Genetics Flashcards
(346 cards)
1
Q
Are any diseases purely genetic
A
Single mutation diseases
2
Q
Is cancer environmental or genetic
What about complex genetic diseases
A
Can be Both
Also both genetic and environmental
3
Q
What are de novo mutation diseases
A
Diseases that occur due to inheritance of a newly arising germ line mutation
Ie affects child but not parents
4
Q
What happens if the de novo mutation occurs within the first 10 cell divisions in the embryo
A
The person will be a germline mosaic
5
Q
Which de novo mutations are homozygous
A
NONE
They are always heterozygous as it is essentially impossible for both sperm and egg to harm the same de novo mutation
6
Q
Can de novo mutations be hemizygous
A
Yes if they involve sex chromosomes
7
Q
What causes Apert syndrome
A
Ser -> Trp mutation in FGFR2
Increases signalling
8
Q
Give an example of a de novo mutation
A
22q11.2 deletion syndrome
Chromosome 22 has q11.2 deleted, removing 40 genes
Leads to a susceptibility to psychiatric illness
9
Q
Why are some de novo births more common than others
A
More frequent mutation or repaired less frequently
Mutation confers a selfish advantage to germ line
Some are caused by different mutations
Mutation may be more compatible with live birth
10
Q
What are many miscarriages causes by
A
The presence of de novo mutations that are incompatible with embryo development
11
Q
Are de novo mutations usually passed on
A
No as suffers tend not to have children
The disease mutation is under negative selection
12
Q
What is an inherited single mutation disease
A
Causes by alleles which segregate in populations
Disease causing variants arise in an individual’s germ line and is passed onto subsequent generations
13
Q
What are the 4 patterns of inheriting an inherited single mutation disease
A
Autosomal dominant
Autosomal recessive
Sex linked
Mitochondrial
14
Q
What is the chance of inheriting a dominant autosomal disease of 1 parent is affected
A
50%
15
Q
What is an example of autosomal dominant diseases
A
Mutation of BRCA1 increasing breast and ovarian cancer susceptibility
Polycystic Kidney disease due to several mutations in PKD1 or 2 (not apparent until 40-50 years)
16
Q
Are autosomal dominant disease alleles under negative selection?
Why
A
Only weakly
Usually manifest after reproductive age
If they manifest before reproductive age, negative selection is strong
17
Q
What is the founder effect
Give an example
A
When 1 individual carries a mutation and has offspring, spreading the disease
Lake Maracaibo- 1 woman with Huntington’s settled here and had 10 children. Huntington’s is v common here.
18
Q
Give an example of transheterozygotes
A
Albinism
2 disease causing loci in same gene present in a population
19
Q
Name a gene associated with albinism
Which alleles have been found
A
OCA
Missense
Nonsense
Frameshift
20
Q
what causes Ellis van Creveld syndrome
Where is it common
A
Caused by a splice site mutation in EVC
Amish populations
21
Q
What causes xeroderma pigmentosum
A
SNV or Indel mutation in NER machinery
22
Q
What are recessive lethals
Name one
What are they observed as in genetic testing
A
Autosomal recessive diseases that are incompatible with foetal development
Not usually named
An absence of homozygotes
23
Q
If a recessive disease is lethal, what is the chance of a child being a carrier if both parents are carriers
A
2/3
Child cannot be born with disease
24
Q
How many heterozygous recessive alleles do humans ja our that would be highly deleterious if homozygous
A
~0.6
25
Which populations are most at risk of autosomal recessive disease
Populations with high rates of consanguinity
26
What is reduced penetrance
When the same mutation causes disease in one individual but not in another individual
27
Give an example of reduced penetrance
Phenylketonuria (PKU)
autosomal recessive
Decreased metabolism of phenylalanine
Causes intellectual disability, seizures and mental disorders
Can be treated by low phenylalanine diet
28
What is variable expressivity
Same mutation
| Severe symptoms in one patient but mild in another
29
What is a medical geneticist
Diagnose genetic conditions
| Counsel couples about the implications of the diagnosis
30
What is SMA
Spinal muscular atrophy
An autosomal recessive neurodegenerative disorder caused by mutations in SMN1 and SMN2
Splice site mutation
Exon skipping leading to protein truncation
31
Difference between germline variation and somatic variation
Germline occurs in cells of the germ cell lineage and are inherited
Somatic = in somatic cells and is private to individual
32
What is a mosaic
An individual composed of cells with multiple different genotypes due to genetic variation that arose since development from fertilised egg
33
What is mosaic Down syndrome
People who carry trisomy 21 in a proportion of their cells
| They have fewer/ less severe symptoms than those with trisomy 21 in all cells
34
What is McCune Albright syndrome
A de novo mutation disease that only occurs as a mosaic
Mutation in GNAS in development
This mutation in all cells in not compatible with life so only mosaic emerges
Cafe au lait spots show clones of affected skin cells
35
What is a clone
A set of cells with a common origin
36
What is germline mosaicism
If it is involved in germline lineage
37
Why may it be difficult to diagnose mosaics
Not all cells contain mutation so sample of cells may miss it
38
Name the 4 key types of disease
Single mutation diseases
Complex genetic diseases
Cancer
Infectious diseases
39
Do single mutation diseases have an environmental contribution
Very little if any
40
How much of cancer is environmental factors and how much is genetic
Can be both or mostly one or the other (spectrum)
41
What is a karyotype
The set of chromosomes for a particular individual or specifies
42
What kind of karyotype do mammals have
Diploid
43
In the dog karyotype, 2n=
78
44
How many chromosomes in the Tasmanian devil karyotype
14
45
How many bases are in a human genome
How many base pairs is this
3. 1 Gb
| 3. 1x10^9
46
How much of DNA is coding
1-2%
These are exons
47
What is a reference genome
What is the human reference genome
A completely sequences genome isolate that is used as a reference for genome studies
A composite of DNA from 13 healthy anonymous volunteers in Buffalo, New York
48
How much DNA is selected for each reference genome
1 strand (5’ to 3’)
49
What is the genome coordinate
chr1:23,786,987
Referring to
A position of chromosome 1, the 23,786,987th base on chromosome 1
50
What are the 4 classes of genome variation
Single Nucleotide Variants
Small insertions and deletions (indels)
Structural variation
Cytogenetic variation
51
What is a locus
A position in the genome
Each locus can have different genetic variants or alleles
52
What is linkage disequilibrium
When two loci are close together in the genome and are frequently inherited together
53
What is a point mutation
The same as a SNV or substitution
When a single nucleotide is changed for another
54
In a C>T variant, which is the reference and which is the alternative allele
C is reference
| T is alternative
55
Why is a C>T variant the same as a G>A variant
One is referring to the reference strand the other is the same SNV from the non reference strand
56
What are the 6 types of SNV
```
C>A or G>T
C>G or G>C
C>T or G>A
T>A or A>T
T>C or A>G
T>G or A>C
```
57
What is a transition
Purine to purine or Pyrimidine to Pyrimidine
58
What is a transversion
A purine to Pyrimidine or vice versa
59
What is the mutation spectrum
The proportion of each SNV type in a given sample
60
Which SNV is common in melanoma
C>T or G>At
61
2 ways to cause an SNV
Exogenous mutational exposures
| Endogenous mutational processes
62
5 exogenous exposures
```
UV
Cigarettes
Chemotherapy
Aristolochic acid
Aflatoxin
```
63
What mutations does UV cause
Pyrimidine dimers
64
What is the key mutational element in cigs
Benzo [a] pyrene
65
Give an example of the an endogenous mutational process
What else may cause an endogenous mutational process
Spontaneous deamination of 5-methylcytosine
Replication errors
66
Where do most SNVs occur
Non coding regions
| Therefore have little effect on the cell
67
Give an example of a SNV that causes disease
BRAF
T>A
BRAF V600E means it is permanently activated and is independent of the associated froths factors and RTK causing cell cycle progression and a malignant melanoma
68
3 ways to repair SNV damage
Base excision repair
Nucleotide excision repair
Mismatch repair
69
Xeroderma pigmentosum is caused by SNVs in what component
NER
70
What is an indel
An insertion or deletion <100bp in length
71
What are indels caused by
Polymerase slippage during DNA replication (usually endogenous)
Eg accidental hairpins
72
What causes Huntington’s disease
Indels - CAG repeats
The mutated protein is toxic to some parts of the brain
73
What about of CAG repeats is required for Huntington’s
<35 repeats = not diseased
36-39= may be affected
40+= affected
74
How do indels affect BRCA1
Insertion of a C
Leads to increased risk of breast and ovarian cancer
75
What kind of repair is usually responsible for repairing indels
Mismatch repair (MMR)
76
Which indels do we see
Those that have not been correctly repaired
77
What are structural variants
Genomic rearrangements
| Large scale DNA mutations that juxtapose DNA that was previously not connected
78
3 types of structural variant mutations
Inter chromosomal
Intra chromosomal
Involving exogenous DNA
79
What kind of DNA break do structural variants usually involve
DSB
80
2 overall types of structural variants
Balanced and unbalanced
81
What is a balanced structural variant
Overall amount of DNA remains constant
Also know as balanced translocations
82
What is a unbalanced structural variant
DNA is gained or lost
| These lead to copy number variants
83
Give an example of a balanced translocation
The Philadelphia chromosome in chronic myeloid leukaemia
84
3 ways to cause copy number variants
Rearrangements in the genome causing gain or loss of host DNA
Integration of transposable elements
Integration of virus DNA
85
Name a disease associated with chromosome 22
22q11.2 deletion syndrome
(When chromosome 22 has q11.2 deleted)
Leads to intellectual disabilities, developmental defects and a susceptibility to psychiatric illness
86
What is 22q11.2 deletion syndrome an example of
An unbalanced structural variant caused by rearrangements in the genome causing gain or loss of host DNA
87
What are transposable elements
Virus like DNA elements encoded within genomes
They replicate themselves and insert into the genome, causing structural variant mutations
88
Give an example of a disease caused by transposable element insertion
Merle dogs - beautiful coats but have a range of hearing and sight problems due to transposable element insertion into the SILV gene
89
What kind of virus integrates into DNA
Retroviruses eg HIV
90
Give an example of non integrating viruses
Papillomaviruses
91
How do integrating viruses work
They permanently integrate into the host DNA as part of their life cycle and can cause disease causing mutations
92
What is Fr-MLV
Friend murine leukaemia virus
An integrating virus
93
Do non retroviruses integrate into host genome
It is not part of their normal life cycle but partial integration can occur
This can disrupt host genes or lead to activation of viral genes
94
What kind of break results from ionising radiation
Double stranded DNA breaks
95
4 endogenous causes of structural variants
Replication fork failure and collapse
Telomere shortening
Aberrant homologous recombination
Transposable element insertion
96
What is cytogenetic variation
What does it lead to
The gain or loss of one or more entire chromosomes
Aneuploidy
It leads to the production of copy number variants
97
What is aneuploidy
Give an example
The presence of an abnormal number of chromosomes in the cell
Trisomy 21 - Causes Down Syndrome
98
Cancers are rarely aneuploid. True or false.
False
| Most cancers are aneuploid
99
Are some cancers tetraploid?
Yes
100
What can cause cytogenetic variation
Segregation errors
| Whole genome duplication
101
What are segregation errors
When the incorrect number of chromosomes are in the daughter cells (eg 47 in one and 45 in the other)
102
Why may whole genome duplication occur
What is this called
When a cell goes through S phase but does not proceed through M phase
Endoreduplication
103
What can prevent aneuploidy
Cellular checkpoints such as the spindle assembly checkpoint
104
How can we identify genome variation
Whole genome sequencing
105
How do we do whole genome sequencing
```
Take cells
Extract DNA
Shear DNA into small fragments (~500bp)
Load fragments into sequencing machine which produces millions of short sequences
These are compared to reference genome
```
106
Can somatic cells contribute to the next generation
No
Germ cells contribute to the next generation
107
What is germline and somatic variation important for respectively
Germline: inherited genetic disease
Somatic: cancer and ageing
108
Which sex acquire more genetic variation
Why
Male
Males undergo more cell divisions before birth (~24 compared to the 20 in females)
109
When are germ cells specified
In 2 week embryo
110
What happens to germ cells between birth and puberty
Nothing much
111
What happens to males at puberty
Spermatogonial stem cells begin replicating to produce a mature sperm
112
How many replications do spermatogonial stem cells undergo before becoming mature sperm
How many differentiation replications are there?
~23 replications per year
4 differentiation replications
113
How many replications are there to the oocyte
None
| the immature oocyte simply mature’s each month and completes meiosis
114
How many replications has a mature oocyte gone through since conception
30
115
How many replications has a mature sperm gone through since conception
Why is this important
383 (in a 30 year old)
Higher rate of de novo mutation
Number of SNV mutations increase with male’s age at conception
116
How much of a man’s de novo mutations are paternally inherited
How many de novo mutations are there in men each generation? Why might it vary?
70-80%
50-100
It’s dependant on father’s age
117
Where do trisomy mutations tend to originate from
Maternal germline
Increases with maternal age
118
Why might trisomy not be passed on by males
Competition between sperm may eliminate it
119
How many gametes will carry the mutation in the particular spermatogonial stem cell from which they were produced
Why is it unlikely for these particular gametes to fertilise the egg
50%
There are millions of sperm from millions of spermatogonial stem cells
120
Every sperm will have a germ line variant. True or false?
True
Each spermatogonial stem cell has its own mutations
121
If a sperm with a mutation fertilises the egg, how many of the child’s cells will have the mutation
Does this include the child’s gametes
All of them
No only 50% of gametes will have this variant (as meiosis occurs here not mitosis)
122
How many variants are there between 2 unrelated people
3 million variants
| ~1 per 1000bp
123
Why can germ line variants be useful for anthropology
We can look at frequency of variants and look at genetic history
124
What determines if a new variant “makes it”?
Genetic drift
| Selection
125
What is genetic drift
Change in frequency of alleles in population due to chance
126
Why is genetic drift relevant to disease
Can lead to an increase in frequency of disease causing alleles
Eg BRCA1 originated in Baltic region. Now very common in Ashenazi population (~1% carry)
127
Genetic drift is particularly important for large populations. True or false?
False
It is particularly important for small generations
128
What is a bottle neck
When a population is drastically reduced in size. If the population subsequently recovers, all individuals will derive from a small number of ancestors
129
What is the founder effect
When a small number of individuals found a new colony etc and all individuals will derive from a small number of ancestors
130
Give an example of the founder effect
Ellis Van Creveld syndrome
Common in Amish community
(Polydactyl)
131
Most variants have a phenotype. True or false.
False
Most genetic variants are neutral with respect to the cell, very rarely do they alter the functioning of the cell
132
When can selection act
When a phenotype is present
133
What is selection
A change in frequency of a variant in a population due to a change in fitness
134
What are the 2 types of variant that lead to a change in phenotype
Coding variant- leads to a change in protein
Non coding variants and copy number variants: cause changes in the amount of protein produced
135
What is a missense variant
What is this found in
A single change in an amino acid in a protein
BRAF
136
What is a nonsense variant
Creates a termination codon leading to a protein truncation
137
What is an in frame deletion or insertion
Give an example
Insertion or deletion of 3 or a multiple of 3 base pairs
Huntington’s
138
What is a frame shift
Indel of non multiple of 3 length
139
What is splicing
Exon skipping and leads to protein truncation
140
What is gene fusion
A mutation when 2 genes fuse such as in BCR-ABL fusion in CML
Diagnostic of Philadelphia chromosome
This must be in frame
141
What can structural variant rearrangement lead to
Gene truncation
142
What is a variant in promoters or enhancers
Affects amount of protein produced
Eg TERT promoter variant in malignant melanomas
143
Discuss TERT promoter variant
TERT encodes component of telomerase
Mutation (C>T) upstream of TERT leading to increased recruitment of RNA polymerase
Increased transcription of TERT leading to a malignant melanoma
144
Is trisomy 21
When there are 3 copies of chromosome 21. Associated with Down syndrome
145
It is the phenotype that is dominant or recessive. True or false?
True
146
Define dominant and recessive
Dominant: generate a phenotype when present in one copy regardless of the number of additional chromosomal copies
Recessive: generates a phenotype only when they present on all chromosomal copies
147
Name a syndrome that is a dominant variant
Alert syndrome
Due to 1 copy variant in the FGFR2
C>G
Ser>Trp
148
Give an example of a disease caused by a dominant mutation
BRAF
| Only one variant needed to predispose for malignant melanoma
149
Name a recessive variant syndrome
Ellis Van Creveld syndrome
150
Give an example of co-dominance
Sickle cell disease
Mutation in HBB
A>T
Glu> Val
HBB 6A/A = round RBC
HBB6A/T = mixture of sickle and round
HBB 6T/T= sickle shaped RBC
151
What are the 2 types of selection
Define them
Positive: acts on a phenotype to increase allele frequency in a population
Negative: acts on a population to reduce allele frequency in a population
152
What is purifying selection
AKA negative selection
153
What types of fitness advantage are there
Adaptive
Selfish
Artificial
154
What is adaptive positive selections
Give an example
Causes individuals to be better adapted to its environment
Homozygous CCR5 mutation means no HIV immunity As CCR5 is a receptor for HIV
155
What is selfish positive selection
Acts to increase the frequency of an allele that confers a phenotype thst is advantageous at the level of the cell rather than at the level of the whole individual
156
Give an example of selfish selection
FGFR2
C>G —> causes spermatogonial stem cells to divide more than neighbouring cells
Also causes Apert syndrome
Also cancer is a classic example
157
Give an example of artificial positive selection
Selecting for dog breeds
158
When does negative selection work
Before birth
| During reproductive lifespan
159
When does negative selection act before birth
Trisomies
Other trisomies are not compatible with birth so embryo does not develop
160
Give an example of negative selection during the reproductive life span
Y chromosome microdeletions
| Leads to azospermia and infertility
161
When is negative selection weak
If the phenotype manifests after reproductive senescence
| Eg Parkinson’s
162
What is balancing selection
When positive and negative selection interact to maintain >1 allele in a population
Eg heterozygote advantage - when the heterozygote has greater fitness than either homozygote
163
Why is there positive and negative selection acting on the same alleles in bulldogs
Artificial positive selection for their big heads
| Negative selection against the big heads during parturition
164
Give an example of selection based on environment in humans
MC1R gene variants are positively selected in northern climates due to the ability to synthesise Vitamin D but has an increased risk of skin cancer in lower latitudes
165
Give an example of when drift overcomes selection
Bernese Mountain Dogs
| CDKN2A - high frequency of hisiocytic sarcoma
166
Why does genetic drift not really affect de novo mutations
De novo dont usually occur in more than one individual
167
Are de novo diseases dominant
Yes
168
Does genetic drift affect autosomal dominant diseases
Yes drift is important
Eg high frequency of BRCA1 in Ashkenazi population
169
What may cause reduced penetrance
Accumulation of additional somatic variants
Mosaicism
Variable copy number of a mitochondrial disease haplotype
Genetic background
Epigenetic factors
Environmental factors
170
What are GRIN1 mutations associated with
De novo mutations in GRIN1 chase intellectual disability and seizures
171
Why is a knowledge of the genetic basis of disease important
Diagnosis
Prognosis
Further understanding of biological basis of disease
Genetic counselling, pre implantation screening and embryo modification
Animal breeding
Therapy
172
What is pre-implantation screening
Check which embryos are affected and select unaffected embryos
173
What is a mosaic
An individual composed of cells with multiple different genotypes, due to genetic variants that arose since development from the fertilised egg
174
How many mutations are there per diploid genome per cell division
2-10
175
When can de novo mutations occur
at any point during embryonic development or during childhood or adult life
176
What is Mosaic Down Syndrome
Patients carry trisomy 21 in a portion of their cells
Tend to have less severe symptoms
If the number of cells is small enough, there may not be any detectable symptoms
177
Name a de novo mutation disease that only occurs as a mosaic
McCune Albright Syndrome
178
What causes McCune Albright syndrome
A mutation in the GNAS gene during embryological development
179
Why can McCune Albright syndrome only occur as a mosaic
GNAS mutations in all cells is not compatible with life
180
What symptoms can you get from McCune Albright syndrome
Bone and endocrine abnormalities
| Cafe au lait spots
181
What do the café au lait spots in McCune Albright syndrome show
They define the clones of the affected skin cells
182
What is the difference between germline and somatic mosaicism I
If the mosaicism is involved with the germline lineage, it is called germline mosaicism
Somatic involves variation between somatic cells. This is private to the individual
183
When must a mutation occur to cause germline mosaicism
Why is this
In the first 10 cell replications after the egg is fertilised
If the mutation occurs in one of these replications, some of the germline and somatic cells will have the variant, others will not
184
Why is mosaicism difficult to diagnose
Blood may or may not carry the mutation
DNA from several tissues may need to be tested in order to confirm presence of mutation
185
How many cells does a cancer arise from
One somatic cell - it is clonal
186
What does malignant mean
Has the ability to invade host tissues and potentially metastasise
187
What kind of selection is the process underlying cancer
Selfish positive selection
188
What do you call somatic mutations that confer phenotypes on which selfish positive selection acts
Driver mutations
189
How many cancer genes do we know of currently
723
190
2 kinds of cancer gene
Dominant acting (oncogene)
Recessive acting (tumour suppressor genes)
191
Name a driver mutation in malignant melanoma
BRAF V600E
Means BRAF is always active and so acts independently of the receptor tyrosine kinase that usually requires a growth factor to activate. This results in uncontrolled cell cycle progression.
192
BRAF is a recessively acting cancer gene. True or false?
False
It is an oncogene and therefore dominantly acting
193
What is the most common driver mutation in BRAF
An SNV that causes a missense mutation
194
What does the Philadelphia chromosome cause
Is this a driver mutation
A fusion gene: BCR-ABL1
This is found in 95% of CML
Yes as it is the only necessary mutation and is sufficient for oncogenic transformation
195
What is ABL1
What about when the Philadelphia chromosome comes along
A kinase which normally phosphorylates only when specifically activated
BCR-ABL1 fusion is always on, even in the absence of upstream signals
196
What are double minutes
What can they lead to
Tiny circular DNA elements created by unbalanced structural variants
Massive copy number variants
197
Is MYC dominant or recessive
Dominantly acting cancer gene
198
What is HPV
Human Papillomavirus
An non integrating virus
199
What genes does HPV encodes
What does this do
E6 and E7
Stimulates the cell to enter the cell cycle
200
Why is it advantageous for HPV to encode E6 and E7 genes
Does this cause cancer
E6 and E7 stimulate the cell to enter the cell cycle and HPV is also replicated in the S phase of the cell cycle
No
201
Why may HPV cause cancer
E6 and E7 May insert as a structural variant so that they are highly expressed, this predisposes to cancer
202
What is P53
How does it usually work
A tumour suppressor
It detects cellular stress and DNA damage and in response causes cell cycle inhibition, apoptosis, DNA repair, and senescence
203
How many copies of P53 must be damaged to confer positive selection advantage to cancer
Both copies of P53
204
Name a recessively acting cancer gene
PTEN
205
What happens if PTEN is lost
How many copies need to be lost to predispose cancer
There is too much cell growth and cell signalling
2 but they can be deactivated by any combination of SNV, indel, structural variant, or cytogenetic variant
206
Will a positively selected driver mutation in one cell type be positively selected in all cell types?
No it depends on the cell context - each somatic cell type has its own unique biology
207
Do Philadelphia chromosome rearrangements always cause cancer
BCR-ABL1 is only found in CML
| but Philadelphia chromosome rearrangements likely occur in other somatic cells but aren’t positively selected
208
How many driver mutations are required to cause cancer
1-10
209
Which cancers only require 1 driver mutation
Sarcomas and leukaemias/ lymphomas especially in paediatric cases tend to require a small number of driver mutations
210
Which cancers require more driver mutations
Carcinomas (epithelial cancers)
211
Which cancers are most common in humans
Carcinomas - those derived from epithelial cells
212
Demonstrate how the incidence of cancers is different between humans and dogs
Sarcomas are rare in humans but relatively common in dogs
213
How likely are you to get small and large intestine cancers
Small - very rare
| Larger - one of the most common cancers
214
True or false: large intestine cancer is very common in dogs
False
| Large intestine cancer is very rare in dogs
215
How can we treat Philadelphia chromosome rearrangements
The BRC-ABL1 fusion can be blocked by Imantinib
216
What is another name for Imantinib
Gleevec
This drug can lead to long lasting remission from CML
217
Which drug specifically inhibits BRAF V600E
Vemurafenib
218
3 things that increase risk of somatic mutation
Age
Exogenous
Germline inheritance of variants that increase risk of somatic mutations
219
How many somatic mutations can be found in a cancer
Several thousand but these are mostly passenger mutations
220
What is a passenger mutation
Somatic mutations that are not under positive selection
221
How is BRCA1 usually repaired
What happens if this is absent
Using HR
NHEJ is used. This is less accurate so the cell is more likely to acquire further mutations leading to an increased risk of cancer
222
BCRA1 is a tumour suppressor gene. True or false?
True it is a recessively acting cancer gene
223
What are HR deficient cancers sensitive to
PARP inhibitors
224
What can happen to breast cancers treated by PARP inhibitors
Wild type BRCA1 is positively selected and it is resistant to PARP inhibitors
225
Can something increase the risk of cancer without increasing risk of somatic mutations?
Yes: asbestos, obesity, etc
226
What can be seen in the genetics of tumours of transmissible cancers
They have the exact same mutations - identical genome
227
How may transmissible cancer be spread between Devils
Biting during mating season, whereby the cancer cells slough off one devil onto the other
228
What is chimerism
Give a day to day example of this
The presence of cells derived from 2 different individuals within the same body
Pregnant female
229
What is tetragametic chimerism
When 2 zygotes (fraternal twins) fuse at an early stage of embryonic development
230
Why can tetragametic chimerism occur
At the early fusion stage, the immune system hasn’t fully developed so cannot detect self and non self
231
How is karyotype usually displayed
As an organised arrangement of all the chromosomes within a cell in
metaphase stage
232
What is an autosome
Non-sex chromosome
233
Does karyotype vary between sexes
Yes due to sex chromosomes
234
What is G banding
A Giemsa staining method used to generate a useful karyotype and identify condensed and open regions of a chromatin
235
What does haploid mean
Containing one half of each pair of chromosomes
236
Do all animals have the same sex chromosome system
No humans have the XY determining system whereas other animals use the ZW system
237
True or false
| Males are heterozygous for the X
False they are hemizygous - they only have 1 copy
238
How is dosage compensation between mammalian sexes achieved
Deactivation of the 2nd female X
239
Which is the heterogametic sex in humans
Male (XY)
Females are homogametic
240
What are the gametes like like birds
Female - ZW
Male - ZZ
males are the homogametic sex
241
Which sex is homogametic in Komodo Dragons
Male (ZZ)
242
Is w+ red or white
So what is w
Red
White
243
3 facts about x linked inheritance in males
For X linked genes, what you see is what you get
Genotype= phenotype
No masking of recessives - X is in a hemizygous state
244
What would breeding a w+/w female fly with a red eyes Male fly
All red eyed daughters
| Half red eyed sons
245
How common are white eyed females and red eyed Males from a W/W female and a W+/Y Male
What would you usually expect
1/2000 (due to aneuploidy)
White eyed female=Xw/Xw/Y
Red eyed Male= Xw+/O
Expect all red eyed females and all white eyed males
246
What is meiotic non disjunction
Unequal segregation of DNA in gametes
247
In the drosophila fly, what determines sex
Number of X chromosomes, NOT the presence of Y
248
Why was XXX never seen in drosophila
It is lethal
249
What determines the presence of the testes
Y
250
What causes Turner’s syndrome
How common is it
45XO (absence of 2nd Sex chromosome)
1/5000
251
What causes Klinefelter’s syndrome
How common is it
47XXY
1/1000
252
What causes XYY Male syndrome
How common
How deadly is this syndrome
47XYY
1/1000
XYY males are clinically normal with normal testosterone, fertility and aggression levels. They may have increased growth velocity
253
3 symptoms of Turner’s syndrome
Webbed neck
Short stature
Infertile
254
What are 4 symptoms of Klinefelter’s syndrome
Often tall and thin
Gynecomastia (with cancer risks
Mild learning impairment
Infertility
255
When can non disjunction lead to sex chromosome aneuploidy
At meiosis I, II, or early cleavage
256
What are the rules of an X linked recessive trait
1. Phenotype/ trait appears in males
2. Mutation never passes from father to son
3. Affected males always pass mutation to daughters who are carriers transmitting to 50% of sons
4. Phenotypes often appear to skip a generation
257
A normal Male procreates with a female whose father had red green colour blindness. What are the chances of any child being a colour blind son
Explain your working
25%
Red-green colour blindness is an X linked recessive trait
50% of father passing on Y and 50% of transmitting mother’s Xcb
.5x.5=.25
258
Name another X linked recessive syndrome (not haemophilia)
Give its incidence and some symptoms
Duchenne muscular dystrophy
1/3600 boys, age of onset ~6
Progressive muscle weakness, degeneration and lethality leading to life expectancy of 25
259
What is the mutation in Duchelle muscular dystrophy
Mutation in Dystrophin, a 2.5Mb gene which codes for a rod shaped cytosolic protein which anchors the membrane to provide cell stability
260
How many types of muscular dystrophy are there
9
261
What is Haemophilia
An X linked recessive syndrome
It is a rare bleeding disorder of compromised coagulation due to a deficiency in clotting factors
262
Give the deficiency, incidence and ethnic group affected by Haemophilia A
Factor VIII deficiency
1/5,000 Male births
All ethnicities
263
Give the deficiency, incidence and ethnic group affected by Haemophilia B
Factor XI deficiency
1:25,000 Male births
All ethnicities
264
What is an obligate carrier
A female clinically unaffected but must be heterozygous for recessive mutation due to family history
265
Give the 3 conditions that would mean a female patient is a obligate carrier of haemophilia
She is biological daughter of a man with haemophilia
She is biological mother of more than one son with haemophilia
She is biological mother of at least one son with haemophilia and has at least one other blood relative with the disease
266
Give an example of an X linked dominant disorder
Rett syndrome
A neurological disorder leading to seizures and inability to speak
267
Why are there no males affected by Rett syndrome
It is early lethal
Girls survive due to X inactivation
268
What are the symptoms of Rett syndrome
How does it usually come about
What gene is associated
Seizures
Stereotypical hand movements
Cannot talk and 50% can’t walk
90% are sporadic
MeCP2 ( a chromatin associated binding protein)
269
What is the key rule for X dominant disorders (in non Male - lethal contexts)
Affected males pass disease/ trait to all female but no male offspring
270
Give 6 points about the anatomy of the Y chromosome
Highly repetitive with a heterochromatic region
Multiple inverted repeats produce palindromes
Gene poor (~1% of diploid genome)
2 regions shared with X so can recombine. These are called pseudoautosomal regions (PARs)
59 million base pairs
60 protein coding genes
271
What were the 4 clues which helped identify the testis determining factor
1. 35kb identified as smallest bit of Y in human XX males with Y translocation
2. This region included a gene called SRY which was mapped to the smallest region of Y known to confer Male-ness
3. SRY was missing in XY female mice
4. Expressed in the somatic cells of the indifferent gonad (before sexual differentiation)
272
How was SRY confirmed to be testis determining factor
What other evidence is there
14kb SRY containing trans gene injectioned into mouse zygotes
This turned females into males
Point mutations in SRY in XY females in humans was also found
273
Tell me about dosage compensation in mammals and in drosophila
Mammals: one of the X chromosomes is inactivated in development in females
Drosophila: both X’s expresses in females, single X has elevated expression in males
274
X inactivation occurs in which species
Placental mammals
275
What are the 3 parts of the Lyon hypothesis
1. Condensed chromosome is genetically inactive
2. X inactivation is random (either paternal or maternal is turned off in females)
3. Stable inheritance of that inactive state to daughter cells
276
Talk about X inactivation in mottled mice
Mottled mutation on the X gives female mice brown and white patches depending on whether the X was activated in those cells
Im males, the mice are unhealthy and do not show mottled colour as they only have 1 X so cannot inactivate
277
Talk about tortoise shell cat
Gene for orange on X
Mutation in orange gene on other X gives “not orange” colour
Some patches of cells have active orange gene others have the orange gene inactivated
278
How is X inactivation initiated
By expression of non coding RNA - Xist
Xist is expressed on the X chromosome that will be inactivated
279
What does expression of Xist do
Triggers hierarchy of epigenetic events - H3K27me3; H3K9me3; DNA methylation
Eventually the inactive X is coated in inactivating chromatin modifications and becomes condensed
280
Can some genes on the inactive X escape inactivation
Yes
PAR 1 and 2 are located at the tips of X and Y and behave like autosomal genes
281
Can non PAR genes escape inactivation
Yes
| 20% of all X genes in humans escape, possibly because some of them have functional homologues on Y
282
What happens if PAR 1 or 2 are haploinsufficient
The contribute to Turner’s syndrome
283
What is the mitotic heritability of methylation
DNA methylation is stable maintained during cell division
284
What 3 essential processes do epigenetic modifications regulate
Functional architecture of chromosomes
Management of repetitive elements and mobile transposons
Contribute to regulation and heritability of gene expression
285
What is the key enzyme in ENA methylation
DNA methyltransferase 1
286
Why can methylation C be dangerous
Methylated cytosine is a potent mutagen and it can easily deaminate to form thymine
287
Which dinucleotide is underrepresented in the genome
Why
Where is this overrepresented
CG
C>T transition
In mutational databases and in CpG islands
288
Why are gene promoters in CoG islands often hypo-methylated
Methylating C could cause a mutation and this would be v bad here
289
Can chromatin markers be stable
Yes
| They can be stable and dynamic
290
4 general rules about a gene that is ‘on’
Active open chromatin
Generally unmethylated
Acetylated histones
H3K4 methylation
291
5 rules about genes that are off
```
Chromatin condensed
C sometimes methylated
Deacetylated histones
H3K9 methylation
H3K27 methylation
```
292
What are the 2 phases that the epigenome undergoes
What do both involve
Germline reprogramming
Early post fertilisation reprogramming
Both involve genome wide erasure and subsequent reestablishment of epigenetic states
293
Describe phase 1 of epigenetic reprogramming
This involves germ cells
As primordial germ cells develop in the embryo all epigenetic marks are erased
The marks are put back on in prospermatogonia phase in males (in the embryo) or in growing oocytes in females (after birth)
294
What is phase 2 of epigenetic remodelling
At adulthood, egg is fertilised by sperm
In newly fertilised egg, marks are lost on both sets of chromosomes
Around implantation, marks come back on both parent ally inherited sets of chromosomes
295
What is genetic imprinting
Genetic reconstruction of mouse embryos indicates functional non equivalence of parental genomes
296
Is being diploid enough to survive
No you need both maternal and paternal set of chromosomes
297
Do maternally inherited chromosomes function differently to paternally inherited ones
Yes - it is a non genetic effect that disobeys Mendel
298
What is an androgenetic zygote
What is the associated event where this occurs in nature? Give details
With 2 paternally inherited sets of chromosomes
Complete hydatidiform mole
Appears as a malignant mass with excessive placental proliferation and no embryonic material
299
What is an ovarian teratoma
Germ cell tumour of the egg
Usually benign
Contains tissue lineages eg bone hair and teeth
Embryo with 2 maternal genomes (parthenogenic 46XX)
300
What is gynogenetic
An embryo with 2 maternal genomes
301
How many genes are imprinted
1%
302
What is uniparental disomy
A gene that is usually turned off in on chromosome is turned on in both chromosomes
303
What is an imprinting disorder that involves a mutation
When a gene is turned off in one chromosome usually but then the same gene on the other chromosome is hit so is non functional meaning the gene isn’t expressed at all
304
What is a cis epigenetic mutation
A sequence mutation that prevents a gene being methylated as it should be
305
What is a trans epimutation
A mutation in the machinery to put methyl on such as in a co factor which helps methyl transferases
This can lead to a paternal to maternal genome type switch due to incorrect methylation
306
Is uniparental isodisomy bad for non imprinting chromosomes
Yes as it can unmask recessive mutations eg cystic fibrosis
307
What is Beckwith Wieldemann syndrome
What is it caused by
What is the biochemistry
Fetal overgrowth disorder with multi organ hyperplasia
Mutation in pUPD11 and can be maternally inherited
Altered dosage of IGF2 and no expression of CDKN1C (cell cycle repressor)
308
What is Prader Willi syndrome caused by
What are the key symptoms
Disruption of imprinting on human chromosome 15 - the defect is loss of paternally expressed imprinted genes
Hyperphagia
Short stature
Hypogonadism
309
Discuss Angelman syndrome
1/25000
Caused by disrupted imprinting on chromosome 15: the defect is a loss of the maternally expressed imprinted gene
Associated with pUPD15
310
6 keys concepts within a imprinted disorder pedigree
Trait maps to autosomes
Males and females equally affected
Males and females can both be carriers
Sex of transmitting parent matters
Skips a generation if parent has mutation in allele to be repressed in offspring (eg if mutation is in a gene expressed in maternal genome but the father is the carrier)
Does not skip if the parent had mutation in allele to be active in offspring
311
What is Developmental origins of adult health and disease
Conditions of mother during pregnancies can have impact on child’s health in adult life
Eg Dutch famine
312
When was the Dutch Famine
What can we learn from it
1944-45
Undernourishment during pregnancy lead to high rates of adult disease
313
What are the critical periods of exposure during the Dutch famine
Early gestation exposure led to normal birth weight but greater incidence of adult onset disease
Later gestation exposure led to low birth weight but lower incidence of obesity as adults
Biggest impact on those conceived during the famine
314
Why were the effect of the Dutch famine different to the siege of Leningrad
Poverty in Leningrad lasted years so babies in utero adapted to poverty and could survive in poverty after birth
The Dutch famine babies adapted to poverty in utero but then went to live with normal nourishment
315
Discuss the trans generational effects of the Dutch famine
Adult offspring of prenatally exposed fathers heavier than unexposed fathers
Adult offspring of prenatally exposed mothers are normal
No adult onset health concerns emerged yet but Average age is 37 so may be too early to tell
316
How genetically identical are mono and dizygotic twins
Monozygotic are genetically identical
Dizygotic are 50% identical
317
Which disease has the highest and lowest discordance rates in monozygotic twins
Colon cancer - most discordant
Schizophrenia- least discordant
318
What does a higher concordance in monozygotic twins than dizygotic twins suggest
Strong genetic factor
Greater MZ:DZ ratio= greater genetic contribution
319
Is there a high genetic factor in Parkinson’s disease
No
MZ:DZ
1.4:1 (ie v close)
320
What does it mean to say mitochondria are dynamic
They can divide, fuse and change shape
321
Do mitochondria contain DNA for all mitochondrial function
No
322
How are mitochondrial diseases inherited
Maternally
323
Do eggs or sperm have more mitochondria
What happens upon fertilisation
Eggs have more
Sperm mitochondria are degraded
324
What is homoplasmy
All mitochondrial are identical
325
What is heteroplasmy
Different strains of mitochondria are present in a cell (normal and mutant)
326
Do the best mitochondria divide the most rapidly
No
Dysfunctional mitochondria tend to accumulate with age
327
What is the endosymbiont theory
Mitochondria were free living cells and taken into the cell in a symbiotic relationship
328
Tell me about mitochondrial DNA
Mitochondria has 2-10 copies of their own circular genomic DNA (16.5kb)
37 genes
13 proteins
22 tRNA
12S and 16S rRNA genes for mitochondrial ribosome
329
How is mitochondrial DNA like that of a prokaryote
No introns
No repeats
95% makes functional gene products
Multigenic transcription
330
How does the pedigree of a mitochondrial disease vary from X linked
Give 2 other facts about this pedigree
All offspring of a mother with the mutation are affected
Males and females both affected
No skipping of a generation
331
What causes intrafamilial variability in mitochondrial disease
Heteroplasmy
332
Which mitochondrial mutation leads to hearing loss
Mutation in 12S rRNA gene
333
Which tissues are most highly affected by mitochondrial disease
What metabolic problem tends to occur
High energy tissue as they have more mitochondria
Lactic acidosis (anaerobic metabolic problems)
334
What causes LHON
Mutation in NADH dehydrogenase
335
What mutation causes MELAS
What about MERRF
Mutation in tRNA for Leu
Mutation in tRNA Lys
336
What is Kearns Sayre syndrome
Multiple genes lost through a mitochondrial DNA deletion
337
2 ways to prevent mitochondrial disease
Pronuclear transfer and spindle transfer
338
Describe pronuclear transfer
Egg from Mother with mitochondrial disease is fertilised via IVF then the nucleus (and genetic information) is removed and fused with an enucleated donor zygote with normal mitochondria
339
How does Spindle transfer work to prevent mitochondrial disease
Affected Mother’s egg’s nucleus is removed and inserted into an unfertilised enucleated donor with normal mitochondria
This is then fertilised by father
340
Is it legal to edit genes In Embryos
Yes but only in culture for 7 days
For research purposes - NOT CLINICAL APPLICATION
Aim is to improve IVF success rate and early human genes in development
341
True or false
Most 45X conceptuses result in a live birth
False
| Fewer than one survive
342
2 things that inhibit PFK1
Citrate
| ATP
343
Which system repairs dsDNA breaks in G0 and G1
Which system repairs dodgy replication forks
NHEJ
HR
344
What is a micro satellite
And category of genetic marker comprising repeats of 1–5 nucleotides in length
345
What is Kennedy disease related to
A translated CAG triplet repeat expansion within the sequence of a X-linked hormone receptor
346
What does the hardy Weinberg equation allow
Discovery of genotype frequencies if you know phenotype frequencies
