Week 1 Flashcards
(113 cards)
1
Q
What is the structure of DNA?
A
double helix strand
2
Q
WHat are the 4 DNA nucleotide?
A
AGCT
3
Q
What are the 4 RNA nucleotides?
A
AGCU
4
Q
Which nucleotide does A bind to?
A
T
5
Q
Which nucleotide does C bind to?
A
G
6
Q
What nucleotide does T bind to?
A
A
7
Q
What nucleotide does G bind to?
A
C
8
Q
Between which nucleotides do stronger bonds form and why?
A
C-G because there are 3 hydrogen bonds instead of 2
9
Q
Describe the process of gene expression
A
RNA polymerase forms primary mRNA mRNA undergoes splicing to remove introns and mature mRNA is formed Translation then occurs in the ribosome. Transfer RNA is involved in translation 1st amino acid is methionine. Codon (mRNA) anti-codon(tRNA) Then post translational modifications occur
10
Q
What relation is the child of your cousin?
A
First cousin once removed
11
Q
What is meant by penetrance?
A
Chance that inherited mutation will lead to disease
12
Q
How do you calculate the chance of someone developing a genetic form of cancer?
A
chance of inheriting mutation multiplied by the chance that the mutation will lead to disease
13
Q
What capabilities must be acquired for a cell develop into cancer?
A
proliferative signalling
avoidance of apoptosis
bypassing replicative senescence
insensitivity to anti-growth signalling
14
Q
WHat part of chromosomes are involved in replicative senescence?
A
telomeres
15
Q
Describe tumour suppressor genes
A
normally inhibit progression through the cell cycle
Promote apoptosis or act as stability genes
16
Q
Give examples of tumour suppressor genes
A
Rb
TP53
DNA repair (BRCA)
17
Q
Describe proto-oncogenes
A
normally stimulate cell cycle
18
Q
Describe how oncogenes are formed
A
1 copy of mutated proto-oncogene leads to gain of function effects
19
Q
What is meant by wt?
A
wild type - normal (non-mutated copy of allele)
20
Q
Describe stability genes
A
a type of TSGs
act to minimise genetic alterations
account for commonest hereditary cancer predisposition syndromes
21
Q
Describe sporadic cancer
A
common
late onset
single primary tumour
22
Q
Describe familial cancer
A
uncommon
early onset
often multiple primaries
23
Q
How are most common familial cancers inherited?
A
autosomal dominant
24
Q
How do you identify the risk of a cancer being hereditary?
A
more than one individual in the same family
affected by similar cancers or cancers at related sites with early onset
multiple primary tumours
early age of onset
25
WHat would a cancer family history clinic offer?
draw family tree and verify diagnoses
estimate likelihood of predisposing gene mutation
discuss screening, risk factors, preventative measures
26
What are the main mutations involved in hereditary breast cancers?
BRCA 1
BRCA 2
TP53
PALB2
27
Which BRCA mutation is more likely when there is a family history of ovarian cancer?
1
28
Which BRCA mutation is most likely when there is a history of male breast cancer?
2
29
WHat is meant by modifier genes?
loci that confer to increased susceptibility to cancer
these are common and each confers a small effect on increased risk
These are mutations outwith genes - enhancer and silencer parts that control the expression of neighbouring genes
30
WHat is the function of the BRCA1 and BRCA 2 proteins?
DNA repair by homologous recombination of double-strand breaks
31
what treatment may BRCA 1 and BRCA 2 carriers offered?
examinations
screening
prophylactic bilateral mastectomies
prophylactic oophorectomies
32
Which mutated genes can lead to ovarian cancer?
BRCA 1
BRCA 2
HNPCC - MLH1 or MSH2
33
Describe how olaparib works
selective lethality
| BRCA cell uses different type of DNA repair mechanism involving PARP - this is inhibited by drug and causes cell death
34
WHat is PARP?
poly ADP polymerase
35
what is the main form of familial colonic cancer?
hereditary non-polyposis colon cancer
36
What is a rare form of familial colonic cancer?
familial adenomatous polyposis
37
Describe HNPCC
usually only a few polyps
uterus, stomach, ovary
Due to inheritance in mutation in MMR systemic genes (repairs point mutations)
38
Which genes are associated with HNPCC?
```
MLH1
MSH2
MSH6
PMS2
these genes encode proteins that act together in a complex to carry out miss-match repair
```
39
Which eye condition is associated with familial adenomatous polyposis?
congenital hypertrophy of the retinal pigment epithelium
40
What is unusual about MYH polyposis?
autosomal recessive inheritance
attenuated form of FAP
base excision repair (BER) gene DNA glycosylase
41
WHat cancers can be caused by Li fraumeni syndrome?
```
breast
brain
sarcoma
leukaemia
adrenocortical carcinoma
```
42
What mutation is involved in Li fraumeni syndrome?
TP53
43
What is TP53 involved in?
control of cell cycle, apoptosis and replicative senescence
44
what is typically meant by a mendelian disorder?
single gene
45
How many genes are there?
20-25 thousand
46
What type of inheritance is achondroplasia?
autosomal dominant
47
Describe autosomal dominant inheritance
effects every generation
vertical pattern of inheritace
only need 1 faulty gene
males and females effected
48
What is meant by variable expression?
2 people in the same family with the same mutation can have different severities of it
49
What is meant by incomplete penetrance?
inheriting the mutation does not necessarily meant you are affected by the condition
50
What is gonadal mosaicism?
When some of the germ cells have undergone mutation and therefore there is a small chance of it being passed on to a child
51
What gene can effect the severity or penetrance in people who carry the BRCA2 gene?
FGFR2
52
Give examples of AD conditions
inherited breast or colon cancer
ADPKD
NF1
53
What are the clues that a condition is autosomal recessive?
usually horizontal pattern of inheritance
both males and females effected
there may be consanguinity in the family
54
What is meant by consanguinity?
parents may be related to each other. This increases the risk that both will carry the same mutation
55
Give examples of AR conditions
cystic fibrosis
phenylketonuria
spinal muscular atrophy
congenital adrenal hyperplasia
56
What are the features of recessive X-linked conditions?
Knight's move pattern
No male to male transmission
only males afffected
57
Why can there be some "manifesting carriers" in recessive X-linked conditions?
Skewed X inactivation
Normally 50% of each X chromosome turned off, but if this balance is skewed then it can lead to a faulty gene being more highly expressed
58
Describe X-linked dominant inheritance
Pattern is like AD but with no male to male transmission
| Females more likely to be affected than males
59
Give examples of X-linked dominant conditions
Vitamin D resistant rickets
incontinentia pigmenti
Rett syndrome
60
What is meant by genetic anticipation?
mutation gets bigger as more repeats are added
| increasing severity of onset in successive generations
61
Give examples of conditions that involve genetic anticipation
Huntington disease
Fragile X syndrome
myotonic dystrophy
62
What is meant by pseudo-dominant inheritance?
If an AR condition but has a very high carrier frequency or consanguinity - it appears like AD
63
Give an examples of a condition that can show pseudo dominant inheritance patterns
Gilbert syndrome
64
What is unusual about mitochondrial DNA?
```
much smaller genome
circular
much smaller than nuclear DNA
37 genes
no introns
```
65
Describe mitochondrial inheritance
inherited only from the mother
all children inherit it from the mother but to a variable extent
there is a threshold of the number of mutations that are required for disease to occur
heteroplasty
syndromes often affect muscle, brain and eyes
66
What is the presentation of Huntingtons disease?
onset between 30 and 50
progressive chorea (involuntary movement)
dementia and psychiatric symptoms
67
What repeat is found in HD?
CAG
| mainly prone to expansion during meiosis in the father
68
Describe the pathophysiology of HD
CAG repeat within the coding sequence
encodes polyglutamine tract
expansion of tract causes insoluble protein aggregates and neurotoxicity
69
Describe the clinical aspects of myotonic dystrophy
AD with genetic anticipation
progressive muscle weakness in early adulthood
also myotonia and cataracts
more risk of increased repeat sequence in mother
70
Describe the genetic basis of myotonic dystrophy
unstable length mutation of a CTG repeat
in the 3' transcribed but untranslated region of DMPK gene
affected if 50 or more repeats
71
Describe the pathogenic mechanism in myotonic dystrophy
abnormal DMPK mRNA
indirect toxic effect upon splicing of other genes
e.g. the chloride ion channel gene (causing myotonia)
72
Describe the clinical aspects of cystic fibrosis
AR
carrier frequency of 1 in 20-25
recurrent lung infections
exocrine pancreas insufficiency
73
How is CF diagnosed?
screening of newborns by immunoreactive trypsin (IRT) level
| confirmation by DNA testing and or sweat testing
74
Describe the pathogenic mechanism of CF
CFTR mutations
defective chloride ion channel
increased thickness of secretions
75
Describe the most common mutation in cystic fibrosis
F508del
in frame deletion of 3bp (one codon)
loss of phenylalanine (F) at position 508
prevents normal folding of protein and insertion into the plasma membrane
76
What is meant by cascade screening?
identification of mutations permits prenatal diagnosis if desired and subsequent identification of carrier relatives
77
Describe NF1
```
neurofibromatosis 1
commonly cafe au lait macule and neurofibromas
short stature
macrocephaly
learning difficulties
very variable expressivity
lisch nodules in eyes
```
78
What are the possible complications of NF1?
```
increased risk;
hypertension
scoliosis
pathological tibial fractures
significant tumours
```
79
Describe the DMD gene
Largest human gene but doesn't encode the largest protein
80
What does dystrophin normally do?
forms link between F-actin intracellular and the dystroglycan complex in the cell membrane
81
What test can be carried out at birth in DMD?
serum creatine kinase
leaks out of damaged muscle cells
massively increased level of DMD from birth before any symptoms occur
82
What sort of mutation is DMD?
out of frame mutation
83
What sort of mutation is BMD?
in frame mutation
84
What does BMD stand for?
Becker muscular dystrophy
85
Describe fragile X syndrome
X linked recessive
genetic anticipation
most common inherited cause of learning disability
phenotype in males can be severe
some carrier females are affected but more mildly
86
Describe Edward's syndrome
```
trisomy 18
small chin
clenched hands with overlapping fingers
malformations of heart, kidneys etc
if survive first year generally have profound LD
```
87
Describe patau syndrome
trisomy 13
congenital heart disease is usual
about 50% die in first month
88
Describe the clinical features of patau syndrome
```
cleft lip and palate
micropthalmia
abnormal ears
clenched fists
post axial polydactyly
```
89
How do trisomies mutations occur?
normally from maternal non-disjunction in meiosis
90
What does PGD stand for?
Pre-implantation genetic diagnosis
91
What are the pros of PGD?
permits implantation of unaffected embryos
| TOP then unnecessary
92
What are the cons of PGD?
possible long wait
not available to all woman
difficulty with multiples visits and procedures
<50% success
93
Describe genetic counselling
providing genetics-related advice and information
information re investigation and interpretation
thinking about implications for relatives
94
What are the main principles of a screening programme?
```
clearly defined disorder
appreciable frequency
advantage to early diagnosis
few false positives
few false negatives
benefits outweigh the costs
```
95
How is sensitivity calculated?
true positives/(all affected)
96
How is specificity calculated?
True negatives out of all unaffected
97
What is CUB screening?
ultrasound and biochemical testing for Downs syndrome
98
Describe chorionic villous sampling
10-12 weeks
1/50 miscarriage
quick results
99
Describe amniocentesis
16-18 weeks
1/100 miscarriage
result 1-2 weeks
100
how is DNA sequencing carried out?
```
automated fluorescent dideoxycytidine (Sanger) sequencing
Massively parallel (next gen) sequencing
```
101
What is allele-specific (ARMS) PCR used for?
for specific known point mutations
102
What is MPLA used for?
to look for specific duplications and deletions
103
What is Array CGH used for?
to detect abnormalities when the location is not known
104
What is quantitive flouresenct PCR used for?
Raoid detection of aneuploidies
105
What are the chromosome based analysis methods?
karyotyping
| FISH
106
Which tests are used to detect sub-microscopic deletions/duplications?
FISH
MLPA (position known)
aCGH
107
What techniques are used to detect point mutations?
DNA sequencing or ARMS
108
What can be analysed with NGS?
single gene
several genes at once
come
genome
109
What are the steps in data analysis in NGS?
```
DNA
massively parallel sequencing
FASTQ file
Sequence alignment
BAM file
Variant calling
VCF file
Data filtering steps (removing common variants)
```
110
WHat is meant by pharmacogenetics?
the study of the genetically controlled variation in response to medication
111
Describe ivacaftor
G551D - the 3rd most common CF mutation
Blocks opening of CFTR chloride channel
Ivacaftor re-opens the channel
112
Describe examples of future therapies in DMD
exon skipping: convert DMD to BMD phenotype by altering splicing patterns to correct the reading frame
or using drugs that allow read-through of premature stop codons
113
What are meant by splicing factors and relate it to DMD
proteins necessary for normal splicing of other genes - include "muscle blind" proteins
These are mopped up (sequestered) by the abnormal DMPK mRNA to which they bind.
