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Molecular Basis of Disease > 15- Structural Chromosomal Abnormalities > Flashcards

15- Structural Chromosomal Abnormalities Flashcards

1
Q

what is translocation?

A

the exchange of two chromosomal segments between non-homologous chromosomes (chromosomes that aren’t pairs)

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2
Q

what are the two types of translocation?

A

reciprocal
Robertsonian

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3
Q

what is non-homologous end joining (NHEJ) and how can it lead to translocations?

A

NHEJ is a DNA repair mechanism that re-joins broken DNA fragments

inappropriate NHEJ can lead to translocations if fragments from two different chromosomes are incorrectly attached

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4
Q

what are balanced translocations and what are their potential consequences?

A

balanced translocations = the exchange of genetic material without a net gain or loss, produce derivative chromosomes

effects:
carriers are usually healthy - may face reproductive problems due to the structural changes in chromosomes

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5
Q

describe the Philadelphia chromosome and its significance

A

results from a translocation between chromosomes 9 and 22 - creates a BCR-ABL fusion gene that activates oncogenic potential, leading to chronic myeloid leukaemia

ABL gene on chromosome 9 is constitutively active as a proto-oncogene because of its tyrosine kinase activity - translocated to chromosome 22 to form the Philadelphia chromosome, influences BCR gene activity = oncogene

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6
Q

what is a reciprocal translocation?

A

exchange of material between non-homologous chromosomes, no net gain/ loss of genetic material

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7
Q

what happens during meiosis in individuals carrying a balanced reciprocal translocation?

A

affected chromosomes form a tetravalent structure - two intact/ normal chromosome copies, two derivative chromosomes

separation during meiosis can lead to unbalanced gametes with trisomy or monosomy, resulting in various outcomes for offspring - unbalanced arrangement no matter how they separate

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8
Q

how can reciprocal translocations be unbalanced?

A

mis-segregation during meiosis and forming gametes - two intact chromosomes and two derivative chromosomes form a tetravalent structure, can segregate unevenly and form gametes with unbalanced genetic material

breakpoints of translocation within genes or regulatory elements - can disrupt gene function

derivative chromosomes from balanced reciprocal translocation can produce gametes with unbalanced genetic material

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9
Q

consequences of unbalanced reciprocal translocations

A

miscarriages - carriers of balanced/ unbalanced chromosomes may have high numbers of miscarriages

learning difficulties, genetic/ developmental abnormalities in pregnancies that carry to term

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10
Q

what is a Robertsonian translocation?

A

breaks at/ near the centromeres of two acrocentric chromosomes - chromosomal exchange gives rise to:
- one large Robertsonian metacentric chromosome with q arms
- one very small chromosome of p arms (often lost)

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11
Q

what chromosomes are involved in Robertsonian translocations?

A

acrocentric chromosomes 13, 14, 15, 21, and 22

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12
Q

why do the loss of p arms of acrocentric chromosomes in Robertsonian translocations not affect the cell?

A

acrocentric p arms have no unique DNA sequences and have identical sets of genes that code for RNA molecules, which other acrocentric chromosomes can compensate for

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13
Q

describe the mechanism of a Robertsonian translocation

A

two acrocentric chromosomes experience double-strand breaks near their centromeres - lose their p arms

their q arms are fused together around a single centromere = form a large metacentric Robertsonian chromosome

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14
Q

what is the difference between a balanced carrier of a Robertsonian translocation and a reciprocal balanced carrier?

A

balanced carrier of a Robertsonian translocation has 45 chromosomes and is typically healthy as the loss of p arms is compensated for by other acrocentric chromosomes

reciprocal balanced carrier has 46 chromosomes and involves non-homologous chromosomes exchanging segments without net loss or gain of genetic material

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15
Q

explain the potential outcomes for offspring of a Robertsonian translocation carrier

A

various outcomes for offspring:
- e.g. trisomy 21 = Down’s syndrome.
- balanced carrier offspring with normal amounts of chromosomes 14 and 21
- lethal combinations = embryonic or foetal death.
- normal disomic offspring if the correct segregation of chromosomes occurs

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16
Q

what are the clinical implications of a Robertsonian translocation involving chromosomes 14 and 21

A

can lead to Down’s syndrome in offspring du to trisomy 21

balanced carriers of a Robertsonian translocation between 14 & 21 are often healthy but have a higher risk of producing gametes that can result in unbalanced offspring

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17
Q

what structure will normal meiotic division of homologous chromosomes form?

A

bivalent structure

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18
Q

what structure will meiotic division of reciprocal translocated chromosomes form?

A

tetravalent structure

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19
Q

what structure will meiotic division of Robertsonian translocated chromosomes form?

A

trivalent structure

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20
Q

two mechanisms by which Trisomy 21 can occur?

A

meiotic non-disjunction
Robertsonian translocation

produce different karyotypes but similar Down’s clinical features

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21
Q

how does meiotic non-disjunction lead to trisomy 21?

A

meiotic non-disjunction = occurs when homologous chromosomes (in meiosis I) or sister chromatids (in meiosis II) fail to separate properly

leads to one gamete receiving two copies of chromosome 21 and the other receiving none (monosomy gamete is often incompatible with life)

if the abnormal gamete is fertilized, the resulting zygote will have 3 copies of chromosome 21 = trisomy 21

22
Q

how does Robertsonian translocation lead to Trisomy 21?

A

a piece of chromosome 21 becomes attached to chromosome 14 - fusion creates a derivative chromosome

if a person with this translocation has a child, the child may inherit an extra chromosome 21 material = trisomy 21

23
Q

outcomes of gametes from a carrier of a Robertsonian translocation?

A

1/3 chance for viable gametes and offspring - balanced genetic material

2/3 chance for unbalanced offspring (trisomy or monosomy) leading to miscarriages or babies with various health problems

unpredictable combinations

24
Q

karyotype differences between Trisomy 21 due to meiotic non-disjunction and Robertsonian translocation

A

meiotic non-disjunction of trisomy 21 = three separate copies of chromosome 21

Robertsonian translocation = fusion 14-21 Robertsonian chromosome and a normal two copies of chromosome 21

25
Q

what is a terminal deletion?

A

loss of a telomeric chunk at the end of a chromosome

potential loss of genes can affect activity

26
Q

what is an interstitial deletion?

A

loss of a chromosomal segment in the middle - two ds breaks causing the loss of a middle chromosomal segment and its genes

27
Q

effects of interstitial deletion?

A

related to many deletion disorders - e.g. Prader-Willi, DiGeorge syndrome

28
Q

what is a chromosomal inversion?

A

when there are two breakpoints within the same chromosome, and during repair the middle section is ‘upside down’

29
Q

what is a ring chromosome?

A

occurs when two ds breaks occur in the same chromosome, and non-homologous end joining joins the two ends of the large chunk together, resulting in a ring

30
Q

two main types of deletions?

A

terminal (of telomeres)
interstitial (of middle chromosomal segments/ genes)

31
Q

effects of deletions?

A

leads to haploinsufficiency of genes within the deleted region

affects clinical phenotype, organs and systems affected depending on how many genes were lost

32
Q

what are microdeletions?

A

chromosomal deletions too small to be detected by traditional karyotyping methods

33
Q

how can deletions be detected?

A

G-banding - chromosomal chemical staining can help visualise missing chromosomal regions within karyotype

34
Q

how does non-allelic homologous recombination lead to deletions and duplications?

A

mis-aligned homologous chromosomes - the wrong regions are aligned causing overlap and simultaneous deletions and duplications

following physical exchange of gene segments and separation, one recombinant chromosome will a duplicated gene and one will have a deletion of that gene (trisomy and monosomy)

34
Q

how can microdeletions be visualised?

A

high-resolution banding - e.g. FISH and CGH

35
Q

what is non-allelic homologous recombination?

A

occurs when homologous sequences on non-allelic positions of chromosomes misalign and recombine - causes unequal crossing over during meiosis

leads to one chromosome with a deletion and the other with a duplication

36
Q

common prenatal methods for obtaining samples to examine foetal chromosomes? associated risks?

A

amniocentesis (sampling amniotic fluid)
chorionic villus sampling (sampling the placenta)
cell-free foetal DNA from maternal plasma

risks: higher risk of miscarriage

37
Q

describe G-banding

A

G-banding with a Giemsa stain is used to visualize chromosome karyotypes

euchromatin is GC rich, loosely packed an gene rich - stains lighter
heterochromatin is AT-rich, tightly packed and gene poor - stains darker

differential staining pattern causes banding patterns on chromosomes

38
Q

steps involved in preparing a blood sample for G-banding chromosome staining

A

obtaining a blood sample

culturing the blood sample for several days to reach a metaphase spread - at metaphase the cells are the most tightly condensed, easy to visualise

fixing the cells in metaphase with trypsin

adding Giemsa stain to visualize the chromosomes

39
Q

disadvantage of G-banding?

A

takes a few days for cells to be cultured to reach a metaphase spread

can’t detect small changes like microdeletions or microduplications - only large chromosomal abnormalities

40
Q

how does Fluorescent In Situ Hybridisation (FISH) work? what are the probes used?

A

fluorescence probes are single-strand nucleic acid sequences designed to detect their complementary specific DNA/RNA sequences

  1. DNA is denatured and probes are labelled with a fluorescent dye
  2. fluorescent probes are hybridised with their target DNA
  3. visualise fluorescence using a fluorescence microscope

probe will bind to specific chromosomal region and allow detection of abnormalities

41
Q

what is spectral karyotyping? what is its advantage over FISH?

A

spectral karyotyping – advanced form of FISH, labels all chromosomes with a unique combination of fluorescent dyes

advantage:
- allows for simultaneous visualisation of all chromosomes and a more comprehensive analysis of the entire karyotype
- easier to detect chromosomal abnormalities

42
Q

examples of disorders that can be detected via FISH?

A

cri du chat syndrome - terminal deletion of chromosome 5p
- probe won’t bind to the 5p of the affected chromosome, but will to the intact chromosome

DiGeorge syndrome - chromosome 22q11 deletion

43
Q

how is array CGH used in detecting chromosomal abnormalities? method?

A

detecting sub-microscopic chromosomal abnormalities – microdeletions/ duplications – that FISH can’t identify

looks for deletions or duplications based on fluorescence emitted and detected by software

44
Q

method and interpretation of array-CGH results

A

1000s of probes stuck on a glass support with red-labelled control DNA and green-labelled patient DNA

different binding levels of DNAs to probes emits a certain fluorescence
- yellow fluorescence = equal patient and control binding
- green fluorescence= duplication in patient DNA from more binding
- red fluorescence = suggests deletion in patient DNA with more control DNA binding

colours are detected and interpreted by software, provides an automated way of detecting microdeletions or duplications

45
Q

what is QF-PCR? how is it used to detect chromosomal abnormalities?

A

quantitative fluorescence polymerase chain reaction

46
Q

how is QF-PCR used to detect chromosomal abnormalities?

A

detects trisomy 13, 18, and 21 by using microsatellites - short repeated, highly polymorphic sequences found throughout the genome

QF-PCR amplifies specific microsatellite regions through PCR, then analyses the resulting DNA fragments using gel electrophoresis to determine the presence of aneuploidies

47
Q

describe the process of detecting microsatellites using QF-PCR

A

isolating DNA from patients, and designing primers specific to the flanking sequences unique to the microsatellite

PCR amplification with the designed primers to produce millions of copies of the microsatellite region

separation of amplified DNA fragments through gel electrophoresis to visualize DNA fragments based on size and determine the number of repeats and alleles present

48
Q

what are the results of QF-PCR, and how are they interpreted?

A

after performing PCR using microsatellites known to be on a chromosome - e.g. chromosome 21 for Down’s

healthy person - QF-PCR shows two peaks of the microsatellite – one maternal and one paternal - if heterozygous, or one single peak if homozygous

trisomy - three peaks of equal height, OR two copies of a chromosome showing a higher peak and one other single peak

49
Q

what is the purpose of QF-PCR, and what are its advantages & disadvantages?

A

determines the number of copies of a chromosome a patient has - specifically detects aneuploidies/ trisomy 13, 18, and 21

advantages - quick, efficient for pre-natal screening by using fluorescent probes for specific microsatellite markers on targeted chromosomes

disadvantages - requires prior knowledge of the targeted microsatellites
- limits its use to known abnormalities
- may not detect abnormalities outside the targeted regions

50
Q

how is NGS used for non-invasive prenatal testing for trismies?

A

cell-free foetal DNA obtained from maternal blood is analysed to generate small chromosomal fragments for analysis, and varying coverage depth of fragments

presence of additional fragments (more than usual) can indicate trisomy

Molecular Basis of Disease (32 decks)

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