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Clin Sci IMS, Respiratory, Renal, Cardiovascular, Nutrition & Energy > Week 2 - Genes, Proteins, Pharmacogenetics > Flashcards

Week 2 - Genes, Proteins, Pharmacogenetics Flashcards

1
Q

What is an intergenic region in a gene?

A

Non coding DNA region, junk DNA used for plasticity and control of gene expression

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2
Q

Describe Upstream regulatory regions

A

5 prime end, binding area of RNA polymerase to control RNA synthesis
Includes: enhancers, silencers, insulators and locus control

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3
Q

Describe the Promoter region

A

controlled binding area containing the upstream regulatory regions and protein binding sites

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4
Q

What is gene expression driven by?

A

RNA polymerase 2 - transcription factors bind around promoter region in specific place, TATA box

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5
Q

Describe activators

A

Bind to enhancer sequence and increase expression than without them ( basal/low expression)

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6
Q

What are the three RNA polymerases

A

RNA polymerase 1 - larger ribosomal RNA
RNA polymerase 2 - mRNA production
RNA polymerase 3 - tRNA + small ribosomal RNA

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7
Q

Describe Transcriptional repressors + example

A
  • interacts with activator to block function
  • overlap the binding site - stops activator binding
    e.g. Wilm’s tumour protein
    EGR-1 gene switching off expression, if mutation occurs tumours in kidney form in early life
    WT1 gene considered tumour suppressor
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8
Q

Describe 5 prime end capping of mRNA

A

Capped by:
- methylated guanine nucleotide by removal of a phosphate via phosphatase enzyme
Addition of GMP via guanayl transferase
- Methyl group via methyl transferase

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9
Q

Describe 3 prime end cleaving in mRNA

A

poly A tail of up to 200 nucleotides added by PolyA polymerase

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10
Q

What occurs if mRNA isn’t capped?

A

Degraded from 5 prime to 3 prime

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11
Q

Describe splicing

A

Removal of introns from coding sequences, responsible for diversity by creating iso- forms due to alternative splicing

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12
Q

What are the 5 types of alternative splicing

A
  • Exon shipping
  • 3 prime splice sites
  • 5 prime splice sites
  • Mutually exclusive exons
  • Intron Retention
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13
Q

Describe the role of small ribosomal unit

A

Initiator tRNA carrying methionine associates with small ribosomal unit along side eukaryotic initiation factor 2 (eIF2)
Small ribosomal unit recognises 5 prime end of mRNA capped with two additional initiation factors eIF4G and eIF4E

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14
Q

Describe translation termination

A
  • Ribosome encounters stop codon

- Cytoplasmic release factors bind to stop codon and free carboxyl end of peptide chain

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15
Q

Describe errors in gene expression

A
  • cause uncommon genetic disorders

- influence predisposition of common diseases

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16
Q

Describe 4 common gene mutations cause

A
  1. DMD gene - duchess muscular dystrophy
  2. SMN gene - spinal muscular atrophy
  3. CFTR gene - cystic fibrosis
  4. BMPR2 gene - PAH
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17
Q

Describe transcriptional errors

A
  • over expression of transcription factor causing cancers
  • one copy of transcription factor gene mutated leading to:
    Haploinsufficiency - one gene copy isn’t enough
    Dominant mutation - exert dominance over wild type
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18
Q

Describe electrophoresis

A
  • 1% agarose gel + 100ml buffer TAE/TBE
  • DNA sample inserted into gel wells created
  • DNA will move from anode to cathode - separated via size
  • DNA can be analysed
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19
Q

Describe the western blot technique

A
  1. Gel electrophoresis
  2. Blotting - transfer proteins to membrane layers - filter paper, membrane, gel, filter paper
  3. Blocking - no specific sites in membrane - prevent antibody binding to unspecific regions - incubate membrane
  4. Antibody Probing -
    Primary - 4 degrees overnight, wash away unbound antibody (TBST)
    Secondary - Horseradish peroxidase, produces detectable signal, leave for 1 hour on shaker and wash with TBST
  5. Detection/ Visualisation
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20
Q

What is gene expression profiling?

A
  • Detects how many copies of genes

- Idea of gene regulation at a specific time

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21
Q

Describe PCR stages

A
  1. Initial denaturation
  2. Second denaturation
  3. Annealing
  4. DNA extension

Repeat 25-30 times

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22
Q

What are pro proteins?

A

Inactive peptides or proteins that need post translational modifications to become their active form

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23
Q

Describe insulin production to its active form

A
  1. cleavage and removal of signal peptide by signal peptidases in ER
  2. Oxidation of SH groups to -s-s- ion ER to crosslink the chain
  3. Cleavage and removal of C chain in ER - the link between A and B insulin chain
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24
Q

Describe post translational modifications and their significance

A
  1. Processing ( proteolytic cleavage to active form)
  2. Covalent modification - chemical modification

Significance

  • extend structural repertoire of proteins
  • chemical and spatial structures
  • some are reversible allowing rapid dynamic regulation of protein activity
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25
Q

What is proteolytic cleavage?

A

One or several amino acids removed from N-terminus or protein - peptide bond = cleaved in the internal protein

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26
Q

Describe proline isomerisation

A

change in proline residue spatial conformation can seriously affect protein structure adopted

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27
Q

Describe PTMs phosphorylation

A

Phosphate group donated via ATP transferred to acceptor protein catalysed by protein kinases - Reversible

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28
Q

Describe the cell cycle control

A

Controlled by cyclins and cyclin dependent kinases

  • type of cyclin influences cyclin dependent kinases
  • cyclin concentration changes the cell cycle
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29
Q

Describe protein acetylation + most characterised target

A

Acetyl group added by acetyl CoA and transferred to acceptor amino acids catalysed by protein acetyl transferases (PATs)
Deacylation catalysed by Protein deacetylase (PDAC)
Main target = histones with specific enzymes
- Histone acetyl transferase (HATs)
- Histone deacetylases (HDACs) - makes DNA less accessible to transcription factors

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30
Q

Describe protein methylation

A

Donated by s-adenosylmethionine catalysed by methyl transferase/ demethylase - not all are reversible

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31
Q

What is a nucleosome?

A

DNA wound around 8 histones

Active chromatin activation when histones are accessible

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32
Q

Describe change in chemical nature in the immune system - protein attack

A

Immunesystem attacks citrullinated proteins - citrullination or deamination of arginine converting it to citrulline - cause of auto immune diseases and arthritis diseases

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33
Q

Describe glycosylation

A

addition of mono/oligosaccharides significant in affecting protein folding increasing protein stability, trafficking and recognition

34
Q

Describe N- Linked glycosylation

A

Polysaccharide added as 14 unit to asparagine residue and polypeptide in ER
-3 glucose and mannose residues (ER) removed and others added (Golgi)

35
Q

Describe O-linked glycosylation

A

sugar added one at a time in the golgi or cytosol added usually to hydroxyl of serine or threonine

  • golgi for secreted proteins
  • cytosol for cellular proteins
36
Q

Describe protein polyubiquitination

A

Ubiquitin = small protein contains 76 amino acids

  • attachment of ubiquitin to proteins changes protein structure
  • attachment of polyubiquitin marks protein for degradation in the proteasome requiring ubiquitin activating enzyme, ubiquitin conjugating and ubiquitin ligase
  • Deubiquitinatingenzyme removes ubiquitin
37
Q

What are the functions of polyubiquitination?

A
  • Removal of damaged and misfiled proteins
  • control protein lifespan
  • control of multi cellular processes by regulating availability of key regulating proteins
  • role in neural activity - regulate synaptic transmission with protein channels and calcium receptors
38
Q

Describe lipidation and the 4 types

A

Method to target proteins to membranes in organelles

  1. G-C terminal glycosyl phosphatidylinostitol (GPI anchor)
  2. N-terminal myristoylation
  3. S- myristolyation
  4. S-prenylation

Each type gives distinct membrane affinities and increases hydrophobicity

39
Q

Why is PTM important?

A
  • Defects in protein PTM and cell signalling are crucial in pathobiology of numerous diseases
  • Used (enzymes) as therapeutic targets
  • GPCR Regulation
40
Q

Describe how mutations arise

A
  1. strand breakage + nucleotides lost
  2. Base lost - glycosidic bond is broken or enzymatically cleaved
  3. Base change - guanine is oxidised to 8-oxyguanine and base pairs with adenine, cytosine loses amino group and becomes uracil. Thymidineglycol blocks replication
  4. DNA cross linking - UV light cause cyclobutqane dimers and anti cancer agent cis-plating cause adjacent guanines to crosslink
  5. DNA replication errors - some not corrected
41
Q

What are some issues caused by DNA repair failure?

A
  1. Cancer susceptibility
  2. Progeria (accelerated ageing)
  3. Neurological defects
  4. Immune deficiency
42
Q

Describe Missense mutations

A

Change in nucleotides, point mutation frame shift, gain or loss of functions

43
Q

Describe nonsense mutations

A

Premature stop codon formed via frame shift usually resulting in a non functional protein

44
Q

Describe Expanding trinucleotide repeats

A

same part of sequence repeated many times - further increased In replication

45
Q

What are transposons?

A

sequence of DNA that can move around the genome and acts as recombination hotspot

46
Q

What are retrosposons?

A

Analogue to copy and paste system, exhibit intermediate RNA stage prior to insertion into genome

47
Q

What are DNA transposons?

A

cut and paste transposable element TE

48
Q

What are All repeats?

A

short interspaced elements (SINEs)

most abundant element in genome, large number of pathogenic deletions

49
Q

What is haploinsufficiency?

A

one copy of chromosomes is deleted or inactivated by a mutation - one functional gene is not enough

50
Q

What is the dosage effect?

A

gene product = quantitative signalling system, amount determines how active a gene may be
gene products compete to determine metabolic or development switch

51
Q

What is stoichiometry?

A

Relationship between quantities of substances involved in reactions - one can’t occur without the other

52
Q

What is penetrance?

A

How frequently disease is manifested

53
Q

What is localisation proteins?

A

Direct pathways - proteins moved from cytosol to mitochondria, nuclei and peroxisomes
-Proteins moved from ER in secretory pathways

54
Q

What are two types of secretion?

A

Constitutive secretion -all cells, continual exporting of substances
Regulated secretion - specialised secretory cells, substances stored in secretory vesicles for release in response to signal

55
Q

Describe pancreatic cells

A 
Exocrine and endocrine organ 
Islets of langerhan - 
B cells - insulin 
A cells - glucagon 
Delta cells - somatostatin

Pancreatic acinar cells - secretion of mainly digestive enzymes (zymogen)

56
Q

Describe the protein secretion pathway

A
  1. initiation of protein synthesis
  2. synthesis segregated from cytosolic proteins
  3. processing of proteins in the ER first then the golgi
  4. packaging and condensation
  5. release via exocytosis
57
Q

Describe the golgi secretion

A

Cis face takes transported vesicles bringing proteins, contents released into lumen of golgi
Trans face secretes packaged proteins according to location and final destination

58
Q

Where are zymogen vesicles stored?

A

The cytoplasm until signal initiates exocytosis

59
Q

Describe DNA polymerase in DNA replication

A

DNA polymerase alpha binds to strand at primer site, once strand reaches 20 base pairs DNA polymerase epsilon takes over.
DNA polymerase epsilon and delta have proof reading 3 prime to 5 prime exonucleases

60
Q

Describe DNA replication in the lagging strand

A
  • multiple RNA primers needed
  • DNA polymerase delta generates complementary DNA to the strands between RNA primers creating Okazaki fragments
  • Replication is not continuous as fragments are not joined
  • RNA primers are degraded and filled by action of RNAse H and DNA polymerase delta
  • DNA ligase joins the breaks in leading and lagging strands to generate a continuous double stranded DNA
61
Q

Why can replication not originate from one site?

A
  • genome replicates in 8 hours

- multiple origins of replication with forks leading in opposite directions to increase replication rate

62
Q

Describe epigenetics

A

Heritable change in phenotype by changes other than DNA base sequence

63
Q

What is consanguineous mating?

A

Insest lol

Mating between family members - first cousins

64
Q

What is a true homozygote?

A

When a child has the same genes due to consanguinity

65
Q

What is multifactorial inheritance?

A

Inheritance and expression of a phenotype being determined by the cumulative action of multiple genes at multiple loci - gene and environmental factors

66
Q

What is mendelian manner?

A

Order where genes are passed from parents to children

67
Q

What are monogenic diseases?

A

Single strong high penetrant phenotype, rare, primary gene dominates

68
Q

What are polygenic diseases?

A

Common, low penetrant phenotypes, environmental contribution reduced penetrance, involves 2 or more genes

69
Q

Describe the threshold model

A

Frequency disorder among relatives compared to frequency of disorder in general population

70
Q

What is heritability?

A

Proportion of disease variation due to genetic variations 1=high 0=low

71
Q

What are monozygotic twins?

A

Identical twins

72
Q

What are Dizygotic twins?

A

Non identical twins share 50% of DNA

73
Q

What is concordance?

A

Probability that identical twins will both have the disease or how often the non identical twins will have the disease given on of the pair has the disease % shows heritability

74
Q

What are SNPs?

A

Single nucleotide polymorphisms
DNA sequence variations that occur when a single nucleotide in the genome sequence is altered at the same genetic location between different chromosomes

75
Q

What are haplotypes?

A

Disease linked genomic loci that are physically linked on a chromosome and segregate together

76
Q

What is GWAS?

A

Genome wide association study to identify variants associated with a disease

77
Q

What is aneuploidy?

A

Presence of an abnormal n.o of chromosomes in a cell

78
Q

Describe Precision medicine

A

Influence of genetic variation on drug response in patients by correlating gene expression or presence of SNPs with drug efficacy and toxicity

79
Q

What is a non synonymous mutation?

A

Mutation that results in a change in protein sequence

80
Q

Describe personalised medicine

A
  • Advanced screening
  • Better drugs
  • Customised drugs
  • Improved dosing - genetic information bell curves
  • Improved drug discovery
81
Q

Describe warfarin treatment pharmacogenomics

A

Specific genes show resistance (VKORC1) and high sensitivity (CYP2C9*3), hence us SNP information to maximise dosing for each patient as warfarin has a narrow therapeutic range, also racemate with S-warfarin being more active form

Clin Sci IMS, Respiratory, Renal, Cardiovascular, Nutrition & Energy (17 decks)

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