Genetics - Chromosomal Abnormalities Flashcards
What is a karyotype?
Collection of chromosomes
What can we use for a karyotype sample?
Peripheral blood, amniotic cells, CVS
If using peripheral blood for karyotype, what must we do?
- Isolate white blood cells
- Then culture cells in presence of phytohemagglutin, which will stimulate T cell growth and differentiation.
- Then, after 48 hours add colchicine to arrest mitosis.
- Place cells in hypotonic solution - cause lysis
- Stain with giemsa and observe results
What is an ideogram?
The distinct pattern a chromosome generates with giemsa
What is the p-arm?
Short arm
What is the q-arm?
Long arm
What are g-dark bands?
Dark bands of chromosome which take up more gisema
what are g-light bands?
Light bands of chromosome which take up less gisema
What does 3p21 mean?
Region found on chromosome 3, p arm, 2nd band, 1st region of 2nd band.
Why are dark bands dark?
They take up more gisema which is used to stain the chromosomes
What is contained in dark bands?
Heterochromatin which contain few, more dense genes so take up more gisema
What is contained in light bands?
Euchromatin with less, more open genes so take up less gisema
What is aneuploidy?
Abnormal number of chromsomes
What is the purpose of meiosis?
Achieve reduction of diploid to haploid
Achieve genetic variation
Enable random assortment of homologues and recombination
What is non disjunction?
When chromosomes don’t split properly between daughter cells
When does non disjunction occur?
Either meiosis 1 or 2
What does M1 non disjunction mean?
All daughter cells are affected
What does M2 non disjunction mean?
Only half of the daughter cells are affected
What does non disjunction always result in?
Either trisomy or monosomy after fertilisation
What is the most common abnormality?
Sex chromosome aneuploidy
Why is a sex chromosome imbalance tolerated?
- Only part of one of the X chromosomes in females in inactivated
- Y chromosome has few genes
- Pseudo autosomal region (PAR) - part of the X chromosome is not inactivated along with the X chromosome.
What is trisomy 21?
Dow’s syndrome: 3 copies of chromosome 21
When do most cases of Downs arise?
Maternal oogenesis
Is there paternal input in Downs?
Some
What increases the risk of Downs?
Maternal age (positive correlation)
Why is there a maternal age effect on Downs?
- Inherent vulnerability of oogenesis with age
- Primary oocytes are produced in utero before prophase 1 and then arrested until puberty
- Secondary oocytes arrest in metaphase 2 until fertilisation.
This causes the degradation of factors which hold chromatids together during division
Does paternal age influence aneuploidy?
No, however it has an effect on single gene disorders
How do spermatocytes influence aneuploidy?
Primary spermatocytes undergo 23 mitotic divisions per year
What is selfish spermatogonial selection?
Mutated spermatids may have an advantage over wild type spermatids
What is a paternal but not maternal risk factor for Downs?
Smoking
What is the effect of aneuploidy on pregnancy?
5% of still births and 50% of abortions/miscarriages are due to anueploidy
How can we detect trisomy?
Prenatally
Why is there little monosomy?
Poorly tolerated, trisomy is also often incompatible with life
When do cross over chromosomes occur?
Prophase 1
What does cross over do?
Increases genetic diversity
What is cross over?
Pairs of chromosomes align, chiasma form and cross over between chromosomes occur
How often does cross over occur?
1-3 times per chromosome per meiosis
What happens when cross over goes wrong?
Unequal crossover can cause duplication in one chromosome and deletion in the other chromsome
What are examples of single chromosome abnormalities?
Deletion
Duplication
Inversion
What is deletion?
part of chromosome deleted
What is duplication?
part of chromosome added onto same chromosome
What is inversion?
Section of chromosome is turned upside down to sometimes cause reproductive issues
What is insertion?
Two chromosomal abnormality - unidirectional manner of transfer from one chromosome to another
What is translocation?
Mutual exchange where different derivative chromosomes are formed after a swap of genetic material
What is an example of translocation mutation?
Philadelphia chromosome (CML)
Are abnormalities always inherited?
No: many are de novo.
Some people are unidentified carriers and can have offspring who are affected
What are microscopic deletions?
Deletion easily detected with microscope and staining e.g. Cri-du-chat syndrome - deletion of whole p arm of chromosome 5
What are microdeletions?
Can only be seen in very high resolutio banding e.g. DiGeorge Syndrome - deletion of one sub band
What occurs in William’s syndrome?
Gene on long arm of chromosome 7 is deleted
Why can’t we use a normal karyotype for detecting William’s?
Too small to detect
What can we use to detect Williams?
Fluorescent in situ hybridisation (FISH assay)
What are the symptoms of Williams?
Long philtrum
Short, upturned nose
Supravalvular aortic stenosis
No social anxiety - friendly
What is the result of a reciprocal duplication that occurs in the same area affected by Williams?
Opposite symptoms of William’s e.g. autistic traits, broad nose and short philtrum
Phenotypically, how do duplications differ to deletion?
Generally, duplications have a milder phenotype than deletions
What are the 3 classes of chromosomes?
- Metrocentric - short P arm, long Q arm, centromere in centre
- Submetacentric - short arm is considerably shorter than long arm
- Acrocentric - short arm reduced to stalk or satellite.
What is Robertsonian translocation?
When two acrocentric chromosomes lose their stalks and their long arms combine to form a derivative chromosome
Can be homologous or non homologous
Why are most carriers of Robertsonian translocation unaffected?
If it occurs during development, they will have a balanced genotype and it only evolves one of each of the 2 chromosomes
Why may carrier offspring not be affected?
If a carrier is homologous, they will have one normal copy of a chromosome which can still be inherited normally.
Which chromosome pairs are most commonly affected by Robertsonian translocation?
13 and 14
14 and 15
14 and 21
What is mosaicism?
Cells of the same population don’t contain the same chromosomes
How may mosaicism arise?
Non disjunction during early development
Loss of extra chromosome in early development
How common is mosaicism?
Everyone is thought to be mosaic
What is the most common mosaic?
46, XX/45,X
46,XY/45,X
