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Difficult Questions! Flashcards

(85 cards)

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1
Q

How is DNA packaged?

A

DNA winds around histone proteins, forming nucleosomes
Nucleosomes are organised into solenoids (tightly packed helix)
Solenoids fold into loops

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2
Q

Define intragenic

A

Introns within genes

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3
Q

Define intergenic

A

Non coding regions between genes

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4
Q

MtDNA

  • Structure
  • How many genes?
A

Double stranded
Circular
37 genes

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5
Q

When is genetic variation introduced during meiosis?

A

Crossing over - Prophase I

Independent assortment - Metaphase I

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6
Q

Give an example of a genetic disorder caused by meiosis going wrong

A

Downs Syndrome is trisomy of chromosome 21

Occurs when chromosomes do not split evenly during meosis I or meosis II

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7
Q

What is checked during G1/S phase?

A

Is the environment favourable?
Presence of growth factors?
Is there enough nutrients?

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8
Q

What is checked during G2/M phase?

A

Is all DNA replicated?

Is all DNA damage repaired?

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9
Q

What is checked during the checkpoint within M phase?

A

Are all chromosomes attached to the mitotic spindle?

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10
Q

What can be some detrimental consequences of apoptosis?

A

Uncontrolled apoptosis can lead to Alzheimers (degeneration of neurons) and Parkinsons (loss of dopinamergic neurons)

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11
Q

Features of a cancer syndrome

A

Inherited autosomal dominantly
Predisposes to cancer
Much more likely to cause early onset cancer

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12
Q

What is Li-fraumeni syndrome?

-increases risk of

A

Cancer syndrome
Inherited mutation in one allele for the p53 gene
Increased risk of osteosarcoma, breast cancer, leukaemia etc

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13
Q

What is hereditary breast-ovarian cancer syndrome?

  • genes mutated
  • role of genes
  • increases risk of
A

Mutations in BRCA1 or BRCA2 genes, which are DNA repair genes, involved in repairing double stranded breaks
DNA damage is not repaired correctly, leading to faster accumulation of mutations
Predisposes to breast, ovarian, fallopian tube carcinoma and prostate cancer in men

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14
Q

How can cancer syndromes be tested for?

A

Take a sample of body fluid or tissue (blood, saliva, amniotic fluid)
Use NGS to determine DNA sequence of mutation
Or use PCR to look for a specific mutation

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15
Q

What is familial adenomatous polyposis?

  • what happens during
  • age of onset
A

Autosomal dominant cancer syndrome
Many polyps form in the epithelium of the large intestine
Start benign, may transform into malignant cancer if left untreated
Usually adult onset

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16
Q

What are the 3 types of familial adenomatous polyposis?

A

FAP
Attenuated FAP
Autosomal recessive FAP

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17
Q

What is the mechanism behind FAP?

A

Mutation in APC gene leads to total loss of function. APC combines with axin and a kinase to form part of the beta-catenin destruction complex in the Wnt signalling pathway. Beta-catenin is a transcription factor for cell proliferation.
93% will develop cancer by age 50

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18
Q

What is the mechanism behind attenuated FAP?

A

A mutation in the APC gene that leads to production of an attenuated APC protein. Still functional but has impaired function.

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19
Q

What is autosomal recessive FAP?

A

Mutation in the MUTYH gene. Has much milder effects, and required a mutation to be inherited from both parents

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20
Q

What are the 4 main cyclins that control the cell cycle (in order of when their concentrations peak)

A

Cyclin D - present throughout cycle
Cyclin E - peaks at G1/S
Cyclin A - peaks in G2
Cyclin B - peaks at G2/M

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21
Q

Name 4 tumour suppressor genes

A

Retinoblastoma
p53
BRCA1/BRCA2
APC

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22
Q

Name 3 proto-oncogenes

A

Myc/c-Myc
HER-2
MDM2

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23
Q

What does Myc do?

  • what is it
  • involved in
  • activity enhanced by
A

Myc is a transcription factor involved in many functions (cell proliferation, apoptosis, cellular transformation)
Involved in Wnt, Hedgehog and MAPK signalling pathways
Enhanced by HIF-2a which is active in hypoxic conditions e.g. in the centre of tumours

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24
Q

What is HER-2?

-what does it stand for?

A 
Human Epidermal growth factor Receptor
Tyrosine kinase receptor
Over expression causes dimerisation when no ligand bound
Initiates MAPK and JAK/STAT pathways
Has role in development of breast cancer
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25
What is MDM2?
In normoxic conditions, MDM2 ubiquitylates p53 to mark it for degradation Mutations in MDM2 lead to constitutive cell proliferation
26
Describe the process of the MAPK cascade
1. Ligand binds receptor 2. Dimerisation, trans auto phosphorylation 3. Recruit SH2 domain of Grb2 4. Brings SOS 5. Activates Ras 6. Activates MAP3K....to MAPK 7. Phosphorylates Myc
27
What is the function of the dishevelled protein?
Inhibits the kinase in the beta-catenin destruction complex
28
What is cellular senescence? | and what is it caused by
Cells lose their ability to divide due to ageing Due to telomere shortening Detected as DNA damage, which activates p53
29
What is hyperplasia?
Enlargement of an organ or tissue to to increased rate in cell proliferation
30
What is dysplasia?
Presence of abnormal cell types within a tissue | May be a pre-indication of cancer
31
What is metaplasia?
The change of one type of differentiated cell into another
32
What is neoplasia?
The presence of a new growth of tissue, due to abnormal cell proliferation
33
Give two examples of genes that beta-catenin transcribes
Cyclin D | Myc
34
What is a polymorphism?
An allele variant that is present in more than 1% of the population
35
What is a variant?
Any loci that has more than one possible allele within the entire population, even if in less than 1%
36
Features of mendelian inheritance
1. The gene has two copies (maternal and paternal) 2. The copies of the gene separate into two gametes 3. The copies of the gene segregate independently
37
Example of an autosomal dominant condition - onset - what is it caused by - what does it do - symptoms
Huntington's Disease Middle age onset Rare Trinucleotide repeat in Huntingtin gene Mutant protein becomes elongated, sticky, doesn't fold correctly, aggregates within cells Damages brain cells Causes decline of motor abilities and cognitive abilities
38
How can a loss of function mutation ever be dominant?
Haploinsufficiency | One correctly functioning allele is not enough to maintain normal function
39
Example of an autosomal recessive condition - what is it - symptoms
Phenylketonuria No production of phenylalanine hydroxylase, so build up of phenylalanine, which is toxic Causes learning difficulties and epilepsy
40
Example of an X-linked recessive condition - what is it - what causes it - symptoms
Duchenne Muscular Dystrophy Progressive neuromuscular disorder Mutation in gene for dystrophin - links muscle cell cytoskeleton to extracellular matrix Causes muscle weakness and wasting
41
Features of an X-linked dominant condition
Usually only found in females, as it is usually lethal in males so they do not survive
42
Example of an X-linked dominant condition
Rett Syndrome Mutation in gene involved in transcriptional silencing of methylated DNA (epigenetics) Causes delayed development, autism, lack of speech, lack of ability to walk
43
What does hemizygous mean?
One copy of a chromosome | e.g. males are hemizygous for the X chromosome
44
Name 5 examples of non-mendelian inheritance
``` De novo mutations Mitochondrial inheritance Mosaicism Epigenetics Trinucleotide repeat disorders ```
45
What is mosaicism? | -how can it occur
The mutation is not present in every genetically related cell Can occur if a mutation occurs during early mitosis of a zygote e.g. If it occurs during the first division, 50% of all cells will be affected
46
What is germline mosaicism vs somatic mosaicism?
Germline mosaicism = a mutation in the germline cells means that some gamtes carry the mutation and some don't. Disease may occur in child and siblings Somatic mosaicism = mutation arises post-fertilisation
47
What is mitochondrial inheritance? | -what effects severity of it and explain this term
Mitochondria come from the ovum, so are inherited maternally Severity depends on if there is heteroplasmy or not - the presence of more than one type of organelle genome (e.g. mitochondrial genome) in a cell
48
What causes trinucleotide repeat disorders?
Happens as a result of slippage during mitosis
49
Example of a disease that shows anticipation
Huntington's disease
50
What are epigenetics?
A modification of gene expression that is heritable | Caused by DNA methylation, histone modifications, non-coding RNAs
51
Example of a disease caused by epigenetics
Prader-Willi Syndrome | Paternal inheritance
52
What is genomic imprinting?
Type of epigenetic mechanism | The pattern of gene expression depends on which parents pattern you inherit
53
What is MODY? - stands for - inheritance pattern - monogenic/polygenic? - main symptom
``` Maturity Onset Diabetes of the Young Inherited form of diabetes Autosomal dominant Monogenic Not related to Type 1 or Type 2 No production of insulin OR beta cells don't release their insulin ```
54
5 features of MODY that mean it could be mistaken for type 1 diabetes
Early onset - usually before age 25 Usually normal body weight (BMI under 25) Causes hyperglycaemia Insulin dependent Genetic component - may have family history
55
What mutations can be the cause of MODY?
Single mutation in hepatocyte nuclear factor genes (HNF1a/1b/4a) which express GLUT1 and GLUT2 transporters Or in glucokinase gene (GCK) that codes for pancreatic glucose sensor Or NEUROD1, IPF1
56
What is the most common mutation cause for MODY?
Single base pair insertion in HNF1a Leads to a premature stop codon The RNA produced is subject to nonsense-mediated-decay Leads to haploinsufficiency of HNF1a
57
What is the best treatment for MODY?
Sulphonylureas | K+ channel blockers, cause depolarisation of beta cells so they are more easily activated and release insulin
58
What is the other type of monogenic diabetes? - what is it - what is the cause of this?
Neonatal diabetes Occurs in first 6 months of life May be permanent or transient Caused by mutations in the K+ channels on beta cell
59
Two ways of testing for gene presence?
Molecular diagnostics = gene sequencing | Biochemical diagnostics = assay for protein presence/activity
60
What are 4 methods of screening foetuses for genetic disorders?
Amniocentesis Chorionic villus sampling Ultrasound cell free fetal DNA
61
Example of when NMD is detrimental
In CF, some mutations result in a truncated protein that NMD decays However
62
What are the 3 RNA surveillance mechanisms?
Nonsense mediated decay Non-stop mediated decay No-go decay
63
What proteins regulate nonsense mediated decay?
UPF1, UPF2, UPF3
64
Which mRNA transcripts undergo nonsense mediated decay?
Transcripts with a premature termination codon that is at least 50 or more nucleotides upstream of the final exon-exon junction
65
How is nonsense mediated decay initiated?
Where exons have been spliced together, exon junction complexes form RNA removes these as it is translating When reaching a PTC, if there a more EJCs down stream, NMD happens
66
What is the process of NMD?
EJCs consist of UPF2/3 UPF1 is assembled at the site of termination translation UPF1 is phosphorylated by UPF2/3 Initiates degradation of the transcript
67
What transcripts are degraded by non-stop mediated decay?
Degrades mRNA that lacks a stop codon | Ski7 mediated or non-ski7 mediated
68
What transcripts are degraded by no-go mediated decay?
Degradation of mRNA transcripts on which the ribosome has stalled, for example due to formation of a secondary structure
69
How do glucose in the blood lead to insulin release?
``` Glucose uptaken into pancreatic beta cells by GLUT2 transporters Metabolised by glucokinase, produces ATP ATP dependent K+ channels close Depolarisation VOCCs open Exocytosis of insulin vesicles ```
70
What happens when there is low amounts of glucose in the blood?
Pancreatic alpha cells secrete glucagon Glucagon increases glycogenolysis Hepatocytes release glucose into blood
71
6 points where gene regulation can occur
``` Chromatin structure Transcription initiation mRNA processing mRNA export Translation initiation mRNA decay ```
72
How is chromatin made into heterochromatin or euchromatin?
Histone modifications Acetylation = turns gene on Methylation = turns genes off
73
Where does methylation usually happen?
On a cytosine adjacent to a guanine | Known as CpG island
74
How is transcription initiated?
TFIID = TBP + 11TAFs TBP binds TATA Box Recruits and positions RNA Pol Forms pre initiation complex
75
What are the two functions of insulators?
Chromatin boundary - prevents the spread of heterochromatin Suppress the activity of enhancers (Bind insulator proteins)
76
How are genes regulated by mRNA processing?
5' Cap and PolyA tail protect from endonucleases Alternative splicing 5' Cap allows nuclear export
77
How is constitutive splicing carried out? Name proteins
``` U1 binds 5' splice site U2 binds branch point U4/5/6 binds in between Branch point attacks 5' splice site Intron lost as lariat ```
78
What happens during Poly adenylation?
1. PolyA site (AAUAAA) recognised by cleavage and polyA specificity factor (CPSF) 2. Cleavage factors CF1 and CF2 make cute 3. Cleavage stimulation factor (CstF) promotes cleavage 4. PolyA tail added by polyadenylate polymerase 5. PolyA binding proteins PAB1 and PAB2 regulate mRNA stability
79
What happens during RNA export?
RNA exits through nuclear pore RNA transport proteins hnRNP, p15 and TAP Sequences in 3'UTR tell transcript where to go
80
What is mRNA turnover?
The rate at which mRNA is degraded intracellularly
81
What shape does mRNA take after transcription and why?
Circular | Cap binding protein interacts with polyA binding protein
82
How is RNA stability regulated?
RNA Binding Proteins AU Rich elements cause degradation C rich elements bind alphaCP proteins, causing stabilisation
83
How do small RNAs regulate gene expression?
About 20 nucleotides long Recognise sequences in the 3' UTR Bind to and blocks ribosome binding site
84
Define heritability | -scale
The degree of variation in a phenotypic trait that can be explained by genetic variation Scale of 0-1 Measure of VARIATION
85
How can the heritability of a trait be determined?
Heritability Studies | Parent-Offspring Correlations

Medical Genetics (8 decks)

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