Aneuploidy leading to pregnancy loss

Question 1

Whats the percentage of pregnancies expected of spontaneoously abort or miscarry?

Answer 1

Approx 15%

Question 2

Number of miscarriages in women under 30?

Answer 2

1 in 10

Question 3

Number of miscarriages in women between 35-39?

Answer 3

2 in 10

Question 4

Number of miscarriages in women over 45?

Answer 4

5 in 10

Question 5

What happens to chromosome number meiosis?

Answer 5

. In humans meiosis reduces the diploid complement of chromosomes, by half – 2n to 1n.

Question 6

How does Meiosis achieve half its complement?

Answer 6

Meiosis achieves this via a single round of DNA replication (which occurs during interphase), followed by 2 successive rounds of chromosome segregation.

Question 7

What is Meiosis 1 (M1?)

Answer 7

Events leading to first segregation

Question 8

WHat is meisos 1 subdivided into?

Answer 8

Subdivided into discrete stages called prophase I (which consists of a highly conserved sequence of events named leptotene, zygotene, pachytene and dictyotene) followed by metaphase I and finally anaphase I when homologous chromosomes part company from one another as they are drawn to opposite poles of the cell by the spindle complex.

Question 9

What happens to cell entering meisos, S-phase and then metaphase?

Answer 9

A cell entering meiosis has 2 copies of each chromosome, on inherited from each parent.

When the cell enters S-phase, these chromosomes are replicated to to generate sister chromatids, which start to become visible in prophase and remain visible through to metaphase. Sister chromatids are visible in some human G-banded preps as shown in the slide.

Question 10

Whats the glue that holds sister chromatids together?

Answer 10

Sister chromatid cohesion - holds chromatids together along their length

important for faithful, correct segregation of sister chromosomes.

Question 11

What does DNA replication happen?

Answer 11

While cells are in interphase

Question 12

What happens to chromosomes in prophase 1?

Answer 12

They start to condense and chromatin becomes organised ready for segregation event.

Question 13

Leptotene stage

Answer 13

the first stage of the prophase of meiosis, during which each chromosome becomes visible as two fine threads (chromatids).

Chromosomes begin to condense

Question 14

Zygotene stage

Answer 14

During zygotene stage, homologous chromosomes pair;

Question 15

Pachytene stage

Answer 15

synapsis is complete and crossing-over and homologous recombination take place.

Question 16

Diplotene stage

Answer 16

during diplotene stage, chromosomes are unsynapsed and, subsequently, the cell divides.

Question 17

What additional protein structure is there as you progress through prophase 1

Answer 17

Synaptonemal complex - the glue between homologous chromosomes. As in meisos homologous chromosomes are paired up ready to be segregated.

Question 18

Describe Synaptonemal complex

Answer 18

A scaffold and catalyst for a really important reaction that takes places.

Question 19

Why do people study meiosis

Answer 19

In order to correctly pair homologous chromosomes and segregate correctly. need to destroy them.

Question 20

WHat is Spo11

Answer 20

topioisomerase. Along the axis of these chromosomes it makes double strand breaks. these DSBs are formed in both homologs in different positions.

Spo11 is laid down on DNA as the DNA is replicated. Spo11 is dropped behind the replication fork in hotspots.

Question 21

Why do cancer researchers like meiosis

Answer 21

Because you have known DNA damage happening in defined places in genome which can be analysed. look at how its repaired.

Question 22

What happens after Spo11 makes DSB?

Answer 22

The break is processed - Spo11 is removed and get resection creating single stranded DNA tracks either side of DSB and one of these strand invades the homolog.

End up with strand invasion between one sister chromatid of one homolog and another chromatid in the homologous chromosome.

Question 23

Function of synaptonemal complex

Answer 23

normally when breaks occur they are repaired off of the sister chromatid (in mitosis).

This complex contains proteins which persuades this piece of ssDNA to invade the
homologous chromsomes instead of the other sister chromatid

Question 24

A double holliday junction is formed, what are one of the ways they can be resolved?

Answer 24

By crossover

Question 25

Why are crossover essential?

Answer 25

Crossovers are therefore absolutely essential to the faithful segregation of chromosomes, which in turn ensures that gametes receive the correct complement of chromosomes and that the next generation of progeny are viable.

Question 26

WHat does crossing over also ensure?

Answer 26

Crossing over also ensures genetic diversity which of course is essential to maintain the health of any sexually reproducing population.

Question 27

What are consequences of cross over events?

Answer 27

Chiasmata

Question 28

Chiamata

Answer 28

Holding homologous chromosomes together

Question 29

What are the maternal and paternal chromosomes linked by?

Answer 29

Chiasmata and sister chromatid cohesion

Question 30

What would happen if we didnt have sister chromatid cohesion or crossing over?

Answer 30

homologous chromosomes could simply untangle from one another and move independently of each other in the cell. Without crossing over there’d be no interaction between the homologs – and again the maternal and paternal chromosomes would be free of one another.

Question 31

WHat does the combination of sister chromatid cohesion and chaismata allow?

Answer 31

Allow chromosomes to be correctly segregated to the gametes

Question 32

Common human aneuploidies

Answer 32

Autosomal aneuploidies: Down syndrome +21 Edwards syndrome +18 Patau syndrome +13 Sex chromosomes aneuploidies: (well tolerated) Turners syndrome Klinefelter syndrome Triple X syndrome

Question 33

Whats the relationship between maternal age and instances of pregnancies affected with extra copy of chromosome 21

Answer 33

Goes up sharply with age - especially after 40

Question 34

Errors accounting of extra copy of chromosome 21

Answer 34

Mostly maternal error (and in vast majority of other aneuploidys). Paternal errors account for minority.

Question 35

When do paternal errors dominate?

Answer 35

In balanced errors

Question 36

When do maternal errors dominate?

Answer 36

Aneuploidies

Question 37

If there is no error maternally or paternally how else error might occur?

Answer 37

46 chromosomes - as that starts to divide, mitotically there was an error in mitosis. leading to asymetric chromosome segregation. these mitotic error might result in mosaic individual.

Question 38

Whats an centimorgan map?

Answer 38

A measure of genetic distance, not necessarily proportional to number of base pairs of one point of the other. Dependent on how often do two points in the genome segregate away from one another - likelyhood of there being a cross over between the two.

Question 39

What happens is there is a trisomy in centimorgan map?

Answer 39

shorter than normal

Question 40

Why is trisomy 21 so common?

Answer 40

Because the size of chromsomse 21 is very small.

Question 41

What ahppens if cross over is located too close to the telomere?

Answer 41

that the two homologs are more likely to mal segregate in MI.

Question 42

What if the position of crossovers are too close to the centromere

Answer 42

then MII errors are more likely.

Question 43

Under normal circumstances, the homologs of chromosome 21 are held together with? what does this mean.

Answer 43

A single crossover. Chromosome is vulnerable to malsegregation.

Question 44

whats different in maternal meiosis to paternal meiosis?

Answer 44

Prophase

Question 45

What may result in chromosomal nondisjuction?

Answer 45

Length of time these structures (crossovers) are held in stasis. Quite liekly what some of the sister chromatids cohesion complexes will degrade. If single crossover holding two chromosomes together is positioned distal to centromere (close to telomere).

Question 46

What if you have too many crossovers holding homologous chromosomes together or postion os crossover is too close to centromere (loads to sister chromatid cohesion holding stucture together)

Answer 46

Still predispose to nondisjuction events - but instead for malsegregation happening in meiosis 1 (separating homologous chromosomes) you are predisopisng to meiosis 2 malsegregation - when trying to separate sister chromatids.