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Clinical Genetics > Chromosomal Abnormalities I - Go back see if need to add last 10slides > Flashcards

Chromosomal Abnormalities I - Go back see if need to add last 10slides Flashcards

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Biology 101 flashcards
1
Q
  1. What form is a chromosome most likely in?
A

A chromatin

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2
Q
  1. Describe the structure of chromatin?
A

DNA double helix bounds to histones; an octamer of histones forms a nucleosome.

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3
Q
  1. What is the difference between Euchromatin and Heterochromatin?
A
  • Euchromatin: Extended state, dispersed through nucleus that allows gene expression
  • Heterochromatin: Highly condensed, genes not expressed.
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4
Q
  1. How do chromosomes appear in G1 and S cell cycle phases?
A
  • Chromosomes are shown with a single chromatid during G1 and as 2 sister chromatids during the S phase.
  • G1 phase duplicates cellular content and G2 checks chromosomal errors before mitosis.
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5
Q
  1. What is an octamer?
A

A histone octamer is the eight protein complex found at the center of a nucleosome core particle.

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6
Q
  1. What is the function of the G1 and G2 phases?
A

G1 = Duplicate cellular content

G2= Check chromosomal errors before mitosis

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7
Q
  1. Humans have 23 pairs of chromosomes, of those 23:

how many are autosomes and how many are sex chromosomes?

A

22 pairs are Autosomes

1 pair is your sex chromosomes

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8
Q
  1. What is your sex pair chromosomes if your a :
    -female
    OR
    -male
A

Female = XX

Male = XY

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9
Q
  1. What is the difference between :
    -Submetacentric
    -Metacentric
    -Acrocentric
    -Telocentric - Humans dont posses these
    ???
A
  • Submetacentric = p arm shorter than q
  • Metacentric = p and q arms are even in length
  • Acrocentric = long q , small p where the p contains no unique DNA
  • Telocentric = no p arm
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10
Q
  1. out of the 23 chromosomes, which ones are:
    - Submetacentric
    - Metacentric
    - Acrocentric

*Humans dont have Telocentric**

A
  • Submetacentric ( 4-12 and 19-20, X)
  • Metacentric (1-3, 16-18)
  • Acrocentric (13-15 , 21-22, Y)
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11
Q
  1. Does every cell have a perfect 23 chromosomes?
A

gametes, mutations, duplications etc.

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12
Q
  1. What is an example of a numerical chromosomal change and how is it detected?
A

Down’s detected through traditional karyotyping, FISH, QF-PCR, NGS.

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13
Q
  1. What’s the genetic change which causes Down’s syndrome?
A

•Structural e.g. Trisomy 21 detected through traditional karyotyping, FISH.

abnormal cell division results in an extra full or partial copy of chromosome 21

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14
Q
  1. What is the difference between :
    -Haploid
    -Diploid
    -Polyploid
    ???
A

Haploid cell has one set of chromosomes (n=23) as in a normal gametes

Diploid cell contains two sets of chromosomes (2n=46; normal in human)

Polyploid have multiple of the haploid number (e.g. 4n=92)

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15
Q
  1. What are Aneuploid Chromosomes?
A

•Aneuploid chromosome number which is not an exact multiple of haploid number - due to extra or missing chromosome(s) (e.g. 2n+1=47)

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16
Q
  1. How do we get variation in Meiosis I?
A

homologous recombination

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17
Q
  1. What is the “Disjunction” that occurs in Meiosis ?
A

The pulling apart of either homologous chromosomes or sister chromatids is called disjunction and occurs during anaphase of meiosis I or meiosis II

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18
Q
  1. The primary mechanism of Aneuploidy (abnormal no of chromosomes) occurs by non-disjunction. What happens in Meiosis I?
A

•Meiosis I: both copies go into 1 daughter cell and the other daughter cell has none- this then results into two daughter cells with no copies (nullisomic) and two daughter cells with double copies

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19
Q
  1. The primary mechanism of Aneuploidy (abnormal no of chromosomes) occurs by non-disjunction. What happens in Meiosis II?
A

•Meiosis II: chromatids pulled apart in meiosis 1 so, So far so good but 1 daughter cells gives its 2 copies to 1 cell and the other cell has none

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20
Q
  1. Non-Disjunction gives rise to :
    - Trisomic
    - Disomic
    - Monosomic
    - Nullisomic
A

Trisomic = three instances of a particular chromosome

Disomic = Two chromosomes

Monosomic = Just one chromosome

Nullisomic = No chromosomes

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21
Q
  1. What happens in pregnancy when the foetus has aneuploidy chromosomes?
A

•Most pregnancies miss-carry naturally while some are terminated.

22
Q
  1. What is Mosaicism?
A

The presence of 2 or more genetically different cell lines derived from a single zygote e.g. mosaic Down’s.

23
Q

** REMINDER: Thoroughly go through mitosis and meiosis **

A

x

24
Q
  1. What are the mains mechanisms in which Mosaicism can occur?
A
  1. Post-zygotic nondisjunction, i.e. mitotic non-disjunction

2. Anaphase lag, i.e. trisomic rescue

25
Q
  1. What is meant by Post-zygotic nondisjunction and how does this result is Mosaicism?
A

okay so what happens is that you have one set of chromosomes that are normal - so one daughter cell and its division will be normal but the other one is where non-disjunction occurred (maybe for eg on the 16th division) so from that divison onwards is where the cells will be abnormal eg 2n –> ( 2n+1) + 2n when normally it would be 2n–> (2n) and (2n)

26
Q
  1. Why does mitotic non-disjunction produce 2n + (2n+1) and NOT 2n + (2n+1) + (2n-1) ?
A

The (2n-1) ie 45 chromosome cell would die , monosomy is lethal aside from Turner Syndrome

•Monosomic cells are degraded whilst trisomic cells are maintained by the body and can survive to term.

27
Q
  1. What is Anaphase Lag?
A

Anaphase lag describes a delayed movement during anaphase, where one homologous chromosome in meiosis or one chromatid in mitosis fails to connect to the spindle apparatus, or is tardily drawn to its pole and fails to be included in the reforming nucleus. Instead, the chromosome forms a micronucleus in the cytoplasm and is lost from the cell.
The lagging chromosome is not incorporated into the nucleus of one of the daughter cells, resulting in one normal daughter cell and one with monosomy= Mosaicism

28
Q
  1. How can anaphase lagging be a trisomic rescue?

explain
“All 2n+1 to mixture of 2n+1 and 2n”

A
  • In trisomic cells, one chromosome is ‘kicked out’ of cells in vesicles. This produces disomic cells which will then have disomic daughter cells.
  • There are other trisomic cells that this hasn’t occurred in.

Trisomic cells are (2n+1) and anaphase lag results in 2n (the +1 is lost because its the anaphase lagging chromosome ) and 2n+1 ( one daughter cell will still be trisomic)

29
Q
  1. What is the clinical relevance of phenotype in Mosaicism?
A

•Phenotype is thought to be less severe but difficult to assess in terms of which organs/tissues are affected and what the proportions of the different cell types are.

30
Q
  1. Give some examples of diseases associated with mosaicism and the % of he affected cell types?
A

Down’s (2% - Trisomy 21/normal)

Klinefelter’s (15%- 46XY/47XXY)

31
Q
  1. In turners syndrome
    -What % of cells affected
    -What kind of gametes produced and why
    -
A

-25%
-nullisomic gametes (no chromosomes) and disomic gametes produced by non-disjunction.
Turner syndrome results when one normal X chromosome is present in a female’s cells and the other sex chromosome is missing or structurally altered

32
Q
  1. What is the difference between XO and YO chromosomes

O= means second chromsome is missing

A

o Turner’s XO: nullisomic gametes are fertilised with sperm carrying X.
o YO: nullisomic gametes fertilised with sperm carrying Y (lethal).

33
Q
  1. Whats more common autosomal or sex chromosomes being monosomic ?
A

• Autosomal are very very rare whilst sex chromosomes monosomy is relatively common e.g. Turner’s

34
Q
  1. How does partial and full monosomy arise?
A

•Full monosomy arises by non-disjunction while more common, partial monosomy (micro-deletion syndromes) arises by a different mechanism.

35
Q
  1. What are the possible combinations after non-disjunction in sex gametes?
A

• Nullisomic gametes: become XO (Turners- physically female) or Y (lethal)

•Disomic gametes:
o XX fertilised with X or Y to become XXX (triple x syndrome) or XXY (Klinefelter’s - physically male).
o XY fertilised with X or Y to become XXY (Klinefelters) or XYY (XYY syndrome).

36
Q
  1. Give a lil summary of numerical abnormalities
    -Eg’s of autosomal and sex chromosomes
    -The mechanisms by which these abnormalities occur
    ?
A
  • Types: autosomal (trisomy 13, 18, 21) and sex chromosomes (XO, XXY, XYY).
  • Mechanism: non-disjunction or anaphase lag.
37
Q
  1. How is a karyotype done and how look does it take?
A
  • A blood sample is taken and cultured for 3 days; the cells are burst to release chromosomes. The chromosomes are fixed (stop them going further) and stained on a slide. Chromosomes are lined up into a karyotype.
  • This takes up to 3 days and other tests are quicker.
38
Q
  1. At how many weeks would you do a prenatal diagnosis using CVS (What is a Chronic Villus Sampling)?

(Invasive)

A

Chorionic villus sampling (CVS) is a prenatal test that is used to detect birth defects, genetic diseases, and other problems during pregnancy

11-14 weeks

39
Q
  1. What are the risks associated with Chronic Villus Sampling?
A
  • Miscarriage rate 0.5% to 1%

* Risk of maternal contamination and transverse limb defects

40
Q

40 At how many weeks would you do a prenatal diagnosis using Amniocentesis (What is a Amniocentesis )?

Invasive

A

It involves removing and testing a small sample of cells from amniotic fluid

> 16 weeks

41
Q
  1. What is G- Banding?
A

G-banding, G banding or Giemsa banding is a technique used in cytogenetics to produce a visible karyotype by staining condensed chromosomes. It is useful for identifying genetic diseases eg trisomy

42
Q
  1. How does G- banding work - ie how is the karyotype produced?
A

• Euchromatin and Heterochromatin stain differently: Light bands are euchromatin and dark are heterochromatin.
o Euchromatin = GC-rich; loosely packed; genes active.
o Heterochromatin = AT-rich; tightly packed; genes inactive.
• Specialist cytogeneticist carries out a metaphase line up based on size, banding and centromere position.

43
Q
  1. How does FISH (Fluorescent in situ hybridisation) detect chromosomal abnormalities?
A

• Cells are cultured and a metaphase spread produced - Fluorescent probe is mixed with denatured, single-stranded, target DNA until probe binds.

44
Q
  1. What is the size range that FISH works in?
A

•Microscopic (resolution 5-10Mb) so cannot detect anything smaller than this.

45
Q
  1. What is one major advantage of Quantitative Fluorescence PCR over FISH and G banding?
A

• Quicker than FISH( because FISH uses cultured cells) and g-banding: 1.5 hour not 3 days.

46
Q
  1. How does Quantitative Fluorescence PCR detect chromosomal abnormalities?
A

It uses micro satellites and the amplification of chromosome-specific DNA sequences polymorphic in length between subjects.

Can be visualised as peaks on automated DNA scanners - higher peaks means more fluorescence which means more of that particular allele. If disomic just two allele’s
If trisomic , three - maybe 2 of one allele and one of the other or maybe 3 separate allele’s

47
Q
  1. Just to summarise, what are TWO prenatal diagnosis techniques that are invasive?
A

o Amniocentesis (14-20 weeks, amniotic fluid)

o Chorionic villus sampling (CVS) (11-14 weeks, placental cells)

48
Q
  1. What is an example of a non-invasive prenatal diagnosis for autosomal chromosomal abnormalities?
A

• SAFE TEST for trisomies 13, 18 and 21 is available privately (£400) but is not free at St Georges.
o Cell free foetal DNA (cffDNA)
• Maternal plasma contains cell free maternal and foetal DNA which allows us to investigate monogenic disorders and aneuploidies.

49
Q
  1. How can we investigate monogenic disorders via cell free foetal DNA?
A

• Monogenic disorders: generate primers that are unique to genes in the foetus that are not present in the mother and use PCR – detect PCR products corresponding to foetal-specific genes such as RHD

50
Q

50 . How can we investigate aneuploidy disorders using cell free foetal DNA?

A

• Aneuploidies: Sequence the total DNA present in the maternal plasma and align the reads to the human genome sequence to determine the chromosome representation.

o Sequences should have an equal coverage around the genome but when there is a trisomy, many more fragments will be present, and the coverage will be deeper.

Clinical Genetics (5 decks)

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