chromosomal abnormalities Flashcards
Define karyotype
What is the human karyotype?
Chromosome set of an individual species in terms of number and structure of the chromosomes.
Human karyotype:
22 pairs of chromosomes
1 pair of sex chromosomes – XX or XY
How do you prepare a karyotype?
- Collect 5ml heparinised venous blood (treated with heparin to prevent coagulation
Can use amniotic cells, CVS (Chorionic villus sampling) - Isolate white cells
- Culture in presence of phytohaemagglutin- Stimulates T-lymphocyte growth/differentiation
- After 48 hours add colchicine - Causes mitotic arrest - metaphase
- Place in hypotonic saline
- Place on slide
- Fix and stain
What do bands in gisema staining represent?
What are dark bands called and what are light bands called?
Regions of different compaction of chromatin
dark - heterochromatin - more compact DNA, fewer genes
light - euchromatin - more open DNA, more genes
What are the three different types of human chromosomes?
Sub-metacentric - long arm and short arm
metacentric - arms are the same length
Acrocentric - short arm replaced by non coding satellites
What are the 5 common structures, identified by the G-Banded architecture of a chromosome?
Telomere on either end of the chromosome p-arm q-arm G-dark and G-light bands Centromere
Why are karyotypes performed more in Prophase rather than Metaphase?
Because the chromosomes are less compact and therefore you get more detail from the karyotype
What is aneuploidy caused by?
Results in uneven number of chromosomes in daughter cells -results in either an extra chromosome (trisomy) or missing chromosome (monosomy)
What is aneuploidy?
Numerical chromosomal abnormailty - aneuploidy- loss or gain of chromosomes
What is the most common form of chromosomal aneuploidy?
Why is it more tolerated than other forms of aneuploidy?
Sex chromosome aneuploidy
more tolerated as
- you get inactivation of excess X chromosomes, only one is active
- Y chromosomes have low gene content so an extra y will not greatly impact phenotype
however both X and Y have some pseudo-autosomal regions which will be active and cause some symptoms
What is caused by trisomy 21?
Downs syndrome - 85-90% due to maternal disjunction
How does maternal non-disjunction change with age and why?
Maternal non-disjunction increases with age as
Proteins become more disfunction with age
Progressive degradation of factors holding homologous chromatids together
This leads to the premature separation of homologs and of chromosomes into separated sister chromatids.
What is turners syndrome caused by?
What is kleinfelders diseases caused by?
- X monosomy
2. XXY chromosome
Why is there a maternal age effect on chromosomal abnormalities?
Vulnerability of oogenesis
- oocyte paused in utero in prophase till puberty
- secondary ooctye paused in metaphase II until fertilised
as the mother ages the oocytes have been arrested in metaphase for 45 years which can cause problems
Degradation of factors that hold the chromatids together
How do paternal genes affect risk of chromosomal abnormalities?
primary spermatocytes undergo 23 mitotic divisions per year and accumulate mutations
smoking is a risk factor
single point mutations in genes FGFR2, FGFR3 and RET which increase sperm viability can lead to certain conditions including:
- apert syndrome
- Crouzon syndrome
- pfeiffer syndrome
When can chromosomal abnormalities occur?
During crossing over
During DNA replication
How does crossing over occur and why?
occurs in prophase I
pairs of chromosomes align
Chiasma forms and crossing over occurs
1-3 times per chromosome per meiosis
Increases genetic diversity
What 5 changes can occur in the banding sequence of a chromosome to cause an abnormality?
Deletion Duplication Inversion Insertion - unequal exchange Translocation - the junction of exchange causes for an abnormal protein
What is robertsonian translocation?
Robertsonian translocation involves acrocentric chromosomes.
Breakage at the centromere, satellites are lost and the two q arms fuse.
Most people are unaffected as satellites don’t code for anything so no genetic information is lost but may affect offspring as they inherit a chromosome with double the amount of genetic information
What is mosaicism and how does it occur?
Presence of two or more populations of cells with different genotypes - an individual will have two different sets of DNA
occurs due to
- mitotic non-disjunction during embryonic development
- Loss of extra chromosome in early development
mutant cell in zygotes mitosis carries on dividing and the normal zygote also divides
What is a structural abnormality?
Number of chromosomes stays the same but the structure of the chromosome is altered
Explain how Unequal Crossing Over occurs?
Chromosomes do not align correctly at centromeres
Unequal lengths of chromatids are exchanged Leading to deletion of genes in one chromosome And duplication of genes in the other chromosome
What are the 2 types of inversion in single chromosome abnormalities?
Paracentric inversion - Breaks in chromosome occur in middle of chromosome arm & that section of chromosome is inverted, creating reinvented piece of DNA
Pericentric inversion - Breaks occur around centromere & that section of chromosome is inverted, creating reinvented piece of DNA
What is the translocation occuring in chronic myeloid leukaemia?
Fusion of part of ABL 1 gene from chromosome 9 with part of BCR gene from chromosome 22, creating abnormal fusion gene called BCR-ABL1
This translocation is written as t(9;22)(q34;q11)
What is meant by a de-novo chromosomal abnormality?
When the abnormality was not inherited from the parent of the patient and so it is new to the individual
What causes William’s syndrome and what are the symptoms of William’s syndrome?
7q11.23 deletion
long philtrum slightly upturned nose lack social anxiety arched eyebrows Supravalvular aortic stenosis
What is one of the chromosomal features of William’s syndrome?
Lack of elastin on affected chromosome
Which chromosomes are generally acrocentric in humans?
Which chromosomes are generally acrocentric in humans?
13
14 15 21 22
