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FRCPath Part 1 written > Session 1 - Background > Flashcards

Session 1 - Background Flashcards

1
Q

Name the 5 different forms of DNA which occur, depending on the hydration of the environment.

A

B-DNA - most common A-DNA Z-DNA Cruciforms H-DNA G4-DNA

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2
Q

How is chromatin structure maintained?

A

Cohesins, CTCF, and histones

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3
Q

What histone modifications are possible?

A

Acetylation Phosphyorlation Methylation Ubiquitination Sumoylation

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4
Q

Name some proteins that are key architectural modellers associated with disease

A

SATBP1 - breast cancer prognosis CTCF - Silver-Russell and Beckwith Weidemann Cohesin - Cornelia de Lange MLL2 - Acute leukaemias MECP2 - Rett syndrome CREBBP - Rubenstein Taybi

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5
Q

What is the function of the centromere?

A

Chromosome segregation during mitosis and meiosis II Site of Kinetochore assembly

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6
Q

Describe the structure of the centromere

A

Alpha-satellite DNA repeats, constitutive heterochromatin, made of multiple centromeric proteins (CENPs)

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7
Q

Name two problems caused by centromere malfunction

A

Premature centromere division - age-depedent process Premature chromatid separation - diagnosed by puffing of the centromeres on Karyotype, cause of Roberts syndrome.

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8
Q

Name some diseases caused by telomere malfunction

A

Dyskeratosis congenita Cri-du-Chat - loss of hTERT gene

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9
Q

List the different types of chromosome banding techniques

A

R-banding G-banding DAPI/DA staining C-banding Q-banding CD-banding T-banding G11-banding Replication-banding (for SCE and chromosome breakage syndromes) NOR staining

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10
Q

Name some disorders associated with DNA replication problems

A

Dyskeratosis congenita Meier-Gorlin syndrome - mutation in one of the ORC components Hutchinson-Gilford Progeria Bloom syndrome - mutation in BLM, a topoisomerase

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11
Q

Whcih DNA polymerase is associated with synthesis of the leading strand and DNA repair?

A

DNA polymerase delta.

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12
Q

In which stage of the mieosis does Crossing over occur?

A

Pachytene of meiosis I

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13
Q

In which stage of the cell cycle so oocytes get halted during foetal development?

A

Diplotene in meiosis I

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14
Q

How is splicing regulated?

A

Regulated by cis-acting and trans-acting elements. Regulation is cell and tissue-specific. Requires the presence of Exonic Splice Enhancer and Intronic Splice Enhancers. SR proteins are required as they bind he ESE/ISE and components of the spliceosome. Exonic Splice Supressors and Intronic Splice Supressors also exist.

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15
Q

How can splicing aberrations cause disease?

A

Mutations disruption of a splicing element - Cancer Generation of toxic RNA - Myotonic Dystrophy Mutations affecting a splicing factor - SMN1 Overexpression of splice factors - Cancer

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16
Q

Name some therapies that target splicing mutations/aberrations

A

Antisense oligonucleotides - bind specific splicing targets and enhancing or repressing. Antisense oligos can also be used to target mutant transcripts. Trans-splicing - introduces artificial wildtype splice site into mutant sequence.

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17
Q

Name the three RNA surveillance mechanisms, and say what they detect.

A
  1. Nonsense mediated decay - premature stop mutation 2. Non-stop mediated decay - STOP lost. extended 3’ sequence and long Poly-A tail 3. No-go mediated decay - not well understood
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18
Q

How does the NMD pathway work?

A

Exon Junction Complexes attach to the exon-exon boundaries of the mRNA. The ribosome displaces EJCs as it traverses the transcript - if it detaches before all EJCs are removed the transcript is flagged for NMD.

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19
Q

Give an example of a target escaping NMD.

A

T cell receptor - NMD can be activated even if a premature STOP occurs within the last 50bp of the exon.

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20
Q

Give examples of how NMD is related to disease

A

NMD is triggered by frameshift mutations in dystrophin resulting in premature STOP codons. This results in haploinsufficiency. If the mutation is in-frame a much milder phenotype (Becker) is observed. Marfan Syndrome - NMD is correlated with disease severity.

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21
Q

How can NMD potentially be treated?

A
  1. Correct the premature STOP mutation - promote read through -CF, DMD, SMA. 2. Eliminate the portion of the gene with the STOP mutation in it 3. Inhibit the NMD pathway, e.g. SMG1 kinase inhibitors.
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22
Q

Name the 4 functions non-coding RNAs

A

rRNA - present in the NORs, transcribed as a single 13kb transcript. (Treacher-Collins) tRNA - transport the amino acid to the ribosome during translation. (MELAS, MERFF) snRNA - spliceosomal RNAs - two subclasses: Sm and Lsm. (SMN2, cancer, RP) snoRNA - RNA processing and modification (Cancer, PWS)

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23
Q

Name the 4 types of regulatory RNAs

A

miRNA - acts to regulate expession via the mRNA transcript - post-transcriptional gene silencing siRNA - acts to regulate transcription via the DNA. Dicer-depedent. piRNA - regulate transposon activity (Infertility) lncRNA - involved in X-inactivation and imprinting, regulate transcription factor activation and alternative splicing.

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24
Q

What roles do ncRNAs play in disease diagnosis and treatment?

A

Diagnostic biomarkers of disease Therapeutic agents to control gene expression: MRX34 drug acts to repress oncogenes in the TP53 pathway. Antisense oligos could be a potential treatment for Angelman syndrome (Anti-UBE3A).

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25
List the types of normal genomic variation
Heterochromatic variation (1qh, 9qh, 16qh, Yqh) CNV - 8p, near GTA4 region. LCRs - repeat tracts SNPs Inversions (chromosome 9 inv common). Chr 11 inv Satellite DNA in centromeres and stalks Fragile sites/repeat regionc - may be BrdU inducible. FRA11B predisposes to del 11q (Jacobsen syndrome). Variable numbers of tandem repeats. Microsatellite repeats Epigenetics
26
What can cause DNA damage?
UV, free-radicals, radiation, chemicals, mutations in proof-reading machinery
27
What repair mechanisms do humans have?
MMR - MutS-Alpha and MutS-beta recruit the MutL complex - identify, and excise incorrect base, DNA ligase fills the gap Base Excision Repair - removed oxidative damage Nucleotide Excision repair - removes UV damage DSB repair - Homologous Recombination Repair - RAD51 required suring S-phase to repair from sister chromatid. BRCA1/2 part of this pathway DSB repair - NHEJ - no homology required, results in ligation of two non-homologous molecules, bases may be missing and leave a scar. DNA polymerase proof-reading and repairing. Gene conversion FoSTeS MMBIR NAHR
28
What are the five types or pseudogene?
Non-processed Processed (reintroduced into the genome by reverse transcription) Unitary - deactivation of gene without duplication RNA pseudogenes Mitochondrial pseudogenes
29
Why are pseudogenes clinically relevant?
Gene conversion can lead to inactivation of active gene (e.g. PMS2) Homologous recombination can lead to del/dup Difficult to accurately sequence
30
Name some clinically relevant pseudogenes
SMA is caused by mutations in SMN1. It has a pseudogene (SMN2 - common mutations in exon 7). Recombination and gene conversion can result in loss of SMN1. However, if SMN2 is duplicated, this can restore some function and result in a less severe phenotype. CYP21A2 - CAH. Has a pseudogene CYP21A1P PKD1 PMS2 BRCA1
31
How can we get around the pseudogene problem in the lab?
Design primers specific to parent gene Long range PCR for parent gene then nested primers to sequence cDNA methods
32
How can dicentric chromosomes be created?
As a result of telomere erosion and breakage-fusion-bridge repair. May be the cause of chromosome instability in cancers
33
What is chromothripsis?
The joining, likely by NHEJ, of multiple fragments of chromosomes. This may cause the highly complex rearrangements seen in cancer cells.
34
Name the mechanisms via which reciprocal translocations can be formed?
NHEJ, FoSTeS, MMBIR, MMEJ.
35
What often mediates recurrent translocation?
LCRs and NAHR
36
Name some recurrent rearrangements
Prader-Willi/Angelman common deletion (3mb) Isodicentric 22q11.2 - cat-eye syndrome. AZFa/b/c deletion in male infertility Robertsonian translocations
37
List the things that can go wrong during meiosis 1 to cause aneuploidy.
Premature homologue separation Anaphase lag Non-disjunction Recombination failure - the chromosomes remain attached.
38
List the things that can go wrong in Meiosis 2 to cause aneuploidy.
Premature chromatid separation Non-disjunction Anaphase lag
39
Define tertiary trisomy
The two normal chromosomes segregate with one derivative chromosome
40
Define interchange trisomy
Two derivative chromosomes segregate with a normal chromosome
41
What factors should be considered when estimating risk of recurrence of chromosome aneuploidy?
Location of imbalance and chromosome involved. If either parent has a balanced translocation Haploid Autsomal Length (basically, smaller chromosomes are more likely to be tolerated in imbalance than larger chromosomes as they contain a smaller proportion of the total genetic material)
42
What should you be particularly aware of when analysing a case with a robertsonian translocation involving chromosomes 14 and 15?
UPD.
43
How are inversions formed?
Inversion loops. Can be paracentric or pericentric. can result in loss/gain through recombination during meiosis 1
44
What is the Minimal Processing Segment?
The shorted section of homology needed for LCR-mediated NAHR.
45
What are the three forms of NAHR rearrangements?
Intrachromatid Intrachromosomal Interchromasomal
46
Do reciprocal deletions and duplications appear at the same rate?
No - deletions are more commonly detected. Possibly because they have a more severe phenotype.
47
Give an example of a reciprocal deleltion/duplication.
Potoki-Lupski syndrome and Smith-Magenis syndrome (17p11.2) - RAI1 gene DiGeorge syndrome and velocardiofacial syndrome (22q11.2)
48
Give some examples of recurrent deletions/duplications mediated by LCR/NAHR.
PWS/AS deletion - common deletion is 4mb, between BP1 or BP2 and BP3. Larger deletion extends to BP4. NF1 - common 1.5mb deletion DiGeorge syndrome and velocardiofacial syndrome (22q11.2) - common deletion between LCR22B and LCR22D; smaller deletion between LCR22A and LCR22B
49
List the types of mosaicism
Somatic Gonadal Sex chromosome (review Hook's tables) Confined placental mosacism Pseudomosaicism Chimaerism Methylation/X-inactivation Vanishing twin UPD
50
How are genes methylated; what proteins are involved?
DNMT1 - maintains DNMT3A/B - de novo methylation
51
Which nucleotide is methylated for epigenetic modidfication?
Cytosine. Forms 5MeC
52
Give a brief overview on how imprints/methylation patterns are set
Gametogenesis - de novo methylation of genes in gametes Early embryogenesis - genome-wide demethylation Post implantation - Large-scale de novo methlation by DNMT3A/B
53
Give some examples of diseases caused by aberrant epigenetic modification or imprinting.
FRAX - expansion in 5' region of FMR1 becomes methylated and prevents gene expression Rett syndrome - duplication of MECP2 Beckwith Weidemann syndrome and Russel-Silver syndrome PW/AS
54
How is epigenetic modification involved in cancer?
Hypermethylation of the MLH1 promoter can cause Lynch syndrome as the tumour suppressor gene function is supressed
55
Give examples of Epigenetic therapies.
5-azacytodine inhibits DNA methylation to retain activity in otherwise inactivated genes. Drugs can also promote methylation. Need to be careful as any alterations to modification must be targeted.
56
What are the two forms of UPD? Describe the differences between each.
Uniparental Isodisomy - 2 identical homologues from one parent. Uniparental Heterodisomy - 2 different homologues from one parent.
57
What are the three types of UPD?
1. Complete chromosomal UPD: all maternal = benign ovarian teratoma, all paternal = hydatidiform mole. 2. Whole chromosome UPD 3. Segmental UPD
58
How can each type of UPD arise?
1. Complete chromosomal UPD - a disomic gamete joins with a nullisomic gamete 2. Whole chromosome UPD - trisomy rescue, monosomy rescue
59
Why don't you see reciprocal segmental matUPD in Beckwith Weideman syndrome?
Considered to be lethal. See only patUPD.
60
List the methods used to detect UPD.
Bisulphite modification and: 1. msPCR 2. Pyrosequencing 3. msPCR and restriction digest 4. SNP array 5. QF-PCR Non-modified DNA: 1. southern blotting - digest the sample with methylation sensitive enzymes to create bands on a gel. 2. msMLPA - two tube reaction, digest one tube with methylation sensitive enzymes 3. Whole Exome/Genome analysis
61
Described 4 methods that ASOs can be used to interfere with gene translation
ASO/RNA can bind to mRNA and flag transcript for degradation by RNase H. ASO/RNA can bind to a specific target (mutation site) on the RNA and flag for degradation. ASO/RNA can bind to the mRNA and prevent binding of the ribosome to disrupt translation ASO/RNA can bind to the mRNA at S/R protein sites (ESE) to cause exon skipping.

FRCPath Part 1 written (15 decks)

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