POM - GENETICS - CHROMOSOMAL ABNORMALITIES Flashcards
What is a karyotype and what is it used for?
A karyotype is an individual’s whole set of chromosomes
Karyotyping is used to examine a person’s whole set of chromosomes and identify any abnormalities in the chromosome
what is a giemsa staining, ideogram and G-banded architecture?
Giemsa staining has been used to identify individual chromosomes
Introduces ‘banding’ of light and dark areas
An ideogram is a schematic used to show the size and banding patterns of the chromosomes.
The Giemsa staining leaves a recognisable pattern of bands
what are band numbers? how do they work?
Bands are caused by different staining
Bands were originally identified with low levels of resolution
There was only a few bands visible per chromosome (1,2,3)
As technology improved, more bands became visible - they were named as sub-bands ie, 11,12,21,22,23
Further improvements in resolutions helps identify smaller aberrations (11.1, 11.2 etc)
what is currently the most detail we can study chromosomes?
We can now study bphs – bands per haploid set. Bands DON’T REPRESENT GENES OR FAMILIES OF GENES. Regions of different compaction can help identify the number of genes in each band. Dark – heterochromatin – means that it is more compact and there are fewer genes. Light – euchromatin- means that there are more genes.
what does the different regions of compaction mean?
Regions of different compaction can help identify the number of genes in each band. Dark – heterochromatin – means that it is more compact and there are fewer genes. Light – euchromatin- means that there are more genes.
when is karyotyping most commonly carried out?
Karyotyping is more commonly done in prophase rather than metaphase
what is meant by WSG? when is it carried out?
We are beginning to see genomic medicine due to the human genome project reading the whole human genome
Cost of WSGs are decreasing
Babies could have their genomes sequenced from birth
This is currently done for some types of cancer patients to inform the best treatment
WSGs are currently done for babies who have a suspected abnormality.
what is an aneuploidy
An aneuploidy is an abnormal number of a chromosome
2 copies are sufficient, 3 is a trisomy and 1 is an insufficient monosomy
what is the ‘normal’ process of meiosis?
To achieve a reduction from diploid (46) to haploid (23) chromosomes in the cell.
This ensures genetic variation in the gametes and enables random assortment of homologues and recombination
what is non-disjunction? what does it lead to? how does it arise?
Results in an uneven number of chromosomes in daughter cells
Occurs in either meiosis I or meiosis II
In meiosis I = all daughter cells are affected
In meiosis II = half are affected
Always results in +1 or -1 chromosomes
After fertilization this results in a trisomy or monosomy
what is sex chromosome anueploidy, how common is it and what is its effects?
Most common form of aneuploidy
Affects 1:400 males and 1 in 650 females
But why is it tolerated? Why doesn’t it result in a non-viable fetus?
There is X-inactivation of excess X-chromosomes so only 1 X chromosome is active
The Y chromosome is only 150 genes low gene content.
However, the inactive X chromosome still has an effect as both the X and Y chromosome have PAR psuedo-autosomal region
what are the classes of chromosomes?
- meta centric,
- arcocentric
- submetacentric
what is targeted fish? what does it pick up?
If the deletion is too small to detect using standard karyotyping, it can be detected using targeted FISH
FISH - fluorescent in situ hybridisation, where the lack of elastin on affected chromosome is picked up.
what is the effect of 2 chromosomal abnormalities? how does it affect carriers? what could it cause instead?
If the 2 chromosomal abnormalities are balanced, it often does not affect carriers. However, it may cause partial trisomy or monosomy (Cri-du-Chat Syndrome.)
Can occur in somatic cells.
what is meant by microscopic?
Chromosomal deletions are microscopic as they can be deleted easily under a microscope.
Microdeletion, which is seen in very high resolution banding has 20+ genes deleted
what is the inheritance of chromosome abnormalities?
Many chromosomes abnormalities are de-novo.
Some people are unidentified carriers who can have offspring which are affected
what is mosaicism?
Presence of two or more populations of cells with different genotypes. X-inactivation results in different mosaic expression
Mosaicism can arise by non-disjuncture in early development and loss of extra chromosome in early development
Results in a milder phenotype.
Some lethal aneuploides are thought to be survivable if mosaic
Everyone is a mosaic!
what is the effect of aneuploidy and pregnancy?
Aneuploidy sadly accounts for 5% of still births and 50% of spontaneous abortions.
They accoutn for 5% of all clinically recognised prenancies
Trisomies of all chromosomes can be detected perenatally
Monosomy is very poorly tolerated most trisomies (21,18 and 13) are not compatible with life
what is the link between maternal age and Downs syndrome? why is oogenesis vulnerable?
Trisomy 21 = down syndrome, resulting from maternal non-disjunction
The risk of down-syndrome increases exponentially with maternal age
This is due to the vulnerability of oogenesis
o Oogenesis is paused in utero in prophase I until puberty
o The secondary oocyte arrests in metaphase II
o It is only completed if it is fertilized
o One primary oocyte yields only one ovum
o There is a finite number of primary oocytes
what is the link between maternal age and female non-disjunction? what’s the cause?
Most aneuploidy caused by non-disjunction arises in oogenesis
This is due to the degradation of factors holding homologous chromatids together
Why is male meiosis still a vulnerable process with age?
There is no equivalent to oocyte mitotic arrest.
However, male meiosis is still a vulnerable process as primary spermatocytes undergo 23 mitotic divisions per year and can potentially accumulate age effects.
does paternal age affect aneuploidy? what paternal factors do affect aneuploidy? what does paternal age affect?
Paternal age doesn’t increase the risk of aneuploidy, however it does affect a subset of single gene disorders (Mendelian) caused by point mutations in FGFR2, FGFR3, RET including Apert syndrome, Crouzon syndrome, Pfeiffer syndrome.
This is enhanced by ‘selfish spermatogonial selection’ leading to an advantage over wild type cells.
Although paternal age doesn’t increase the risk of aneuploidy, smoking is a risk factor. Eg, 80% of people who are 45 X have fathers who smoked.
