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Flashcards in Structural Rearrangements Deck (66):
1

What is the cause of LCR mediated rearrangements

Non-allelic homologous recombination
Recombination between lengths of homology in different genomic positions.

2

Name the 2 types of NAHR

Unequal crossing over
BIR (Break-induced replication)

3

What is BIR (Break-induced replication)

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

4

What is unequal crossing over

Recombination based
Forms del/dup in same event

5

What are NAHR hotspots

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

6

Define MEPS: Minimal efficient processing segment

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)

7

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

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

8

Describe NHEJ (non-homologous end joining)

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

9

Describe MMEJ (microhomology-mediated end joining)

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

10

Describe Breakage-fusion-bridge cycle

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

11

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

FoSTeS (Fork stalling & template switching)
MMBIR (microhomology-mediated break-induced replication)

12

Describe FoSTeS (Fork stalling & template switching)

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

13

Describe MMBIR (microhomology-mediated break-induced replication)

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

14

Define tertiary trisomy. Give an example.

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)

15

Define retrotransposon

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

16

Describe different types of repeat sequences in genome

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

17

Describe a rearrangement associated with LCRs

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)

18

Describe disease associated with Alu sequences

neurofibromatosis
Alports syndrome
Ewing's sarcoma

19

What type of relate sequence likely causes robertsonian translocations

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

20

What's a fragile site

Point on chromosome that shows a gap or break.
Always in a gene silenced by hypermethylation

21

How do you define a fragile site

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

22

Define 3 categories of fragile sites

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

23

What are the 2 intermediate fragile sites

Fra(10)(q25): 2.5% ppl. BrdU inducible
Fra(16)(q22): 1-5% ppl. Distamycin inducible

24

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

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

25

Define copy number variant

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

26

Define heteromorphism

Visible chromosome variation in morphology, structure and staining properties

27

What is normal cytogenetically visible variation

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

28

Give examples of normal variation in heterochromatin

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

29

Give examples of normal variation in euchromatin

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

30

Define Recombination

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

Name 2 potential Consequences of recombination

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

32

Define non disjunction

The failure of homologous chromosomes to segregate symmetrically at cell division

33

Define anueploidy

The presence or absence of a chromosome on a diploid background

34

Name poss mechanisms for formation of robertsonian translocations

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

Define interchange trisomy

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

What does DNA stand for

Deoxyribonucleic acid

37

What 3 element makes up DNA

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

38

Name the purines

Adenine
Guanine

39

What makes a purine a purines

2 carboxy rings

40

Name the pyrimidines

Cytosine
Thymine

41

What makes a pyrimidine a pyrimidine

1 carboxy ring

42

What a nucleoside

Base + sugar

43

What's a nucleosome

Nucleoside + phosphate

44

Name 5 configurations of DNA

B-DNA
Z-DNA
G4-DNA
cruciform
Hairpin

45

What's the common configuration of DNA

B DNA
Right handed

46

What's Z DNA and when it's used

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

47

What's a hairpin configuration

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

48

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

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

49

What's G4DNA and where's it seen

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

50

What's a nucleosome

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

51

What's a solenoid

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

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

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

53

What are he causes of anueploidy

Altered recombination.
Maternal age

54

How does altered recombination cause anueploidy

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

55

How does maternal age cause anueploidy

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

56

What factors influence LCR mediated NAHR

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

57

What is a synonymous mutation

A mutation that doesn't change the amino acid sequence

58

What's a non-synonymous mutation

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

59

Explain U-type exchange

The cause of an inverted duplication:
Premeiotic DSB followed by subsequent fusion of sister chromatids

60

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

10-15%

Less than 1% UPD

61

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

Less than 1%

Less than 0.5% UPD

62

What causes t(11;22)

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

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

63

What the risk of abn child with Complex translocation

About 20%

64

What's the risk of abn offspring with pericentric inversion

0.12-0.7%

65

What's the risk of abn child with paracentric inversion

0.1-0.5%

66

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

High especially if small insertion

Up to 50% if loops outs