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PoM - Principles of Medicine Week 3 > Chromosomal Abnormalities > Flashcards

Chromosomal Abnormalities Flashcards

1
Q

What are chromosomes?

A

Tightly packed DNA around histone proteins

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2
Q

What are chromatids?

A

Unwound DNA created during mitosis / meiosis

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3
Q

What is a karyotype?

A

An individual collection of chromosomes Also refers to a lab technique that produces an image of an individuals chromosomes - used to look for abnormal numbers or structures of chromosomes

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4
Q

When can chromosomes be karyotyped?

A

During metaphase, when they are condensed and replicating

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5
Q

How many chromatids is each chromosome made of during replication?

A

2 chromatids make one chromosomes during replication

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6
Q

What is DNA compaction?

A

DNA helix is wrapped around a histone core to form a nucleosome Nucleosomes are coiled into the chromatin fibres These chromatin fibres are further condensed / looped onto the histone core This forms the chromosome

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7
Q

Why is DNA compaction important?

A

Not just about ‘fitting in’ all the DNA into the nucleus Compaction affects gene expression e.g. proteins bound to chromatin affect its regulation

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8
Q

What is G-band architecture?

A

A visible karyotype by staining condensed chromosomes - shows the banding of the chromosome

G light bands are more easily accessible parts of DNA (more expression)

G dark bands are less accessible parts of DNA (less expression)

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9
Q

What is an ideogram?

A

Chromosomes have some common structural features An ideogram is a diagram / image of a ‘normal’ chromosome (stained to show the common bands) Can be used to compare against a patient’s DNA to look for banding abnormalities

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10
Q

What type of stain is used for the ideogram?

A

Giemsa staining - leaves a recognisable pattern of bands

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11
Q

What features do all chromosomes have and why?

A

Telemore - ends capped with this to stop the chromatin unravelling

Centromere - for spindle attachment

p-arm - small arm

q-arm - big arm

‘G’ dark - tightly bound DNA (less expressed)

‘G’ light - more loosely bound DNA (more expressed)

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12
Q

How is the banding referred to on a chromosome?

e.g. What does 24.3 mean?

A

Previously, the staining method was less effective, so chromosomes had larger, less detailed bands, so were named 1, 2, 3, 4… etc.

Now, the staining is more effective and the banding is more detailed, so it was found all the bands were comprised of smaller sub-bands

So for 24.3 (pronounced as two four point three), it is band 2, sub-band 4, sub-band 3

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13
Q

How is the normal karyotype presenting using cytogenetic nomenclature?

What is the abbreviation for a translocation?

What is the abbreviation for a deletion?

How is the loss of a chromosome documented?

How is the gain / extra chromosome documented?

What is the abbreviation for inversion?

A

46,XX or 46,XY

t

del

Subtract from the overall number of chromosomes, e.g. monosomy (loss of a whole chromosome) results in 45 instead of 46. Then use a - symbol

Add to the overall number of chromosomes e.g. 47 instead of 46, then use a + symbol

inv

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14
Q

Describe what is meant by:

46,XX,t(5;10)(q34.1;q11.2)

46,XX,del(5)(q21q23)

45,XX,-7

47,XX,+8

46,XX,inv(3)(q21q26)

A

t = translocation, first bracket are the chromosome numbers that the translocations involve, the second bracket contains the arm and the specific sub-bands that are the breakpoints

del = deletion (part of chromosome material missing), first bracket is the chromosomes involved, the second bracket is the breakpoints, inbetween which the material is missing

Monosomy

Trisomy

inv = inversion, first bracket is the chromosome involved, the second bracket are the breakpoints, inbetween which the DNA has inversed

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15
Q

What are the 3 different mechanisms of gene expression and their descriptions?

(HINT: haploinsufficient, haplosufficient, imprinting)

A

Haploinsufficient - need expression from both alleles to have a normal phenotype

Imprinting - methylation pattern that is parent-of-origin specific, i.e. some things may be expressed only on the paternal homologue and not on the maternal, and if that is inherited correctly, that is normal

Haplosuffient - need expression from one allele to another

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16
Q

What are the different types of specific expressions to have the right control over the genome?

A

Tissue specific expression - e.g. genes only expressed in the brain etc.

Time specific expression - during development e.g. different stages of embryonic development, puberty etc.

Response specific expression - e.g. in response to environmental factors

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17
Q

What is the purpose of mitosis?

A

To create 2 identical daughter cells

Growth and repair

To replace exhausted cells

2n –> 2n

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18
Q

What is the purpose of the culture and harvest of cells?

A

To karyotype them

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19
Q

What is the procedure for the culture and havest of cells?

A
  1. Get blood samples from patients e.g. children with developmental delay, adults with reproductive issues etc. - 0.5ml of blood is put in a 5ml culture medium
  2. Add phytohemagglutinin (stimulates lymphocytes to divide)
  3. Culture them (24-72hrs)
  4. Add colemid (stops the cell replication cycle at metaphase by acting as a poison that blocks the spindles) - increases the proportion of cells at metaphase
  5. Harvest: Add hypotonic KCl to swell cells (so chromosomes have more volume to spread out over)
  6. Add fix (to fix the chromosomes in place?) - composed of a 3:1 ration of methanol: acetic acid
  7. Drop onto microscope slide
  8. Add trypsin for brief digestion
  9. Lastly, add the stain, Giemsa, to see the chromosomes and their banding

5.

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20
Q

Which step of the culture and harvest improved the banding details from how it was previously done?

A

Step 8: Add trypsin before adding Giemsa - before the giemsa was added straight away, with no input of the trypsin so the chromosomes could be seen, but the banding structures could not

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21
Q

What is the purpose of meiosis?

A

To create 4 unique daughter cells

2n –> n

Diploid to haploid

Random assortment of homologues and recombination

Ensures genetic variation in the gametes

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22
Q

What is non-disjunction and where are the 2 points this can occur in meiosis?

A

Non-disjunction during meiosis produces eggs or sperm cells that don’t have the normal number of chromosomes

Meiosis 1 and meiosis 2

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23
Q

What is non-disjunction of meiosis 1?

A

One daughter cell is given 2 chromosomes whilst the other has none?

Consequently, during the second round of division (meiosis 2), 2 gametes have 2 chromatids and 2 gametes have none

Therefore, if each of these gametes were to be fertilised by another normal gamete, 2 zygotes end up with 3 chromatids (trisomy) and 2 have only 1 chromatid (monosomy)

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24
Q

What is non-disjunction of meiosis 2?

A

Meiosis 1 occurs normally, so one chromosome in each daughter cell

One of the daughter cells, however, divide during meiosis 2 to produce one daughter cell with 2 chromatids and one daughter cell with no chromatids

Therefore, when these gametes get fertilised with a normal set of gametes, one zygote has trisomy, another with monosomy, and 2 normal zygotes

25
Q

What are the cells called, from which gametes are derived from in males and females?

A

Spermatocytes

Oocytes

26
Q

How are male and female meioses very different?

A

The female meioses (oogenesis) are more vulnerable

27
Q

What are the 3 reasons why there is an increased vulnerability in female meiosis?

A
  1. Meiosis 1 of the oocytes occur in utero in the girl, then is paused til puberty. This pause is thought to be problematic.
  2. One primary oocyte gives rise to only one secondary oocyte, which gives rise to only one ovum (so one oocyte produces one egg cell)
  3. There are a finite number of primary oocytes in a female
28
Q

How is spermatogenesis different (male meiosis)?

A

Starts at puberty

Will continue potentially life-long, inexhaustible pool as they are made the whole time

Every primary spermatocyte produces 4 gametes

29
Q

What are some problems being seen in male meiosis? (Male vulnerability)

A

A female undergoes meiosis 1 in utero, so the primary oocyte is risen from a total of 23 mitoses, however, for males, once this process starts at puberty, it continues

Do to no equivalent menopausal limit, 23 mitotic divisions are made every year and there is potential to accumlate defects

30
Q

What is the maternal age problem and why does it occur?

A

Increased risk of female non-disjunction, leading to increased risk of aneuploidy (abnormal chromosome number in haploid set)

Likely due to degradation of factors that hold homologous chromatids together e.g. spindles disintegrate and chromosomes are more disordered

As age increases, so does risk (more after 35)

31
Q

What are the syndromes of trisomy 13 and 18?

A

Trisomy 13 - Patau syndrome

Trisomy 18 - Edwards syndrome

32
Q

What causes Down Syndrome?

A

Trisomy 21

Mostly arises from maternal non-disjunction in meiosis 1, some from meiosis 2

Very few contributed from paternal meiosis

Few contributions from mitotic non-disjunction, during some of the first divisions after conception

33
Q

What are some of the characteristric features of down syndrome?

A

Epicanthal fold - skin fold of the upper eyelid covering the inner corner of the eye

Large protruding tongue

34
Q

What can be used to test if a zygote / foetus has down syndrome?

A

Karyotyping (though quite slow so generally not used nowadays)

Quantitative Flourescence PCR

35
Q

Can meiotic non-disjunction be detected and what are their compatibilities with life?

A

Trisomy for all chromosomes can be detected pre-natally

Monosomy is poorly tolerated, less so than trisomies - generally lost before pregnancy occurs or doesn’t form fully after conception (leading to miscarriage)

Ploidy (number of sets of chromosomes in a cell) abnormalities more tolerated

36
Q

How common are sex chromosome aneuploidy and why are they well tolerated?

A

Occur fairly frequently in comparison to others

Excess ‘X’ chromosomes are inactivated by X-inactivation (full methylation) - in normal females one ‘X’ chromosome is inactivated alomst entired, except for a few genes

Low gene content of ‘Y’ chromosome (therefore imbalances / deletions in Y is well tolerated)

37
Q

What sex chromosome aneuploidy can lead to male loss of fertilisation?

A

XXY

38
Q

If the ‘Y’ chromosome has so few genes, why is it important?

A

Contains the SRY gene to kickstart puberty in males

39
Q

What are the 3 types of chromosomal reciprocal abnormalities?

A
  1. Translocation
  2. Insertion
  3. Inversion
40
Q

What are reciprocal translocation chromosomal abnormalities?

A

Exchange of segments between non-homologous chromosomes

Majority of those with translocations are phenotypically fine / normal, though some risk of miscarriage from the formation of unbalanced gametes

41
Q

What are reciprocal insertion chromosomal abnormalities?

A

A segment of one chromosome is inserted into another, causing one of the chromosomes to get smaller, and the other bigger

Usually results in a normal phenotype, unless the insertion disrupts a gene halfway

42
Q

What are reciprocal inversion chromosomal abnormalities?

A

A swtitch of the genetic information on a chromosome

43
Q

What do the reciprocal chromosomal abnormalities have in common?

A
  1. Carriers (1 in 1000) are usually phenotypically normal
  2. During synapsis (pairing up of chromosomes during meiosis / mitosis) the chromosomes need to contort into unusual figurations to achieve this
  3. Increased reproductive risk - increased chance of unbalanced gametes due to random segregation
44
Q

What can unbalanced chromosomal abnormalities be caused by and what can they cause ?

A

Reciprocal chromosomal abnormalities - translocation, insertion and inversion

Terminal deletion (ends of chromosomes deleted), interstitial deletion (lose a bit from within a chromosome), duplication (opposite of the deletion), ring chromosome (unstable)

Affect phenotype - severity dependent on the affected segment i.e. size of the imbalance and the gene content

Trisomy more tolerated than monosomy

May arise de novo (newly) or from a reciprocal parental abnormality

45
Q

How were contiguous gene deletion syndromes intially found and classified?

A

The ‘phenotype first’ approach

Group children together on symptoms presented - e.g. similar developmental delay, dysmorphism etc.

Then look for common genetic abnormalities by karyotyping, finding abnormality, creating probe, then screening other children using the probe for the same abnormality

This method helped discover many ‘classical’ contiguous gene deletion syndromes

46
Q

Why was the ‘phenotype first’ approach not very effective?

A

IDK WHAT THIS MEANS:

Phenotypes caused by an imbalance of genes that are completely unrelated to each other apart from their genomic location

47
Q

What can be used instead of karyotyping chromosomes in this ‘modern era’ and why is it preferred?

A

Array Comparative Genome Hybridisation (aCGH)

Can scan the genome for an imbalance at a much higher resolution

48
Q

How does Array Comparative Genome Hybridisation (aCGH) work?

A
  1. Test DNA is labelled red
  2. Reference DNA labelled in green
  3. Hybridise both together onto a genomic array that has oligonucleotides that span the whole genome and can be designed to be as specific or vague as required.
  4. Software added analysis - computer reads the hybridisation, if all is equally hybridised, it is fully yellow. The red and green regions (not hybridised) shows / gives ratios of inbalance
49
Q

What is the mechanism for contiguous gene deletion / duplication syndromes?

A

Have common breakpoints

Mediated by low copy repeats (LCRs)

During recombination (during cell division), the chromosome segments search for homology

With LCRs, there is a risk of non-allelic homologous recombination (NAHC), where they find a bit of homology with another section of DNA on another chromosome, but it’s not the right section

50
Q

Why were the duplication syndromes not recognised previously?

A

May have had milder phenotypic effects than reciprocal deletion

51
Q

What can increase the risk of NAHR (non-allelic homologous recombination)?

A

From inheritance of a parental LCR inversion that the person now carries

52
Q
A
53
Q

Why is the ‘Genotype first’ era now in use?

A

Cost of genomic analysis has greatly reduced due to use of aCHG instead of karyotyping

Easier as aCHG is more automated

Able to detect smaller imbalances

Increased appetite for genetic diagnosis - allows for the child to have the required support e.g. social care, schooling etc.

54
Q

What is another way to find chromosomal abnormalities?

A

Next generation sequencing (NGS)

Used mainly to pick up point mutations

Can use it to find copy number variants (CNV) - use pair end reading: this is reading from each end of a fragment to compare the lengths of the sections to look to see if it is normal, inserted, deleted or inverted

55
Q

What are indels?

A

Small insertions / deletions

56
Q

What can indels and point mutations cause and describe their effects?

A

A missense mutation - point mutation where a single nucleotide change results in a codon that codes for a different amino acid

Depending on how similar or different the amino acid is, it can completely ablate / alter the function of the gene

A nonsense mutation - introduce a stop codon, though sometimes the cell recognises the error and RNA undergoes a nonsense mediated decay so no protein is made ultimately

A frameshift - shift in the read of the genetic code that changes every consequent codon / amino acid

57
Q

What are some examples of the paternal age effect?

A

A group of single gene disorders caused by point mutations in FGFR2, FGFR3, RET

Causing Apert, Crouzon or Pfeiffer Syndromes - fusion of the fetal skull too early, leaving little room to grow

These mutations appear more common than average in the sperm, although the mutation rate is as expected - thought to be caused by ‘selfish spematogonial selection’, selective advantage over neighbouring sperm causing them to grow in patches

58
Q

What is a rare disease?

A

A disease that affects 1 in 2000

1 in 17 in the population suffer from a rare disease

50% of these diagnoses in children

Around 5000 - 8000 rare disease, about 80% due to genetic origin

Rare diseases are collectively not rare

PoM - Principles of Medicine Week 3 (9 decks)

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