Anomalies of Chromosome Number & Structure* Flashcards
define chromosome
a single molecule of DNA with a set order of genes
what is the P and Q arm of a chromosome?
P arm = short
Q arm = long
what is the difference between the light and dark bands on a chromosome?
Light bands: replicate early in S phase, less condensed chromatin, transcriptionally active. Gene and GC rich.
Dark Bands: Replicate later, contain condensed chromatin, AT rich.
how do we examine chromosomes?
ordered lowest to highest resolution:
1. Karyotype
2. Florescent in situ Hybridisation (FISH)
3. Array CGH
what is a karyotype test used for?
Karyotype test identifies and evaluates the size, shape, and number of chromosomes in the nuclei of a sample of body cells.
what is colchicine?
a drug that specifically inhibits microtubule formation
how is the karyotype test carried out?
1) isolate metaphase chromosomes
2) Colchicine is added- cells enter mitosis, but chromosomes remain at metaphase plate
3) Chromosomes are recognised based on their banding pattern
4) Chromosomes are arranged in order of size (1 biggest, 22 smallest)
We can then examine:
- whether the correct number of chromosomes are present
- whether there are copy number variants (duplications or deletions)
- whether there are changes in the position of genetic material etc.
what is the fluorescent in situ hybridisation (FISH) test used for?
uses hybridisation
provides a way for researchers to see the location of a gene and number of a specific chromosome present
how is a FISH test carried out?
1) The first step is to prepare short sequences of single-stranded DNA that matches a portion of the gene the researcher is looking for. These are called probes.
2) The next step is to label these probes by attaching different colours of fluorescent dye to each of them.
3) Since the researchers’ probes are single-stranded, they are able to bind to the complementary strand of DNA, wherever it may reside on a person’s chromosomes.
When a probe binds to a chromosome, its fluorescent tag is highlighted
what is array CGH used for?
Uses hybridisation
Allows us to look at all the chromosome material (not targeted like FISH) and at a higher resolution.
how is the array CGH carried out?
1) You take a DNA microarray containing probes representing genomic regions of interest
2) You then add test and reference DNA (tagged with different colours (i.e. red & green)
3) The two sets of DNA compete for same probe sites of microarray:
- More green dots if there are more copies of the target sequence on the test DNA (duplication)
- Yellow if there are equal copies of the target sequence on both reference and test DNA
- More red dots if there is a deletion of sequences of the test DNA (more probes bind to the normal DNA)
what type of chromosome abnormalities are there?
- Abnormalities of chromosome number
- Abnormalities of chromosome structure
- Chromosome abnormalities are also classified according to which cells of the body they are distributed in:
Constitutional: all cells of the body
Somatic: only in certain cells/tissues of the body
define trisomy
an extra copy of a chromosome is present in the cell nuclei, causing developmental abnormalities
e.g trisomy 21 - extra copy of chromosome 21
what order is the karyotype method of description of chromosomes abnormalities written in?
Written in the format: total no. of chromosomes, sex chromosome constitution, & finally anomalies/variants
examples:
46, XY = normal
47, XX, +21 = trisomy 21 (Down’s syndrome) (+ 21 means additional 21st chromosome so there are three in total)
47, XXX = Triple X syndrome
69, XXY = triploidy
define Aneuploidy
changes in a single chromosome number
give examples of aneuploidy
Trisomy – additional chromosome (47)
E.g. 47 XX +21
Monosomy – missing chromosome (45)
define polyploidy
duplication in all chromosomes
give examples of polyploidy
Triploidy (69)
Tetraploidy (92)
where do abnormalities in chromosomes come from?
give examples
errors in cell division
e.g. non - disjunction
what is non- disjunction and use trisomy to explain this?
failure of homologous chromosomes or sister chromatids to separate properly during cell division. (Meiosis 1, Meiosis 2 or mitosis).
Non-disjunction during meiosis result in the production of disomic gametes => trisomy
Trisomy can occur due to non-disjunction in meiosis I (homologous chromosomes fail to separate) or meiosis II (sister chromatids fail to). There are now two of e.g. chromosome 21 in the cells which then become 3 copies when fertilised by the other gamete.
when do the chances of getting trisomy increase?
Incidence of trisomy 21 increases with maternal age, this is because of the way the eggs are produced.
All oocytes are ready by 5 months gestation. Each remains in maturation arrest at the crossing over stage of meiosis I.
There is a lengthy interval between onset of meiosis in an oocyte and completion (up to 50 years).
The accumulating effects on the primary oocyte during this phase may damage the cell’s spindle formation and repair mechanism predisposing to non-disjunction.
what are the clinical consequences of abnormalities in chromosome number?
often lethal consequences
the only type of abnormalities in chromosome number that will lead to life are difference in number of sex chromosomes or trisomy of chromosome 21, 18 and 13.
Trisomy or monosomy of other chromosomes are not compatible with life.
Significant development abnormalities occur due to the imbalance of gene products.
The effect of reducing the gene copy usually has more severe consequences than increasing the gene copy
what are the 3 known causes of Down syndrome?
Trisomy 21: 95% of people with Down Syndrome have three separate copies of chromosome 21. This is occurring via non-disjunction.
Robertsonian translocation: 4% gain the extra copy of chromosome 21 because of Robertsonian translocation.
Mosaicism causes the last 1%:
This is where the genetic trisomy occurs after fertilisation – not present in gametes.
Non-dysfunction occurs during mitosis so you get two different cell lines, one with trisomy 21 and one with a normal number of chromosomes.
They usually have much milder features because of the presence of the normal cells
Why do chromosome conditions cause problems?
“gene dosage effect” - features of the syndromes are caused by the 1.5 x amount of specific gene products being produced from e.g. (chromosome 21 – DS)
“amplified developmental instability” - overall effect of imbalance on development of human.
