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Flora Ross > Basics of genomics > Flashcards

Basics of genomics Flashcards

1
Q

Pyrimidine nucleotides

A

Single ring bases

Cytosine
Thymine

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2
Q

Purine nucleotides

A

Double ring bases

Adenine
Guanine

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3
Q

How do nucleotides pair on each strand?

A

A-T (2 H bonds)
C-G (3 H bonds)

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4
Q

Start & Stop codon sequences

A

AUG

UAA, UAG, UGA

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5
Q

3 types of gene regulatory factors

A

Cis-acting: Promoter and enhancer

Trans-acting: transcription factor

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6
Q

Promoter structure

A

Near 5’ end of gene, contains TATAAA sequence for RNA polymerase binding

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7
Q

Example of a disease affecting a Silencer

A

D4Z4 repeats for DUX4 expression in FSHD1

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8
Q

4 features of mitochondrial genes

A

Transmitted maternally

Circular molecule

37 genes encode RNAs and enzyme subunits of OXPHOS complexes

No introns

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9
Q

Name the 3 enzymes for DNA replication INITIATION

A

Topoisomerase
Helicase
Polymerase

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10
Q

Describe the replication fork structure in DNA replication ELONGATION

A

Allows polymerase to move in opposite directions

Leading strand = 5’-3’ replication
Lagging strand = discontinuous synthesis by Okazaki fragments followed by ligase to continue synthesis

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11
Q

What is the end replication problem?

A

At the end of a chromosome there is no template ahead of the replicating region for a primer to be made for Okazaki frag synthesis. This results in shortening of the lagging strand

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12
Q

What is the function of telomerase?

A

Reverse transcriptase enzyme that carries its own RNA molecule TERC to use as a template TTAGGG to elongate telomeres and address the end replication problem. Telomerase is active in rapidly dividing cells e.g. gametes and cancer

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13
Q

2 proof-readers to maintain fidelity of replication

A

DNA polymerase 3’-5’ exonulease activity

MMR complex to remove DSBs

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14
Q

Name 1 telomeropathy

A

Cri du chat -5p (deletion of hTERT)

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15
Q

Name 1 polymerase defect

A

Hutchinson-Gilford Progeria (LMNA) - premature aging

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16
Q

Name 1 helicase defect

A

Bloom Syndrome (BLM) - chromosome instability

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17
Q

What is the error rate of DNA replication?

A

1 x 10^9 per cell division

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18
Q

Purpose of mitosis

A

Division of nucleus to generate 2 identical daughter cells

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19
Q

Mitosis stages

A

Prophase
Metaphase
Anaphase
Telophase
+cytokinesis

ACRONYM
Please
Make
Another
Two

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20
Q

Describe metaphase

A

Checkpoint to ensure cell is ready to complete division

Chromosome align at spindle

Anaphase-Promoting-Complex activates separase that cuts cohesin and allows sister chromatid separation in anaphase

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21
Q

What are the purpose of cell cycle checkpoints?

A

Control order and timing of transitions to ensure critical events are completed with high fidelity

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22
Q

2 components of checkpoint proteins

A

Cyclins
Cyclin-dependent kinases

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23
Q

What is the function of cyclin-dependent kinases?

A

Phosphorylate target proteins to coordinate entry into next phase of cell cycle

Only active when dimerised with cyclin, which are expressed in response to stimuli/signals

24
Q

Describe the G1-S phase checkpoint

A

‘Restriction’ checkpoint

CDK4/6-cyclinD phosphorylates RB, activates E2F transcription factor and expression of cyclinE-CDK2

p53 activation if DNA damage detected to inhibit progression past checkpoint > senescence or apoptosis

25
Q

Meiosis 1 metaphase crucial stage

A

Pachytene

26
Q

What are the mechanisms of generating diversity in meosis?

A

Random independent assortment of chr pairs

Crossovers enabling genetic recombination prior to separation

27
Q

What are chiasma?

A

Physical connections at points of recombination. Mark location of crossover and are essential for meiosis 1 segregation

28
Q

Name a mechanism for disease occurring in meiosis and 1 example

A

Non allelic homologous recombination

DiGeorge syndrome deletion due to NAHR between LCRs in 22q11.2

29
Q

Key protein for transcription

A

RNA polymerase II

30
Q

2 diseases due to defective transcription initation

A

FMR1 5’UTR CGG expansion = abnormal methylation of promoter and silencing

Germline GATA TF variant = predisposition to haem malignancies

31
Q

2 key components for translation

A

tRNAs + anti-codon to deliver amino acid

Ribosome rRNA complexes provide structure and catalyse translation

32
Q

Canonical/consensus splice site sequences

A

Donor = GU (start of intron)
Acceptor = AG (end of intron)

GU-AG motifs are highly conserved. Muts +/-2bp are likely to affect splicing (PVS1)

33
Q

Spliceosome structure and function

A

5 snRNAs and associated proteins = 60S complex

Step-wise cleavage at 5’ donor and 3’ acceptor to ligate exons

34
Q

What does ESE stand for?

A

Exonic Splicing Enhancer

35
Q

What is ESE’s function?

A

Direct/enhances splicing by binding ‘SR’ proteins which increase interactions with snRNAs

36
Q

Example ESE in disease

A

c.480C>T in SMN2 disrupts an ESE, resulting exon 7 skipping and truncated/inactive protein. Can’t completely compensate for SMN1 in SMA patients

37
Q

Role of alternative splicing

A

Regulates gene expression and increases protein diversity. Allows multiple proteins to be translated from 1 gene

38
Q

3 alternative splicing mechanisms

A

Exon skipping

Alternative 3’ acceptor site

Alternative 5’ donor site

39
Q

3 disease mechanisms that affect splicing

A

Disruption of splicing element

Toxic RNA

Splicing factor dysfunction

40
Q

1 example of ‘leaky splicing’ in disease

A

CFTR poly(T)(TG) in exon 8
5T/10TG = increased exon 9 skipping

Modifies phenotypes in alleles with mild mutations and when in trans with severe muts

41
Q

How can antisense oligonucleotides be used to treat genetic diseases?

A

Enhance or repress splice sites to promote skipping or inclusion of exons

42
Q

What are mRNA surveillance pathways? name 1 example

A

Conserved quality control processes that protect cells by decreasing production of potentially harmful proteins from abnormal mRNA

Nonsense Mediated Decay

43
Q

When is NMD predicted to occur?

A

If a premature termination codon is upstream of the last exon-exon junction

44
Q

What happens when a PTC occurs in the first 100nt of a gene?

A

NMD does not happen. Translation is initiated at a downstream AUG

45
Q

What % of pathogenic variants are associated with PTC?

A

30

46
Q

Name the mechanism of NMD

A

Exon Junction Complex model

Involving SURF complex and mRNA degradation factors

47
Q

1 example of NMD affecting disease phenotypes

A

DMD muts disrupt ORF = NMD and no functional dystrophin

BMD muts maintain ORF = translation of abnormal but partially functional dystrophin

48
Q

1 example of targeting PTCs for treatment of genetic disease

A

Ataluren is a PTC readthrough therapy for DMD caused by nonsense variants. It allows full length dystrophin to be expressed and ameliorates phenotype

49
Q

4 functional non-coding RNAs

A

Ribosomal

Small nuclear

Small nucleolar

Transfer

50
Q

2 example ribosomopathies

A

del5q in MDS/AML due to loss of RP514

Schwann Diamond syndrome due to biallelic muts in SBDS

51
Q

What are pseudogenes?

A

Redundant copies of protein coding genes with high sequence homology to parent genes

52
Q

2 mechanisms for pseudogene origin

A

Derived from retrotransposition of mRNA into a new genomic location. Often contain exons abut lack regulatory elements

Derived from segmental dups of PCGs

53
Q

1 somatic pseudogene example

A

PTENP1 absorbs miRNAs targeting PTEN for degradation = growth inhibition. Often deleted in cancers so PTEN can be degraded

54
Q

2 germline pseudogene examples

A

SMN1/2 - SMA

CYP21A2/CYP21A1P - CAH

55
Q

Describe the significance of CYP21A2 pseudogene

A

20% of CAH cases = CYP21A2 deletion

75% of deletions are mediated by gene conversion with non-functional regions of the pseudogene

56
Q

How do pseudogenes affect diagnostic testing?

A

Co-amplification of gene/pseudogene in Sanger can result in false negatives

57
Q

5 technical strategies to over-come pseudogenes in Dx testing

A

Long range PCR followed by nested PCR for individual exons

Highly specific primer design

cDNA methods

Long read sequencing

WGS (not amplicon/capture based)

Flora Ross (12 decks)

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