more likely that susceptible bivalents will become mal-aligned than will bivalents with normal exchange patterns. It does not explain all trisomies however (it works for 16 and 21 but not for 15 and maternal sex chromosome trisomy).

Question 31

What are the risks in further pregnancies in women who have previously had trisomic conceptuses?

Answer 31

There is an increased risk of aneuploidy in women with previous trisomic conceptions, independent of maternal age. This risk is higher for younger women.

This could be due to gonadal mosaicism (if it is a recurrent aneuploidy).

other genetic factors such as mutation of genes involved in meiosis (specifically, recombination). Some evidence to suggest mutations in genes that create the synaptonemal complex – further work required.