Chromosomal Abnormalities I Flashcards
As a recap, describe the condensation of DNA.
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.
What are the two states in which chromosomes can exist?
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
Why are chromosome somtimes shown with a single chromatid, and sometimes with two?
This is due to the fact that there will be two chromatids during cell replication.
Describe the different types of chromosomes that can be classifies from a karyotype.
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
What are the two different types of chromosomal changes and how can you detect them?
NUMERICAL:
- can detect through traditional karyotyping, FISH, QF-PCR, NGS
STRUCTURAL:
- can detect through traditional karyotyping, FISH
Define terms common in numerical abnormalities - haploid, diploid, polyploid and aneuploid.
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)
List some examples of aneuploid numerical abnormalities.
- trisomy
- monosomy
- mosaicism
How does aneuploidy arise?
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.
What are the two mechanisms of mosaicism?
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.
What is anaphase lag?
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.
What is the clinical relevance of a mosaic phenotype?
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
Describe the different types of monosomies.
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.
Considering how Turner’s arises (45,X), what are some possible combinations of chromosomes in monosomies?
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
Describe chorionic villus sampling for prenatal diagnosis.
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.
Describe amniocentesis for prenatal diagnosis.
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%).
