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Postnatal > Structural Rearrangements > Flashcards

Structural Rearrangements Flashcards

1
Q

What is the cause of LCR mediated rearrangements

A

Non-allelic homologous recombination

Recombination between lengths of homology in different genomic positions.

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2
Q

Name the 2 types of NAHR

A

Unequal crossing over

BIR (Break-induced replication)

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3
Q

What is BIR (Break-induced replication)

A

Replication based
Occurs when replication fork collapses / breaks & the broken molecule uses ectopic homology to restart the replication fork
Forms del/dup in separate events

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4
Q

What is unequal crossing over

A

Recombination based

Forms del/dup in same event

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5
Q

What are NAHR hotspots

A

Positions within LCRs where crossovers preferentially occur. Usually in regions
of identical sequence of at 200 ~450bp. Where
rearrangement bkpts are typically found.

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6
Q

Define MEPS: Minimal efficient processing segment

A

Min stretch of identity required to enable
homologous recombination.
Length = diff between meiosis (~300-500bp) & mitosis (~shorter) & diff between diff events. Distance between LCRs determines length of MEPS (further away = longer MEPS)

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7
Q

Name the causes of non recurrent rearrangements from the repair of DSB

A

NHEJ (non-homologous end joining)
MMEJ (microhomology-mediated end joining)
Breakage-fusion-bridge cycle

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8
Q

Describe NHEJ (non-homologous end joining)

A

Non-homologous because the break ends are directly ligated without the
need for a homologous template
NHEJ can repair the double stranded break accurately or lead to small (1-4bp)
del/ins at the breakpoint
A major mechanism for chromosome translocations in cancer

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9
Q

Describe MMEJ (microhomology-mediated end joining)

A

Requires very short homologies (5-25bp) that anneal at either side of DSB
Lead to deletion of sequences between regions of homology
Ass. W. chrom. Fusions formed between shortened telomeres

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10
Q

Describe Breakage-fusion-bridge cycle

A

DSB that͛ results in a chrom that’s lost its telomere therefore sister chromatids that both lack a telomere
Fusion of the two sister chromatids – form dicentric chrom
At anaphase sister chromatids form a bridge results in centromeres will be pulled in opposite directions
Sister chromatids break apart but not necessarily at the site that they fused
The two resulting chromatids lack telomeres, the BFB cycle will repeat at replication & continue every cycle until chromatids acquire telomeres
Involved in amplification and the occurrence of large inverted repeats in cancer
BFB cycle = important role in the instability in cancer

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11
Q

Name the causes of non recurrent rearrange to that occur at DNA replication

A

FoSTeS (Fork stalling & template switching)

MMBIR (microhomology-mediated break-induced replication)

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12
Q

Describe FoSTeS (Fork stalling & template switching)

A

Replication forks stall
3͛ lagging DNA strand of one replication fork can transfer & anneal to a ssDNA template of another fork, resulting in a template switch

Likely influenced by local genomic architecture (e.g. palindromes / cruciform) with fork stalling caused by 2◦ structure formation/lesions in template
strand/ shortage of dNTPs.

Results in deletions, duplications, inversions, translocations and complex rearrangements

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13
Q

Describe MMBIR (microhomology-mediated break-induced replication)

A

A dsDNA break resulting from a collapsed replication fork (w. single strand overlap)
3͛ end of collapsed fork anneals to any single-stranded template that it shares microhomology
DNA synthesis is re-initiated.
The broken end has now been extended by a length of different sequence.

Results in deletions, duplications, inversions, translocations and complex rearrangements
MMBIR = 1 model of FoSTeS

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14
Q

Define tertiary trisomy. Give an example.

A

A mode of segregation from a translocation resulting in an imbalance consisting of the segregation of 3 chromosomes: the two normal chromosomes not involved in the translocation and one of the derivatives.
An example: Emmanuel syndrome: resulting from a parental t(11;22) the progeny contain an additional chromosome : der(22)t(11;22)

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15
Q

Define retrotransposon

A

Also called transposons. Genetic elements that can amplify themselves in the genome and are ubiquitous throughout the genome.
SINE: Alu sequences
LINE

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16
Q

Describe different types of repeat sequences in genome

A

Transposons (SINE (Alu) & LINE).
Low copy number repeats LCRs/ segmental duplications (Interspersed throughout genome).
Variable tandem repeats: minisatellites & microsatellites (STRs) (clustered together)

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17
Q

Describe a rearrangement associated with LCRs

A

Palindromic AT rich repeats : t(11;22)
LCR22: digeorge; cat eye syndrome; distal 22q11.2 del/dup
LCR15: PWS/AS; idic(15); 15q11.2 del; 15q11-13 dup;
? Olfactory receptor (OR) gene clusters: invdup(8p); del(8)(p23.1p23.1); t(4;8)(p16;p23)

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18
Q

Describe disease associated with Alu sequences

A

neurofibromatosis
Alports syndrome
Ewing’s sarcoma

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19
Q

What type of relate sequence likely causes robertsonian translocations

A

Satellite III sequence on chr 14
Satellite I Sequence & rDNA sequence on chr 13 & 21
cause centric fusion

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20
Q

What’s a fragile site

A

Point on chromosome that shows a gap or break.

Always in a gene silenced by hypermethylation

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21
Q

How do you define a fragile site

A

Frequency in population and culture conditions needed to induce them.
Folate sensitive
Thymidine, BrdU, distamycin A inducible

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22
Q

Define 3 categories of fragile sites

A

Rare: 1/several hundred ppl
Intermediate: 1-5% ppl
Common:

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23
Q

What are the 2 intermediate fragile sites

A

Fra(10)(q25): 2.5% ppl. BrdU inducible

Fra(16)(q22): 1-5% ppl. Distamycin inducible

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24
Q

What are the 2 pathogenic fragile sites what clinical feature are they associated with?
Name another fragile site that’s proposed to be pathogenic

A

FRAXA: Xq27.3
FRAXE:Xq28
Associated with mental retardation

FRA11B (11q23.3) in CBL2 gene- CCG expansion is a vulnerable spot for dn del(11q): Jacobsen syndrome

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25
Q

Define copy number variant

A

Generic term for a segment of DNA present at a variable copy number compared to the reference Genome, irrespective of pathogenicity

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26
Q

Define heteromorphism

A

Visible chromosome variation in morphology, structure and staining properties

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27
Q

What is normal cytogenetically visible variation

A

Cytogenetically detectable differences between the heteromorphisms of chromosome homologous pairs that are not associated with any phenotypic effect

28
Q

Give examples of normal variation in heterochromatin

A

1qh, 9qh, 16qh,
Yqh: size, translocation, pericentric inversion, satellites
Acrocentric p arm morphology: size, length, appearance

29
Q

Give examples of normal variation in euchromatin

A

Var(4)(p16.1p16.1)
Var(8)(p23.1p23.1)
Var(15)(q11.2q11.2)

30
Q

Define Recombination

A

A complex process = alignment of two homologous DNA strands, precise breakage of each strand, equal exchange of DNA segments
between the two strands & sealing of the resultant recombined DNA molecules through the action of enzymes called ligases.

31
Q

Name 2 potential Consequences of recombination

A

Non–allelic homologous recombination (NAHR)
Single gene disorders
Contiguous gene disorders
Segmental aneuploidy syndromes

32
Q

Define non disjunction

A

The failure of homologous chromosomes to segregate symmetrically at cell division

33
Q

Define anueploidy

A

The presence or absence of a chromosome on a diploid background

34
Q

Name poss mechanisms for formation of robertsonian translocations

A
  1. Centric fusion
  2. Breaks in p arm & q arm
  3. Break in both short arms (dicentric)
  4. Misdivision of centromere (homologous robs only)
  5. U-type exchange (break in both chromatids that then loop around to join each other)
  6. Formation of isochromosome at next cell cycle
35
Q

Define interchange trisomy

A

Mode of segregation that results from a balanced reciprocal translocation where by the gamers consists of the two reciprocal derivative chromosomes and a copy of one of either of the 2 remaining intact chromosomes

36
Q

What does DNA stand for

A

Deoxyribonucleic acid

37
Q

What 3 element makes up DNA

A

5 carbon sugar (deoxyribose)
1-3 phosphate groups
Nitrogenous base

38
Q

Name the purines

A

Adenine

Guanine

39
Q

What makes a purine a purines

A

2 carboxy rings

40
Q

Name the pyrimidines

A

Cytosine

Thymine

41
Q

What makes a pyrimidine a pyrimidine

A

1 carboxy ring

42
Q

What a nucleoside

A

Base + sugar

43
Q

What’s a nucleosome

A

Nucleoside + phosphate

44
Q

Name 5 configurations of DNA

A 
B-DNA
Z-DNA
G4-DNA
cruciform
Hairpin
45
Q

What’s the common configuration of DNA

A

B DNA

Right handed

46
Q

What’s Z DNA and when it’s used

A

Left handed DNA
high GC content so can’t form nucleosome
Occur during gene transcription

47
Q

What’s a hairpin configuration

A

Inverts repeats of purine or pyrimidine stretches cause intra-strand pairing and folding back on itself

48
Q

What’s a cruciform configuration and an example of when it’s used

A

Two hairpin loops arranged in a four way junction (Holliday junctions at recombination)

49
Q

What’s G4DNA and where’s it seen

A

Quadruplex: dsDNA folds back on itself because of pairing between 4 guanines.
Found near telomeres/ promoters

50
Q

What’s a nucleosome

A

146bp DNA wrapped 1.7 times around a core of 8 histones: 2x H2A, H2B, H3, H4
‘Beads on a string’

51
Q

What’s a solenoid

A

Is a 30nm fibre of 6-8 nucleosome a per turn with Histone H1 attached at the bottom of the nucleosomes to hold them I place, with linker DNA between the nucleosomes

52
Q

Describe the next level of chromatin folding, after 30nm fibre

A

The fibers loop with the loops attached at the bottom by non Histone proteins: topoisomerase 2 and cohesins.
Tight packaging to maintain shape

53
Q

What are he causes of anueploidy

A

Altered recombination.

Maternal age

54
Q

How does altered recombination cause anueploidy

A 
Recombination failure (achiasmata).
Premature homologue separation.
Premature sister chromatid separation.
Anaphase lag.
Failure of chiasmata to resolve
55
Q

How does maternal age cause anueploidy

A

Usually occurs at M1:
Deterioration of sister chromatid cohesion.
Deterioration of spindle assembly checkpoint.
Bi alerts misaligned.

56
Q

What factors influence LCR mediated NAHR

A

Repeat size.
Degree of homology.
Distance between them.
Orientation of LCRs with respect to each other.
MEPS (minimum efficient processing segment)

57
Q

What is a synonymous mutation

A

A mutation that doesn’t change the amino acid sequence

58
Q

What’s a non-synonymous mutation

A

A mutation that changes the amino acid sequence. Missense (change aa leads to misfunction) and nonsense (premature stop codon)

59
Q

Explain U-type exchange

A

The cause of an inverted duplication:

Premeiotic DSB followed by subsequent fusion of sister chromatids

60
Q

For a maternal robertsonian carrier with a 21 or 13 what’s the risk of offspring with downs or patau. And risk of UPD with 14, 15

A

10-15%

Less than 1% UPD

61
Q

For a paternal robertsonian carrier with a 21 or 13 what’s the risk of offspring with downs or patau. And risk of UPD with 14, 15

A

Less than 1%

Less than 0.5% UPD

62
Q

What causes t(11;22)

A

Palindromic AT rich repeats (PATRR) on 11 and 22. NHEJ

t(11;22)(q23.3;q11.2)

63
Q

What the risk of abn child with Complex translocation

A

About 20%

64
Q

What’s the risk of abn offspring with pericentric inversion

A

0.12-0.7%

65
Q

What’s the risk of abn child with paracentric inversion

A

0.1-0.5%

66
Q

What’s the risk of abn child with an inter chromosomal insertion

A

High especially if small insertion

Up to 50% if loops outs

Postnatal (9 decks)

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