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MIMS > Genetics > Flashcards

Genetics Flashcards

1
Q

Are any diseases purely genetic

A

Single mutation diseases

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2
Q

Is cancer environmental or genetic

What about complex genetic diseases

A

Can be Both

Also both genetic and environmental

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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

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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

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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

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6
Q

Can de novo mutations be hemizygous

A

Yes if they involve sex chromosomes

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7
Q

What causes Apert syndrome

A

Ser -> Trp mutation in FGFR2

Increases signalling

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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

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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

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10
Q

What are many miscarriages causes by

A

The presence of de novo mutations that are incompatible with embryo development

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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

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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

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13
Q

What are the 4 patterns of inheriting an inherited single mutation disease

A

Autosomal dominant
Autosomal recessive
Sex linked
Mitochondrial

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14
Q

What is the chance of inheriting a dominant autosomal disease of 1 parent is affected

A

50%

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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)

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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

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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.

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18
Q

Give an example of transheterozygotes

A

Albinism

2 disease causing loci in same gene present in a population

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19
Q

Name a gene associated with albinism

Which alleles have been found

A

OCA

Missense
Nonsense
Frameshift

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20
Q

what causes Ellis van Creveld syndrome

Where is it common

A

Caused by a splice site mutation in EVC

Amish populations

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21
Q

What causes xeroderma pigmentosum

A

SNV or Indel mutation in NER machinery

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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

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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

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24
Q

How many heterozygous recessive alleles do humans ja our that would be highly deleterious if homozygous

A

~0.6

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25
Q

Which populations are most at risk of autosomal recessive disease

A

Populations with high rates of consanguinity

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26
Q

What is reduced penetrance

A

When the same mutation causes disease in one individual but not in another individual

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27
Q

Give an example of reduced penetrance

A

Phenylketonuria (PKU)

autosomal recessive
Decreased metabolism of phenylalanine
Causes intellectual disability, seizures and mental disorders

Can be treated by low phenylalanine diet

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28
Q

What is variable expressivity

A

Same mutation

Severe symptoms in one patient but mild in another

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29
Q

What is a medical geneticist

A

Diagnose genetic conditions

Counsel couples about the implications of the diagnosis

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30
Q

What is SMA

A

Spinal muscular atrophy

An autosomal recessive neurodegenerative disorder caused by mutations in SMN1 and SMN2

Splice site mutation
Exon skipping leading to protein truncation

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31
Q

Difference between germline variation and somatic variation

A

Germline occurs in cells of the germ cell lineage and are inherited

Somatic = in somatic cells and is private to individual

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32
Q

What is a mosaic

A

An individual composed of cells with multiple different genotypes due to genetic variation that arose since development from fertilised egg

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33
Q

What is mosaic Down syndrome

A

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

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34
Q

What is McCune Albright syndrome

A

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

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35
Q

What is a clone

A

A set of cells with a common origin

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36
Q

What is germline mosaicism

A

If it is involved in germline lineage

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37
Q

Why may it be difficult to diagnose mosaics

A

Not all cells contain mutation so sample of cells may miss it

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38
Q

Name the 4 key types of disease

A

Single mutation diseases
Complex genetic diseases
Cancer
Infectious diseases

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39
Q

Do single mutation diseases have an environmental contribution

A

Very little if any

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40
Q

How much of cancer is environmental factors and how much is genetic

A

Can be both or mostly one or the other (spectrum)

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41
Q

What is a karyotype

A

The set of chromosomes for a particular individual or specifies

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42
Q

What kind of karyotype do mammals have

A

Diploid

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43
Q

In the dog karyotype, 2n=

A

78

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44
Q

How many chromosomes in the Tasmanian devil karyotype

A

14

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45
Q

How many bases are in a human genome

How many base pairs is this

A
  1. 1 Gb

3. 1x10^9

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46
Q

How much of DNA is coding

A

1-2%

These are exons

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47
Q

What is a reference genome

What is the human reference genome

A

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

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48
Q

How much DNA is selected for each reference genome

A

1 strand (5’ to 3’)

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49
Q

What is the genome coordinate
chr1:23,786,987
Referring to

A

A position of chromosome 1, the 23,786,987th base on chromosome 1

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50
Q

What are the 4 classes of genome variation

A

Single Nucleotide Variants
Small insertions and deletions (indels)
Structural variation
Cytogenetic variation

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51
Q

What is a locus

A

A position in the genome

Each locus can have different genetic variants or alleles

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52
Q

What is linkage disequilibrium

A

When two loci are close together in the genome and are frequently inherited together

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53
Q

What is a point mutation

A

The same as a SNV or substitution

When a single nucleotide is changed for another

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54
Q

In a C>T variant, which is the reference and which is the alternative allele

A

C is reference

T is alternative

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55
Q

Why is a C>T variant the same as a G>A variant

A

One is referring to the reference strand the other is the same SNV from the non reference strand

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56
Q

What are the 6 types of SNV

A 
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
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57
Q

What is a transition

A

Purine to purine or Pyrimidine to Pyrimidine

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58
Q

What is a transversion

A

A purine to Pyrimidine or vice versa

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59
Q

What is the mutation spectrum

A

The proportion of each SNV type in a given sample

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60
Q

Which SNV is common in melanoma

A

C>T or G>At

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61
Q

2 ways to cause an SNV

A

Exogenous mutational exposures

Endogenous mutational processes

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62
Q

5 exogenous exposures

A 
UV
Cigarettes
Chemotherapy 
Aristolochic acid
Aflatoxin
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63
Q

What mutations does UV cause

A

Pyrimidine dimers

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64
Q

What is the key mutational element in cigs

A

Benzo [a] pyrene

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65
Q

Give an example of the an endogenous mutational process

What else may cause an endogenous mutational process

A

Spontaneous deamination of 5-methylcytosine

Replication errors

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66
Q

Where do most SNVs occur

A

Non coding regions

Therefore have little effect on the cell

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67
Q

Give an example of a SNV that causes disease

A

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

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68
Q

3 ways to repair SNV damage

A

Base excision repair
Nucleotide excision repair
Mismatch repair

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69
Q

Xeroderma pigmentosum is caused by SNVs in what component

A

NER

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70
Q

What is an indel

A

An insertion or deletion <100bp in length

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71
Q

What are indels caused by

A

Polymerase slippage during DNA replication (usually endogenous)

Eg accidental hairpins

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72
Q

What causes Huntington’s disease

A

Indels - CAG repeats

The mutated protein is toxic to some parts of the brain

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73
Q

What about of CAG repeats is required for Huntington’s

A

<35 repeats = not diseased
36-39= may be affected
40+= affected

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74
Q

How do indels affect BRCA1

A

Insertion of a C

Leads to increased risk of breast and ovarian cancer

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75
Q

What kind of repair is usually responsible for repairing indels

A

Mismatch repair (MMR)

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76
Q

Which indels do we see

A

Those that have not been correctly repaired

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77
Q

What are structural variants

A

Genomic rearrangements

Large scale DNA mutations that juxtapose DNA that was previously not connected

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78
Q

3 types of structural variant mutations

A

Inter chromosomal
Intra chromosomal
Involving exogenous DNA

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79
Q

What kind of DNA break do structural variants usually involve

A

DSB

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80
Q

2 overall types of structural variants

A

Balanced and unbalanced

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81
Q

What is a balanced structural variant

A

Overall amount of DNA remains constant

Also know as balanced translocations

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82
Q

What is a unbalanced structural variant

A

DNA is gained or lost

These lead to copy number variants

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83
Q

Give an example of a balanced translocation

A

The Philadelphia chromosome in chronic myeloid leukaemia

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84
Q

3 ways to cause copy number variants

A

Rearrangements in the genome causing gain or loss of host DNA

Integration of transposable elements

Integration of virus DNA

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85
Q

Name a disease associated with chromosome 22

A

22q11.2 deletion syndrome

(When chromosome 22 has q11.2 deleted)

Leads to intellectual disabilities, developmental defects and a susceptibility to psychiatric illness

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86
Q

What is 22q11.2 deletion syndrome an example of

A

An unbalanced structural variant caused by rearrangements in the genome causing gain or loss of host DNA

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87
Q

What are transposable elements

A

Virus like DNA elements encoded within genomes

They replicate themselves and insert into the genome, causing structural variant mutations

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88
Q

Give an example of a disease caused by transposable element insertion

A

Merle dogs - beautiful coats but have a range of hearing and sight problems due to transposable element insertion into the SILV gene

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89
Q

What kind of virus integrates into DNA

A

Retroviruses eg HIV

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90
Q

Give an example of non integrating viruses

A

Papillomaviruses

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91
Q

How do integrating viruses work

A

They permanently integrate into the host DNA as part of their life cycle and can cause disease causing mutations

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92
Q

What is Fr-MLV

A

Friend murine leukaemia virus

An integrating virus

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93
Q

Do non retroviruses integrate into host genome

A

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

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94
Q

What kind of break results from ionising radiation

A

Double stranded DNA breaks

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95
Q

4 endogenous causes of structural variants

A

Replication fork failure and collapse
Telomere shortening
Aberrant homologous recombination
Transposable element insertion

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96
Q

What is cytogenetic variation

What does it lead to

A

The gain or loss of one or more entire chromosomes

Aneuploidy

It leads to the production of copy number variants

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97
Q

What is aneuploidy

Give an example

A

The presence of an abnormal number of chromosomes in the cell

Trisomy 21 - Causes Down Syndrome

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98
Q

Cancers are rarely aneuploid. True or false.

A

False

Most cancers are aneuploid

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99
Q

Are some cancers tetraploid?

A

Yes

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100
Q

What can cause cytogenetic variation

A

Segregation errors

Whole genome duplication

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101
Q

What are segregation errors

A

When the incorrect number of chromosomes are in the daughter cells (eg 47 in one and 45 in the other)

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102
Q

Why may whole genome duplication occur

What is this called

A

When a cell goes through S phase but does not proceed through M phase

Endoreduplication

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103
Q

What can prevent aneuploidy

A

Cellular checkpoints such as the spindle assembly checkpoint

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104
Q

How can we identify genome variation

A

Whole genome sequencing

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105
Q

How do we do whole genome sequencing

A 
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
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106
Q

Can somatic cells contribute to the next generation

A

No

Germ cells contribute to the next generation

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107
Q

What is germline and somatic variation important for respectively

A

Germline: inherited genetic disease
Somatic: cancer and ageing

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108
Q

Which sex acquire more genetic variation

Why

A

Male

Males undergo more cell divisions before birth (~24 compared to the 20 in females)

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109
Q

When are germ cells specified

A

In 2 week embryo

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110
Q

What happens to germ cells between birth and puberty

A

Nothing much

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111
Q

What happens to males at puberty

A

Spermatogonial stem cells begin replicating to produce a mature sperm

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112
Q

How many replications do spermatogonial stem cells undergo before becoming mature sperm

How many differentiation replications are there?

A

~23 replications per year

4 differentiation replications

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113
Q

How many replications are there to the oocyte

A

None

the immature oocyte simply mature’s each month and completes meiosis

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114
Q

How many replications has a mature oocyte gone through since conception

A

30

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115
Q

How many replications has a mature sperm gone through since conception

Why is this important

A

383 (in a 30 year old)

Higher rate of de novo mutation
Number of SNV mutations increase with male’s age at conception

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116
Q

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?

A

70-80%

50-100
It’s dependant on father’s age

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117
Q

Where do trisomy mutations tend to originate from

A

Maternal germline

Increases with maternal age

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118
Q

Why might trisomy not be passed on by males

A

Competition between sperm may eliminate it

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119
Q

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

A

50%

There are millions of sperm from millions of spermatogonial stem cells

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120
Q

Every sperm will have a germ line variant. True or false?

A

True

Each spermatogonial stem cell has its own mutations

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121
Q

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

A

All of them

No only 50% of gametes will have this variant (as meiosis occurs here not mitosis)

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122
Q

How many variants are there between 2 unrelated people

A

3 million variants

~1 per 1000bp

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123
Q

Why can germ line variants be useful for anthropology

A

We can look at frequency of variants and look at genetic history

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124
Q

What determines if a new variant “makes it”?

A

Genetic drift

Selection

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125
Q

What is genetic drift

A

Change in frequency of alleles in population due to chance

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126
Q

Why is genetic drift relevant to disease

A

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)

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127
Q

Genetic drift is particularly important for large populations. True or false?

A

False

It is particularly important for small generations

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128
Q

What is a bottle neck

A

When a population is drastically reduced in size. If the population subsequently recovers, all individuals will derive from a small number of ancestors

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129
Q

What is the founder effect

A

When a small number of individuals found a new colony etc and all individuals will derive from a small number of ancestors

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130
Q

Give an example of the founder effect

A

Ellis Van Creveld syndrome
Common in Amish community
(Polydactyl)

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131
Q

Most variants have a phenotype. True or false.

A

False

Most genetic variants are neutral with respect to the cell, very rarely do they alter the functioning of the cell

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132
Q

When can selection act

A

When a phenotype is present

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133
Q

What is selection

A

A change in frequency of a variant in a population due to a change in fitness

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134
Q

What are the 2 types of variant that lead to a change in phenotype

A

Coding variant- leads to a change in protein

Non coding variants and copy number variants: cause changes in the amount of protein produced

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135
Q

What is a missense variant

What is this found in

A

A single change in an amino acid in a protein

BRAF

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136
Q

What is a nonsense variant

A

Creates a termination codon leading to a protein truncation

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137
Q

What is an in frame deletion or insertion

Give an example

A

Insertion or deletion of 3 or a multiple of 3 base pairs

Huntington’s

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138
Q

What is a frame shift

A

Indel of non multiple of 3 length

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139
Q

What is splicing

A

Exon skipping and leads to protein truncation

140
Q

What is gene fusion

A

A mutation when 2 genes fuse such as in BCR-ABL fusion in CML
Diagnostic of Philadelphia chromosome

This must be in frame

141
Q

What can structural variant rearrangement lead to

A

Gene truncation

142
Q

What is a variant in promoters or enhancers

A

Affects amount of protein produced

Eg TERT promoter variant in malignant melanomas

143
Q

Discuss TERT promoter variant

A

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
Q

Is trisomy 21

A

When there are 3 copies of chromosome 21. Associated with Down syndrome

145
Q

It is the phenotype that is dominant or recessive. True or false?

A

True

146
Q

Define dominant and recessive

A

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
Q

Name a syndrome that is a dominant variant

A

Alert syndrome
Due to 1 copy variant in the FGFR2
C>G
Ser>Trp

148
Q

Give an example of a disease caused by a dominant mutation

A

BRAF

Only one variant needed to predispose for malignant melanoma

149
Q

Name a recessive variant syndrome

A

Ellis Van Creveld syndrome

150
Q

Give an example of co-dominance

A

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
Q

What are the 2 types of selection

Define them

A

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
Q

What is purifying selection

A

AKA negative selection

153
Q

What types of fitness advantage are there

A

Adaptive
Selfish
Artificial

154
Q

What is adaptive positive selections

Give an example

A

Causes individuals to be better adapted to its environment

Homozygous CCR5 mutation means no HIV immunity As CCR5 is a receptor for HIV

155
Q

What is selfish positive selection

A

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
Q

Give an example of selfish selection

A

FGFR2
C>G —> causes spermatogonial stem cells to divide more than neighbouring cells
Also causes Apert syndrome

Also cancer is a classic example

157
Q

Give an example of artificial positive selection

A

Selecting for dog breeds

158
Q

When does negative selection work

A

Before birth

During reproductive lifespan

159
Q

When does negative selection act before birth

A

Trisomies

Other trisomies are not compatible with birth so embryo does not develop

160
Q

Give an example of negative selection during the reproductive life span

A

Y chromosome microdeletions

Leads to azospermia and infertility

161
Q

When is negative selection weak

A

If the phenotype manifests after reproductive senescence

Eg Parkinson’s

162
Q

What is balancing selection

A

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
Q

Why is there positive and negative selection acting on the same alleles in bulldogs

A

Artificial positive selection for their big heads

Negative selection against the big heads during parturition

164
Q

Give an example of selection based on environment in humans

A

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
Q

Give an example of when drift overcomes selection

A

Bernese Mountain Dogs

CDKN2A - high frequency of hisiocytic sarcoma

166
Q

Why does genetic drift not really affect de novo mutations

A

De novo dont usually occur in more than one individual

167
Q

Are de novo diseases dominant

A

Yes

168
Q

Does genetic drift affect autosomal dominant diseases

A

Yes drift is important

Eg high frequency of BRCA1 in Ashkenazi population

169
Q

What may cause reduced penetrance

A

Accumulation of additional somatic variants
Mosaicism
Variable copy number of a mitochondrial disease haplotype
Genetic background
Epigenetic factors
Environmental factors

170
Q

What are GRIN1 mutations associated with

A

De novo mutations in GRIN1 chase intellectual disability and seizures

171
Q

Why is a knowledge of the genetic basis of disease important

A

Diagnosis
Prognosis
Further understanding of biological basis of disease
Genetic counselling, pre implantation screening and embryo modification
Animal breeding
Therapy

172
Q

What is pre-implantation screening

A

Check which embryos are affected and select unaffected embryos

173
Q

What is a mosaic

A

An individual composed of cells with multiple different genotypes, due to genetic variants that arose since development from the fertilised egg

174
Q

How many mutations are there per diploid genome per cell division

A

2-10

175
Q

When can de novo mutations occur

A

at any point during embryonic development or during childhood or adult life

176
Q

What is Mosaic Down Syndrome

A

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
Q

Name a de novo mutation disease that only occurs as a mosaic

A

McCune Albright Syndrome

178
Q

What causes McCune Albright syndrome

A

A mutation in the GNAS gene during embryological development

179
Q

Why can McCune Albright syndrome only occur as a mosaic

A

GNAS mutations in all cells is not compatible with life

180
Q

What symptoms can you get from McCune Albright syndrome

A

Bone and endocrine abnormalities

Cafe au lait spots

181
Q

What do the café au lait spots in McCune Albright syndrome show

A

They define the clones of the affected skin cells

182
Q

What is the difference between germline and somatic mosaicism I

A

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
Q

When must a mutation occur to cause germline mosaicism

Why is this

A

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
Q

Why is mosaicism difficult to diagnose

A

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
Q

How many cells does a cancer arise from

A

One somatic cell - it is clonal

186
Q

What does malignant mean

A

Has the ability to invade host tissues and potentially metastasise

187
Q

What kind of selection is the process underlying cancer

A

Selfish positive selection

188
Q

What do you call somatic mutations that confer phenotypes on which selfish positive selection acts

A

Driver mutations

189
Q

How many cancer genes do we know of currently

A

723

190
Q

2 kinds of cancer gene

A

Dominant acting (oncogene)

Recessive acting (tumour suppressor genes)

191
Q

Name a driver mutation in malignant melanoma

A

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
Q

BRAF is a recessively acting cancer gene. True or false?

A

False

It is an oncogene and therefore dominantly acting

193
Q

What is the most common driver mutation in BRAF

A

An SNV that causes a missense mutation

194
Q

What does the Philadelphia chromosome cause

Is this a driver mutation

A

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
Q

What is ABL1

What about when the Philadelphia chromosome comes along

A

A kinase which normally phosphorylates only when specifically activated

BCR-ABL1 fusion is always on, even in the absence of upstream signals

196
Q

What are double minutes

What can they lead to

A

Tiny circular DNA elements created by unbalanced structural variants

Massive copy number variants

197
Q

Is MYC dominant or recessive

A

Dominantly acting cancer gene

198
Q

What is HPV

A

Human Papillomavirus

An non integrating virus

199
Q

What genes does HPV encodes

What does this do

A

E6 and E7

Stimulates the cell to enter the cell cycle

200
Q

Why is it advantageous for HPV to encode E6 and E7 genes

Does this cause cancer

A

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
Q

Why may HPV cause cancer

A

E6 and E7 May insert as a structural variant so that they are highly expressed, this predisposes to cancer

202
Q

What is P53

How does it usually work

A

A tumour suppressor

It detects cellular stress and DNA damage and in response causes cell cycle inhibition, apoptosis, DNA repair, and senescence

203
Q

How many copies of P53 must be damaged to confer positive selection advantage to cancer

A

Both copies of P53

204
Q

Name a recessively acting cancer gene

A

PTEN

205
Q

What happens if PTEN is lost

How many copies need to be lost to predispose cancer

A

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
Q

Will a positively selected driver mutation in one cell type be positively selected in all cell types?

A

No it depends on the cell context - each somatic cell type has its own unique biology

207
Q

Do Philadelphia chromosome rearrangements always cause cancer

A

BCR-ABL1 is only found in CML

but Philadelphia chromosome rearrangements likely occur in other somatic cells but aren’t positively selected

208
Q

How many driver mutations are required to cause cancer

A

1-10

209
Q

Which cancers only require 1 driver mutation

A

Sarcomas and leukaemias/ lymphomas especially in paediatric cases tend to require a small number of driver mutations

210
Q

Which cancers require more driver mutations

A

Carcinomas (epithelial cancers)

211
Q

Which cancers are most common in humans

A

Carcinomas - those derived from epithelial cells

212
Q

Demonstrate how the incidence of cancers is different between humans and dogs

A

Sarcomas are rare in humans but relatively common in dogs

213
Q

How likely are you to get small and large intestine cancers

A

Small - very rare

Larger - one of the most common cancers

214
Q

True or false: large intestine cancer is very common in dogs

A

False

Large intestine cancer is very rare in dogs

215
Q

How can we treat Philadelphia chromosome rearrangements

A

The BRC-ABL1 fusion can be blocked by Imantinib

216
Q

What is another name for Imantinib

A

Gleevec

This drug can lead to long lasting remission from CML

217
Q

Which drug specifically inhibits BRAF V600E

A

Vemurafenib

218
Q

3 things that increase risk of somatic mutation

A

Age
Exogenous
Germline inheritance of variants that increase risk of somatic mutations

219
Q

How many somatic mutations can be found in a cancer

A

Several thousand but these are mostly passenger mutations

220
Q

What is a passenger mutation

A

Somatic mutations that are not under positive selection

221
Q

How is BRCA1 usually repaired

What happens if this is absent

A

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
Q

BCRA1 is a tumour suppressor gene. True or false?

A

True it is a recessively acting cancer gene

223
Q

What are HR deficient cancers sensitive to

A

PARP inhibitors

224
Q

What can happen to breast cancers treated by PARP inhibitors

A

Wild type BRCA1 is positively selected and it is resistant to PARP inhibitors

225
Q

Can something increase the risk of cancer without increasing risk of somatic mutations?

A

Yes: asbestos, obesity, etc

226
Q

What can be seen in the genetics of tumours of transmissible cancers

A

They have the exact same mutations - identical genome

227
Q

How may transmissible cancer be spread between Devils

A

Biting during mating season, whereby the cancer cells slough off one devil onto the other

228
Q

What is chimerism

Give a day to day example of this

A

The presence of cells derived from 2 different individuals within the same body

Pregnant female

229
Q

What is tetragametic chimerism

A

When 2 zygotes (fraternal twins) fuse at an early stage of embryonic development

230
Q

Why can tetragametic chimerism occur

A

At the early fusion stage, the immune system hasn’t fully developed so cannot detect self and non self

231
Q

How is karyotype usually displayed

A

As an organised arrangement of all the chromosomes within a cell in
metaphase stage

232
Q

What is an autosome

A

Non-sex chromosome

233
Q

Does karyotype vary between sexes

A

Yes due to sex chromosomes

234
Q

What is G banding

A

A Giemsa staining method used to generate a useful karyotype and identify condensed and open regions of a chromatin

235
Q

What does haploid mean

A

Containing one half of each pair of chromosomes

236
Q

Do all animals have the same sex chromosome system

A

No humans have the XY determining system whereas other animals use the ZW system

237
Q

True or false

Males are heterozygous for the X

A

False they are hemizygous - they only have 1 copy

238
Q

How is dosage compensation between mammalian sexes achieved

A

Deactivation of the 2nd female X

239
Q

Which is the heterogametic sex in humans

A

Male (XY)

Females are homogametic

240
Q

What are the gametes like like birds

A

Female - ZW
Male - ZZ

males are the homogametic sex

241
Q

Which sex is homogametic in Komodo Dragons

A

Male (ZZ)

242
Q

Is w+ red or white

So what is w

A

Red

White

243
Q

3 facts about x linked inheritance in males

A

For X linked genes, what you see is what you get

Genotype= phenotype

No masking of recessives - X is in a hemizygous state

244
Q

What would breeding a w+/w female fly with a red eyes Male fly

A

All red eyed daughters

Half red eyed sons

245
Q

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

A

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
Q

What is meiotic non disjunction

A

Unequal segregation of DNA in gametes

247
Q

In the drosophila fly, what determines sex

A

Number of X chromosomes, NOT the presence of Y

248
Q

Why was XXX never seen in drosophila

A

It is lethal

249
Q

What determines the presence of the testes

A

Y

250
Q

What causes Turner’s syndrome

How common is it

A

45XO (absence of 2nd Sex chromosome)

1/5000

251
Q

What causes Klinefelter’s syndrome

How common is it

A

47XXY

1/1000

252
Q

What causes XYY Male syndrome

How common

How deadly is this syndrome

A

47XYY

1/1000

XYY males are clinically normal with normal testosterone, fertility and aggression levels. They may have increased growth velocity

253
Q

3 symptoms of Turner’s syndrome

A

Webbed neck
Short stature
Infertile

254
Q

What are 4 symptoms of Klinefelter’s syndrome

A

Often tall and thin
Gynecomastia (with cancer risks
Mild learning impairment
Infertility

255
Q

When can non disjunction lead to sex chromosome aneuploidy

A

At meiosis I, II, or early cleavage

256
Q

What are the rules of an X linked recessive trait

A
  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
Q

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

A

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
Q

Name another X linked recessive syndrome (not haemophilia)

Give its incidence and some symptoms

A

Duchenne muscular dystrophy

1/3600 boys, age of onset ~6

Progressive muscle weakness, degeneration and lethality leading to life expectancy of 25

259
Q

What is the mutation in Duchelle muscular dystrophy

A

Mutation in Dystrophin, a 2.5Mb gene which codes for a rod shaped cytosolic protein which anchors the membrane to provide cell stability

260
Q

How many types of muscular dystrophy are there

A

9

261
Q

What is Haemophilia

A

An X linked recessive syndrome

It is a rare bleeding disorder of compromised coagulation due to a deficiency in clotting factors

262
Q

Give the deficiency, incidence and ethnic group affected by Haemophilia A

A

Factor VIII deficiency
1/5,000 Male births
All ethnicities

263
Q

Give the deficiency, incidence and ethnic group affected by Haemophilia B

A

Factor XI deficiency
1:25,000 Male births
All ethnicities

264
Q

What is an obligate carrier

A

A female clinically unaffected but must be heterozygous for recessive mutation due to family history

265
Q

Give the 3 conditions that would mean a female patient is a obligate carrier of haemophilia

A

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
Q

Give an example of an X linked dominant disorder

A

Rett syndrome

A neurological disorder leading to seizures and inability to speak

267
Q

Why are there no males affected by Rett syndrome

A

It is early lethal

Girls survive due to X inactivation

268
Q

What are the symptoms of Rett syndrome

How does it usually come about

What gene is associated

A

Seizures
Stereotypical hand movements
Cannot talk and 50% can’t walk

90% are sporadic

MeCP2 ( a chromatin associated binding protein)

269
Q

What is the key rule for X dominant disorders (in non Male - lethal contexts)

A

Affected males pass disease/ trait to all female but no male offspring

270
Q

Give 6 points about the anatomy of the Y chromosome

A

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
Q

What were the 4 clues which helped identify the testis determining factor

A
  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
Q

How was SRY confirmed to be testis determining factor

What other evidence is there

A

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
Q

Tell me about dosage compensation in mammals and in drosophila

A

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
Q

X inactivation occurs in which species

A

Placental mammals

275
Q

What are the 3 parts of the Lyon hypothesis

A
  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
Q

Talk about X inactivation in mottled mice

A

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
Q

Talk about tortoise shell cat

A

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
Q

How is X inactivation initiated

A

By expression of non coding RNA - Xist

Xist is expressed on the X chromosome that will be inactivated

279
Q

What does expression of Xist do

A

Triggers hierarchy of epigenetic events - H3K27me3; H3K9me3; DNA methylation

Eventually the inactive X is coated in inactivating chromatin modifications and becomes condensed

280
Q

Can some genes on the inactive X escape inactivation

A

Yes

PAR 1 and 2 are located at the tips of X and Y and behave like autosomal genes

281
Q

Can non PAR genes escape inactivation

A

Yes

20% of all X genes in humans escape, possibly because some of them have functional homologues on Y

282
Q

What happens if PAR 1 or 2 are haploinsufficient

A

The contribute to Turner’s syndrome

283
Q

What is the mitotic heritability of methylation

A

DNA methylation is stable maintained during cell division

284
Q

What 3 essential processes do epigenetic modifications regulate

A

Functional architecture of chromosomes

Management of repetitive elements and mobile transposons

Contribute to regulation and heritability of gene expression

285
Q

What is the key enzyme in ENA methylation

A

DNA methyltransferase 1

286
Q

Why can methylation C be dangerous

A

Methylated cytosine is a potent mutagen and it can easily deaminate to form thymine

287
Q

Which dinucleotide is underrepresented in the genome

Why

Where is this overrepresented

A

CG

C>T transition

In mutational databases and in CpG islands

288
Q

Why are gene promoters in CoG islands often hypo-methylated

A

Methylating C could cause a mutation and this would be v bad here

289
Q

Can chromatin markers be stable

A

Yes

They can be stable and dynamic

290
Q

4 general rules about a gene that is ‘on’

A

Active open chromatin
Generally unmethylated
Acetylated histones
H3K4 methylation

291
Q

5 rules about genes that are off

A 
Chromatin condensed
C sometimes methylated
Deacetylated histones
H3K9 methylation
H3K27 methylation
292
Q

What are the 2 phases that the epigenome undergoes

What do both involve

A

Germline reprogramming

Early post fertilisation reprogramming

Both involve genome wide erasure and subsequent reestablishment of epigenetic states

293
Q

Describe phase 1 of epigenetic reprogramming

A

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
Q

What is phase 2 of epigenetic remodelling

A

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
Q

What is genetic imprinting

A

Genetic reconstruction of mouse embryos indicates functional non equivalence of parental genomes

296
Q

Is being diploid enough to survive

A

No you need both maternal and paternal set of chromosomes

297
Q

Do maternally inherited chromosomes function differently to paternally inherited ones

A

Yes - it is a non genetic effect that disobeys Mendel

298
Q

What is an androgenetic zygote

What is the associated event where this occurs in nature? Give details

A

With 2 paternally inherited sets of chromosomes

Complete hydatidiform mole
Appears as a malignant mass with excessive placental proliferation and no embryonic material

299
Q

What is an ovarian teratoma

A

Germ cell tumour of the egg
Usually benign
Contains tissue lineages eg bone hair and teeth

Embryo with 2 maternal genomes (parthenogenic 46XX)

300
Q

What is gynogenetic

A

An embryo with 2 maternal genomes

301
Q

How many genes are imprinted

A

1%

302
Q

What is uniparental disomy

A

A gene that is usually turned off in on chromosome is turned on in both chromosomes

303
Q

What is an imprinting disorder that involves a mutation

A

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
Q

What is a cis epigenetic mutation

A

A sequence mutation that prevents a gene being methylated as it should be

305
Q

What is a trans epimutation

A

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
Q

Is uniparental isodisomy bad for non imprinting chromosomes

A

Yes as it can unmask recessive mutations eg cystic fibrosis

307
Q

What is Beckwith Wieldemann syndrome

What is it caused by

What is the biochemistry

A

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
Q

What is Prader Willi syndrome caused by

What are the key symptoms

A

Disruption of imprinting on human chromosome 15 - the defect is loss of paternally expressed imprinted genes

Hyperphagia
Short stature
Hypogonadism

309
Q

Discuss Angelman syndrome

A

1/25000

Caused by disrupted imprinting on chromosome 15: the defect is a loss of the maternally expressed imprinted gene

Associated with pUPD15

310
Q

6 keys concepts within a imprinted disorder pedigree

A

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
Q

What is Developmental origins of adult health and disease

A

Conditions of mother during pregnancies can have impact on child’s health in adult life

Eg Dutch famine

312
Q

When was the Dutch Famine

What can we learn from it

A

1944-45

Undernourishment during pregnancy lead to high rates of adult disease

313
Q

What are the critical periods of exposure during the Dutch famine

A

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
Q

Why were the effect of the Dutch famine different to the siege of Leningrad

A

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
Q

Discuss the trans generational effects of the Dutch famine

A

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
Q

How genetically identical are mono and dizygotic twins

A

Monozygotic are genetically identical

Dizygotic are 50% identical

317
Q

Which disease has the highest and lowest discordance rates in monozygotic twins

A

Colon cancer - most discordant

Schizophrenia- least discordant

318
Q

What does a higher concordance in monozygotic twins than dizygotic twins suggest

A

Strong genetic factor

Greater MZ:DZ ratio= greater genetic contribution

319
Q

Is there a high genetic factor in Parkinson’s disease

A

No

MZ:DZ
1.4:1 (ie v close)

320
Q

What does it mean to say mitochondria are dynamic

A

They can divide, fuse and change shape

321
Q

Do mitochondria contain DNA for all mitochondrial function

A

No

322
Q

How are mitochondrial diseases inherited

A

Maternally

323
Q

Do eggs or sperm have more mitochondria

What happens upon fertilisation

A

Eggs have more

Sperm mitochondria are degraded

324
Q

What is homoplasmy

A

All mitochondrial are identical

325
Q

What is heteroplasmy

A

Different strains of mitochondria are present in a cell (normal and mutant)

326
Q

Do the best mitochondria divide the most rapidly

A

No

Dysfunctional mitochondria tend to accumulate with age

327
Q

What is the endosymbiont theory

A

Mitochondria were free living cells and taken into the cell in a symbiotic relationship

328
Q

Tell me about mitochondrial DNA

A

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
Q

How is mitochondrial DNA like that of a prokaryote

A

No introns
No repeats
95% makes functional gene products
Multigenic transcription

330
Q

How does the pedigree of a mitochondrial disease vary from X linked

Give 2 other facts about this pedigree

A

All offspring of a mother with the mutation are affected

Males and females both affected
No skipping of a generation

331
Q

What causes intrafamilial variability in mitochondrial disease

A

Heteroplasmy

332
Q

Which mitochondrial mutation leads to hearing loss

A

Mutation in 12S rRNA gene

333
Q

Which tissues are most highly affected by mitochondrial disease

What metabolic problem tends to occur

A

High energy tissue as they have more mitochondria

Lactic acidosis (anaerobic metabolic problems)

334
Q

What causes LHON

A

Mutation in NADH dehydrogenase

335
Q

What mutation causes MELAS

What about MERRF

A

Mutation in tRNA for Leu

Mutation in tRNA Lys

336
Q

What is Kearns Sayre syndrome

A

Multiple genes lost through a mitochondrial DNA deletion

337
Q

2 ways to prevent mitochondrial disease

A

Pronuclear transfer and spindle transfer

338
Q

Describe pronuclear transfer

A

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
Q

How does Spindle transfer work to prevent mitochondrial disease

A

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
Q

Is it legal to edit genes In Embryos

A

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
Q

True or false

Most 45X conceptuses result in a live birth

A

False

Fewer than one survive

342
Q

2 things that inhibit PFK1

A

Citrate

ATP

343
Q

Which system repairs dsDNA breaks in G0 and G1

Which system repairs dodgy replication forks

A

NHEJ

HR

344
Q

What is a micro satellite

A

And category of genetic marker comprising repeats of 1–5 nucleotides in length

345
Q

What is Kennedy disease related to

A

A translated CAG triplet repeat expansion within the sequence of a X-linked hormone receptor

346
Q

What does the hardy Weinberg equation allow

A

Discovery of genotype frequencies if you know phenotype frequencies

MIMS (12 decks)

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