Chromosomal Abnormalities I Flashcards

1
Q

As a recap, describe the condensation of DNA.

A

Histones are highly positively charged proteins that are attracted to the negative charge of DNA.They give the DNA a support to wrap around.
A chromosome is an organized package of DNA found in the nucleus of the cell. Different organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes - 22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, X and Y.
Each parent contributes one chromosome to each pair so that offspring get half of their chromosomes from their mother and half from their father.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the two states in which chromosomes can exist?

A

Chromosomes usually exists as chromatin. The DNA double helix binds to histones, and an octamer of histones form a nucleosome.

EUCHROMATIN:

  • extended state, dispersed through nucleus
  • allows gene expression

HETEROCHROMATIN:
- highly condensed, genes not expressed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Why are chromosome somtimes shown with a single chromatid, and sometimes with two?

A

This is due to the fact that there will be two chromatids during cell replication.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe the different types of chromosomes that can be classifies from a karyotype.

A

METACENTRIC:

  • p & q arms even length
  • 1-3, 16-18

SUBMETACENTRIC:

  • p arm shorter than q
  • 4-12, 19-20, X

ACROCENTRIC:

  • long q, small p
  • p contains no unique DNA
  • 13-15, 21-22, Y
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the two different types of chromosomal changes and how can you detect them?

A

NUMERICAL:
- can detect through traditional karyotyping, FISH, QF-PCR, NGS

STRUCTURAL:
- can detect through traditional karyotyping, FISH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Define terms common in numerical abnormalities - haploid, diploid, polyploid and aneuploid.

A

HAPLOID:
one set of chromosomes (n=23) as in a normal gamete.

DIPLOID:
cell contains two sets of chromosomes (2n=46; normal in human)

POLYPLOID:
multiple of the haploid number (e.g. 4n=92)

ANEUPLOID:
chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) (e.g. 2n+1=47)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

List some examples of aneuploid numerical abnormalities.

A
  • trisomy
  • monosomy
  • mosaicism
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

How does aneuploidy arise?

A

The primary mechanism is non-disjunction, where the homologues don’t pull apart during metaphase and both go into the same cell.

if this occurs during meiosis I, you end up with two diploid cells.
If this occurs in meiosis II, we will end up with 2 haploid cells and one diploid cell.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the two mechanisms of mosaicism?

A

Post-zygotic nondisjunction:
i.e. mitotic non-disjunction = all the cells start as 2n, then go to a mixture of 2n and 2n+1.

Anaphase lag:
i.e. trisomic rescue = all the cells start as 2n+1, then go to a mixture of 2n+1 and 2n.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is anaphase lag?

A

Anaphase lag describes a delayed movement during anaphase, where one homologous chromosome in meiosis or one chromatid in mitosis fails to connect to the spindle apparatus, or is tardily drawn to its pole and fails to be included in the reforming nucleus. Instead, the chromosome forms a micronucleus in the cytoplasm and is lost from the cell.

The lagging chromosome is not incorporated into the nucleus of one of the daughter cells, resulting in one normal daughter cell and one with monosomy.Anaphase lag is one of several causes of aneuploidy and one of several causes of mosaicism.

Anaphase lag can also cause a rescue of the daughter cell if the cell was originally trisomy.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the clinical relevance of a mosaic phenotype?

A

The mosaic phenotype sis thought to be less severe.

However, it is difficult to assess:

  • what are the proportions of the different cell types?
  • which tissues/organs are affected?

Examples of mosaic phenotypes include:

  • Down
  • Klinefelter
  • Turner
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe the different types of monosomies.

A

Autosomal monosomies are very rare; have found one case report from 1967.

Sex chromosome monosomy is relatively common, such as Turner’s.

A full monosomy arises by NDJ (non-disjunction).

Partial monosomies (microdeletion syndromes) are far more common, thought the mechanism is different to non-disjunction.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Considering how Turner’s arises (45,X), what are some possible combinations of chromosomes in monosomies?

A

NULLISOMIC GAMETES:

    • X chr = XO = Turner’s (physically female)
    • Y chr = lethal

DISOMIC GAMETES:
XX
- + X chr = XXX = triple X syndrome
- + Y chr = XXY = Klinefelter’s (physically male)

XY
+ X chr = XXY = Klinefelter’s
+Y chr = XYY = XYY syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Describe chorionic villus sampling for prenatal diagnosis.

A

It occurs at 11-14 weeks.
There is a miscarriage rate of 0.5% to 1%.

There can be possible maternal contamination, and can cause the foetus transverse limb defects.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe amniocentesis for prenatal diagnosis.

A

It happens >16 weeks, and involves the extraction of amniotic fluid .

Biochemical diagnosis is possible.
The miscarriage risk is quite low, though still there (0.5-1%).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How does G-banding work?

A

You stain the sample with a Giemsa stain during metaphase. Giemsa highlights heterochromatic regions which are less likely to contain genes. But the crucial thing is that the banding can be used to differentiate between chromosomes and to compare chromosomes.

We can create a line-up based on:

  • size
  • banding
  • centromere position
17
Q

How can quantitative fluorescence PCR be used to identify numerical abnormalities?

A

We can design primers for a specific microsatellite on chromosome 21 (for Down’s, for e.g.) and amplify the region using PCR.

We would then essentially see how big the regions are, and how many copies there are.

18
Q

What are some ways in which we can get a prenatal diagnosis?

A

INVASIVE:

  • amniocentesis (14-20 wks, amniotic fluid)
  • chorionic villus sampling (CVS) (11-14 wks, placental cells)

NON-INVASIVE:

  • cell free foetal DNA (cffDNA): DNA fragments in maternal plasma (10 wks onwards)
  • actually, for trisomies, we still need confirmation with amnio/CVS