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Difficult Questions! Flashcards

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USMLE® Step 1 flashcards Biology 101 flashcards
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
Q

What is MDM2?

A

In normoxic conditions, MDM2 ubiquitylates p53 to mark it for degradation
Mutations in MDM2 lead to constitutive cell proliferation

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26
Q

Describe the process of the MAPK cascade

A
  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
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27
Q

What is the function of the dishevelled protein?

A

Inhibits the kinase in the beta-catenin destruction complex

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28
Q

What is cellular senescence?

and what is it caused by

A

Cells lose their ability to divide due to ageing
Due to telomere shortening
Detected as DNA damage, which activates p53

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29
Q

What is hyperplasia?

A

Enlargement of an organ or tissue to to increased rate in cell proliferation

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30
Q

What is dysplasia?

A

Presence of abnormal cell types within a tissue

May be a pre-indication of cancer

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31
Q

What is metaplasia?

A

The change of one type of differentiated cell into another

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32
Q

What is neoplasia?

A

The presence of a new growth of tissue, due to abnormal cell proliferation

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33
Q

Give two examples of genes that beta-catenin transcribes

A

Cyclin D

Myc

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34
Q

What is a polymorphism?

A

An allele variant that is present in more than 1% of the population

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35
Q

What is a variant?

A

Any loci that has more than one possible allele within the entire population, even if in less than 1%

36
Q

Features of mendelian inheritance

A
  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
Q

Example of an autosomal dominant condition

  • onset
  • what is it caused by
  • what does it do
  • symptoms
A

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
Q

How can a loss of function mutation ever be dominant?

A

Haploinsufficiency

One correctly functioning allele is not enough to maintain normal function

39
Q

Example of an autosomal recessive condition

  • what is it
  • symptoms
A

Phenylketonuria
No production of phenylalanine hydroxylase, so build up of phenylalanine, which is toxic
Causes learning difficulties and epilepsy

40
Q

Example of an X-linked recessive condition

  • what is it
  • what causes it
  • symptoms
A

Duchenne Muscular Dystrophy
Progressive neuromuscular disorder
Mutation in gene for dystrophin - links muscle cell cytoskeleton to extracellular matrix
Causes muscle weakness and wasting

41
Q

Features of an X-linked dominant condition

A

Usually only found in females, as it is usually lethal in males so they do not survive

42
Q

Example of an X-linked dominant condition

A

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
Q

What does hemizygous mean?

A

One copy of a chromosome

e.g. males are hemizygous for the X chromosome

44
Q

Name 5 examples of non-mendelian inheritance

A 
De novo mutations
Mitochondrial inheritance
Mosaicism
Epigenetics
Trinucleotide repeat disorders
45
Q

What is mosaicism?

-how can it occur

A

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
Q

What is germline mosaicism vs somatic mosaicism?

A

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
Q

What is mitochondrial inheritance?

-what effects severity of it and explain this term

A

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
Q

What causes trinucleotide repeat disorders?

A

Happens as a result of slippage during mitosis

49
Q

Example of a disease that shows anticipation

A

Huntington’s disease

50
Q

What are epigenetics?

A

A modification of gene expression that is heritable

Caused by DNA methylation, histone modifications, non-coding RNAs

51
Q

Example of a disease caused by epigenetics

A

Prader-Willi Syndrome

Paternal inheritance

52
Q

What is genomic imprinting?

A

Type of epigenetic mechanism

The pattern of gene expression depends on which parents pattern you inherit

53
Q

What is MODY?

  • stands for
  • inheritance pattern
  • monogenic/polygenic?
  • main symptom
A 
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
Q

5 features of MODY that mean it could be mistaken for type 1 diabetes

A

Early onset - usually before age 25
Usually normal body weight (BMI under 25)
Causes hyperglycaemia
Insulin dependent
Genetic component - may have family history

55
Q

What mutations can be the cause of MODY?

A

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
Q

What is the most common mutation cause for MODY?

A

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
Q

What is the best treatment for MODY?

A

Sulphonylureas

K+ channel blockers, cause depolarisation of beta cells so they are more easily activated and release insulin

58
Q

What is the other type of monogenic diabetes?

  • what is it
  • what is the cause of this?
A

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
Q

Two ways of testing for gene presence?

A

Molecular diagnostics = gene sequencing

Biochemical diagnostics = assay for protein presence/activity

60
Q

What are 4 methods of screening foetuses for genetic disorders?

A

Amniocentesis
Chorionic villus sampling
Ultrasound
cell free fetal DNA

61
Q

Example of when NMD is detrimental

A

In CF, some mutations result in a truncated protein that NMD decays
However

62
Q

What are the 3 RNA surveillance mechanisms?

A

Nonsense mediated decay
Non-stop mediated decay
No-go decay

63
Q

What proteins regulate nonsense mediated decay?

A

UPF1, UPF2, UPF3

64
Q

Which mRNA transcripts undergo nonsense mediated decay?

A

Transcripts with a premature termination codon that is at least 50 or more nucleotides upstream of the final exon-exon junction

65
Q

How is nonsense mediated decay initiated?

A

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
Q

What is the process of NMD?

A

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
Q

What transcripts are degraded by non-stop mediated decay?

A

Degrades mRNA that lacks a stop codon

Ski7 mediated or non-ski7 mediated

68
Q

What transcripts are degraded by no-go mediated decay?

A

Degradation of mRNA transcripts on which the ribosome has stalled, for example due to formation of a secondary structure

69
Q

How do glucose in the blood lead to insulin release?

A 
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
Q

What happens when there is low amounts of glucose in the blood?

A

Pancreatic alpha cells secrete glucagon
Glucagon increases glycogenolysis
Hepatocytes release glucose into blood

71
Q

6 points where gene regulation can occur

A 
Chromatin structure
Transcription initiation
mRNA processing
mRNA export
Translation initiation
mRNA decay
72
Q

How is chromatin made into heterochromatin or euchromatin?

A

Histone modifications
Acetylation = turns gene on
Methylation = turns genes off

73
Q

Where does methylation usually happen?

A

On a cytosine adjacent to a guanine

Known as CpG island

74
Q

How is transcription initiated?

A

TFIID = TBP + 11TAFs
TBP binds TATA Box
Recruits and positions RNA Pol
Forms pre initiation complex

75
Q

What are the two functions of insulators?

A

Chromatin boundary - prevents the spread of heterochromatin
Suppress the activity of enhancers
(Bind insulator proteins)

76
Q

How are genes regulated by mRNA processing?

A

5’ Cap and PolyA tail protect from endonucleases
Alternative splicing
5’ Cap allows nuclear export

77
Q

How is constitutive splicing carried out? Name proteins

A 
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
Q

What happens during Poly adenylation?

A
  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
Q

What happens during RNA export?

A

RNA exits through nuclear pore
RNA transport proteins hnRNP, p15 and TAP
Sequences in 3’UTR tell transcript where to go

80
Q

What is mRNA turnover?

A

The rate at which mRNA is degraded intracellularly

81
Q

What shape does mRNA take after transcription and why?

A

Circular

Cap binding protein interacts with polyA binding protein

82
Q

How is RNA stability regulated?

A

RNA Binding Proteins
AU Rich elements cause degradation
C rich elements bind alphaCP proteins, causing stabilisation

83
Q

How do small RNAs regulate gene expression?

A

About 20 nucleotides long
Recognise sequences in the 3’ UTR
Bind to and blocks ribosome binding site

84
Q

Define heritability

-scale

A

The degree of variation in a phenotypic trait that can be explained by genetic variation
Scale of 0-1
Measure of VARIATION

85
Q

How can the heritability of a trait be determined?

A

Heritability Studies

Parent-Offspring Correlations

Medical Genetics (8 decks)

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