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Molecular Basis of Disease > Structural Chromosomal Abnormalities > Flashcards

Structural Chromosomal Abnormalities Flashcards

1
Q

Examples of structural chromosomal abnormalities?

A 
Translocations (reciprocal and robertsonian)
Deletion (terminal, interstitial)
Inversion
Duplication
Ring chromosome
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2
Q

What is translocation?

A

Exchange of two segments between non-homologous chromosomes

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3
Q

What are the 2 types of translocation?

A

Reciprocal translocation

Robertsonian translocation

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4
Q

What causes translocation?

A

Innappropriate NHEJ (non homologous end joining) - incorrectly sticks wrong chromosome pieces to wrong chromosomes when trying to repair a break in the DNA

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5
Q

What is non homologous end joining?

A

DNA repair mechanisms - DNA physically reaks and NHEJ repairs this by sticking chromosomes pieces back together

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6
Q

What type of derivative chromosomes are formed from innappropriate NHEJ translocation?

A

Balanced (right number of chromosomes just in wrong place, normally ok) and unbalanced (wrong number of chromosomes) translocations

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7
Q

Where does innappropriate NHEJ happen?

A

In any chromosomes and any size fragments

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8
Q

When can balanced translocation be bad? example

A

Depending on which chromosome broke and where it broke, the joining may directly affect the expression of a gene such as a proto-oncogene

  • ABL gene from a chromosome 9 and BCR gene from chromosome 22. When fused together, derivative chromosome is philadelphia chromosome triggers oncogene = cancer
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9
Q

How are unbalanced chromosomes produced?

A

When a CARRIERS balanced derivative chromosomes align with homologue for meiosis, the homologous chromosomes are different (carry diff genes since balance derivative has genes from a diff chromosome - not the correct allele lined up with homologous pair). Recombination of different chromosomes happens and genes are lost. (e.g. there is only one copy of a gene in translocated areas)

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10
Q

What consequences does unbalanced reciprocal translocation lead to?

A

Miscarriage (so women with lots of miscarriages are screened for translocations - if they are a carrier for a derivative)

Or learning difficulties and physical disabilities

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11
Q

What type of chromosomes are involved in robertsonian translocations and why?

A

only acrocentric chromosomes since short p arms can be lost during double breaks rather than being stuck back on.

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12
Q

What is robertsonian translocation?

A

Combination of two q arms. - p arms are lost and q arms from both chromosomes join near centromere to form a single chromosome that has q on bottom and top

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13
Q

What is the purpose of p arms on acrocentric chromosomes?

A

Contain identical repeats of genes that codes for rRNA

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14
Q

Which chromosome numbers are the acrocentric chromosomes?

A

13, 14, 15, 21 and 22

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15
Q

How many chromosomes do people with robersonian translocations have?

A

45 chromosomes but same number of genes since genes weren’t lost (p arms of acrocentric chromosomes don’t have genes)

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16
Q

Which robertsonian translocation leads to down’s syndrome? !!!

A

21-21 translocation

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17
Q

Explain the difference between recombination, reciprocal translocation and robertsonian translocation?

A

Recombination happens on the same pair of homologous chromosome.
Reciprocal (normal balanced) Translocation is between 2 different pairs of homologous chromosomes (1 chromatid from each) = 2 pairs of chromosomes (4 individual chromosomes), just genes switched
Robertsonian translocation happens between 2 different pair of acrocentric homologous chromosomes (1 chromatid each, instead of switching gene, q arms join = 1 acrocentric chromosome left from pair 1 and 1 acrocentric chromosome left from pair 2 and 1 join robertsonian chromosome = instead of 2 pairs giving 4, we now have 3 individual chromosomes)

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18
Q

What are the 2 mechanisms of trisomy 21?

A

Non disjunction = 3 full copies of chromosome 21

Robertsonian translocation = 2 copies of chromosome 21 + robertsonian chromosome (mixture of chromosome 14 and 21)

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19
Q

What happens after unbalanced translocation occurs?

A

Spontaneous miscarriage

If baby is born, many health issues

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20
Q

What are the 2 types of deletion structural chromosome changes?

A

Intersitital and terminal

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21
Q

What does deletion of genes result in genetically?

A

An area of monosomy - gene is only on one chromosome

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22
Q

What are the consequences of deletions of genes?

A

Haploinsufficiency in some genes (1 gene is not enough to preserve normal function)
Contiguous gene syndrome - small deletion causes certain genes to cause recognisable phenotype (clinical features) - phenotype is specific to where the deletion happened

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23
Q

How is deletion detected/viewed? !!!

A

Gross deletions are seen on metaphase spread on G banded karyotype

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24
Q

How are microdeletions viewed/detected?

A

Too small, few genes lost so not visible on metaphase spread

  • use high resolution banding, FISh or CGH
25
Q

What is unequal crossing over?

A

Non-allelic homolgous recombination (exchange of genetic material between homologous pairs but not aligned properly (misalignment) so deletion in some areas and insertion in some areas.

26
Q

What are the 3 ways to obtain a sample prenatally?

A

Amniocentesis (amniotic fluid contains foetal DNA and is invasive)
Chorionic villus sampling (piece of placenta for foetal DNA - invasive)
Cell free foetal DNA (in maternal plasma so is non invasive)

27
Q

What are the 2 ways to obtain a sample postnatally?

A

Blood and saliva

28
Q

Why are the 2 invasive prenatal testing methods not good?

A

Can cause miscarriage

29
Q

What is the most common form of chromosome staining?

A

G banding - shows diff bands within karyotype of metaphase spread

30
Q

What does G banding show?

A
  • under microscope

2 types of chromatin stain diff colours (euchromatin and heterochromatin)

31
Q

Why do the different types of chromatin stain different in G banding?

A

Euchromatin is GC rich and genes are active since it is loosely packed so stain differently compared to heterochromatin which is AT rich and tightly packed so genes are inactive.

32
Q

What stage must the chromosomes be in in G banding?

A

Metaphase spread - must be cultured so takes several days

33
Q

What conditions can be identified using G banding?

A

Large defects including

  • aneuploidies
  • translocations
  • large deletions (not microdeletions)
34
Q

What is FISH?

A

Fluorescent in situ hybridisation

35
Q

What stage must chromosomes be at in FISH?

A

Must be cultured and during metaphase spread

36
Q

What is hybridisation?

A

Single stranded nucleic acid binds to a new single stranded nucleic acid strand (DNA/DNA or DNA/RNA)

37
Q

What are the steps in FISH?

A

Specific fluorescent PROBE not dye and is mixed with denatured target DNA. Probe binds to target since probe annealing is favoured over DNA renaturation (loads of probes flooded/used) which is viewed as fluorescence.

38
Q

What is a probe?

A

specific single stranded DNA(after denaturing) /RNA molecule that is complementary to specific/target gene

39
Q

Explain how FISH can show deletion?

A

No fluorescence of a chromosome = DNA missing = deletion

- on end of chromosome = telomeric deletion

40
Q

How can FISH detect trisomy 21?

A

3 spots glow showing specificity to chromosome 21

- spectral karyotyping preferred

41
Q

Why is FISH more complicated to spectral karyotyping?

A
  • need to know wha you’re looking for

Fluorescent probes specific for parts of genome

42
Q

What does FISH detect?

A

Aneuploidies, translocations and large deletions (not smaller deletions)

43
Q

What does arrayCGH stand for and what is it used to detect?

A

Array comparative genomic hybridisation

  • detects sub microscopic chromosomal abnormalities e.g. deletions
44
Q

Why might we use array CGH over spectral karyotyping and FISH?

A

Can look for smaller abnormalities if FISH/spectral karyotyping doesn’t show it such as microdeletions and microduplications

45
Q

What are the steps in arrayCGH? + how does it diagnose

A
  • Patient DNA labelled with green tag and control healthy patient DNA labelled with red tag
  • Put both DNA in array containing probes
  • yellow colour = equal hybridisation of patient’s and control DNA to the probes = patient is healthy
  • red = patient has deletions (more of the healthy DNA attached to the probes)
  • green = patient has duplication (more patients DNA attached to probes
46
Q

What is QF-PCR and what does it detect?

A

Quantitative fluorescence polymerase chain reaction

- detects trisomies (aneuploidies) using microsatellites

47
Q

What are microsatellites?

A

Short repeated sequences

48
Q

How do QF-PCR results show trisomy?

A

3 peaks (heterozygous all equal peaks) or 2 peaks (homozygous with one larger than other instead of the 2 normal)

49
Q

How do microsatellites vary?

A

Lot of variation in number of repeats between individual + highly polymorphic

50
Q

Where are microsatellites found’?

A

Usually in non gene regions distributed throughout genome

51
Q

How are microsatellites identified?

A

Unique SPECIFIC flanking sequences on the ends of microsatellites - primers SPECIFIC to the flanking seqeuences for the SPECIFIC MICROSATELLITE added then PCR to replicate only that region. the entire region between these primed flanking sequences is the microsatellite that will be amplified in PCR)

52
Q

What is done after PCR in QF-PCR?

A

Gel electrophoresis of PCR product (microsatellite amplification) to see if target gene is present
- 3 bands for gene = trisomy

53
Q

What are the components in a PCR reaction?

A

Template (DNA that needs to be amplified)
Primers (short ssDNA)
Thermostable polymerase (Taq) - extends DNA
Nucleotides (dNTP)
Buffer (maintain pH)
MgCl2 (NEEDED FOR POLYMERASE ACTIVITY)

54
Q

WHAT ARE THE 3 STAGES OF PCR with diff temps? + explain each stage briefly

A

Denaturation - separate DNA strands at 94 degrees
Annealing - Primers anneal to template at 60 degrees (loads of primers favours over renaturation of DNA)
Extension - DNA polymerase binds to primer at 72 degrees and extends

55
Q

Why does PCR slow down and stop eventually?

A

PCR initially quick but components needed for PCR runs out

56
Q

How can you see if someone is homozygous or heterozygous for a microsatellite (one from other and from from father)? in a normal person

A

Homzygous - single high signal peak

Heterozygous - 2 peaks of similair and lower signal

57
Q

What is NIPT and what is done after this?

A

Non-invasive pre-natal testing for cell free fetal DNA in maternal blood sample for aneuploidies (trisomy)
- Must do NGS after (next generation sequencing)

58
Q

When is invasive tests done?

A

Only if high chance since NIPT is only indicative not diagnostic (so invasive test is done after NIPT is there is a high chance of trisomy)

Molecular Basis of Disease (29 decks)

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