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CELS 191 > Human Molecular Genetics > Flashcards

Human Molecular Genetics Flashcards

1
Q

Why was the human genome sequenced? (5)

A

to:

  1. identify all human genes and their roles
  2. analyse genetic variation between humans as a species
  3. sequence the genomes of several model organisms used in genetics, such as the fruit fly
  4. develop new sequencing techniques and computational analysis
  5. to share genome information with scientists and the general public as fast as possible
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2
Q

What is a genome?

A

a complete set of DNA of an organism

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3
Q

What is the human reference genome?

A

A genome made from 10 anonymous volunteers that is used as a reference to compare individuals genome to

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4
Q

What are some key findings from the human genome? (6)

A
  1. there are fewer genes than expected (we have about the same as a type of worm)
  2. less than 2% of our genome codes for proteins
  3. the genome is dynamic (contains evidence of recent evolution)
  4. we don’t know what many of our protein coding genes do
  5. most human genes are related to those of other animals
  6. all humans are 99.9% similar at sequence level
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5
Q

Describe the makeup of the human genome:

  • what percentage exons/coding?
  • what percentage introns?
  • what percentage regulatory sequence?
  • roughly how many genes?
  • about what percentage have an unknown function?
A
  • 1.5% coding (exons)
  • 20% introns
  • 5% regulatory sequences
  • ~21,000 genes
  • about 25% still have an unknown function
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6
Q

How do we find a gene?

A
  • genes tend to start with ATG
  • have open reading frame
  • have exons and introns
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7
Q

Which part of the genome is making functional proteins and what percentage of the genome does this make up?

A

the exons making up 1.5% of the genome

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8
Q

What do the regulatory sequences do?

A

sit around the genes and determine whether the genes should be turned on or not

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9
Q

How much of the human genome does introns, exons and regulatory sequence account for?

A

25%

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10
Q

What are 4 different types of variation in the genome?

A
  • SNPs
  • STRs
  • InDels
  • CNVs (structural variants)
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11
Q

What does SNPs stand for?

A

Single nucleotide polymorphisms

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12
Q

What does STRs stand for?

A

Short Tandem Repeats

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13
Q

What does InDels stand for?

A

insertions and deletions

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14
Q

What does CNVs stand for?

A

Copy number variations

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15
Q

What is the importance of variation?

  • what is it the key driver for?
  • knowledge of variation can be used to….? (4)
A
  • variation is the key driver for evolution
  • knowledge of variation can be used to diagnose genetic disease, to determine which drugs will work best on a patient, to determine our close relatives, or our species’ origin
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16
Q

What are SNPs?

A
  • common single base pair changes or variants

ie. sites in the DNA that vary within populations

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17
Q

How common are SNPs?

A
  • common: about 1 in every 300 nucleotides
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18
Q

What are some effects of SNPs?

A

in the coding region: could change the protein (only if it changes an amino acid and only if it’s an important amino acid in the protein)

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19
Q

What are STRs?

A

repeats of 2-5 nucleotides found in specific regions of the genome

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20
Q

Give an example of an STR

A

Each person inherits 2 alleles, one from each parents which could vary in length

eg. at one site:
CAGCAGCAGCAGCAGCAGCAGCAG 8 repeats of ‘CAG’ from mum
CAGCAGCAG 3 repeats of ‘CAG’ from dad

this person is 3,8 at STR1

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21
Q

What are InDels?

A

small insertions or deletions which causes a “frame shift” in the way DNA is read if in a protein coding region

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22
Q

What are copy number variants?

A

A type of structural variation where individuals vary in the number of copies of a region of DNA they have in their genome

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23
Q

How many CNVs do humans have?

A

10,000 found within and between genes

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24
Q

What can we see from comparing genomes?

A

We can see what is the same and what is different and learn about which parts of the genome do what

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25
Q

How do we compare sequences?

A

By lining them up next to each other and marking each point where sequences are the same.

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26
Q

What is it called when DNA sequences are lined up next to each other and each point where sequences are the same is marked?

A

aligning

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27
Q

Differences in genomes of individuals with the same species might be associated with

A
  • disease
  • characteristics of an individual
  • evolutionary history
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28
Q

Comparing genomes within a species can help us identify

A

variants that might be related to phenotype

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29
Q

What was found from the Denisova cave?

A
  • 4 billion Neanderthal nucleotides
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30
Q

What were some findings when human DNA was compared to Neanderthal DNA?

A
  • some of us carry Neanderthal DNA
  • modern humans from Europe and Asia carry Neanderthal alleles
  • those from Africa show no signs of these alleles
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31
Q

What do the findings when DNA between humans and Neanderthals were compared suggest?

A

That where modern human humans met Neanderthals, they interbred

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32
Q

What percentage of the genome of non-Africans is made up of variants that arose in Neanderthals?

A

2-4%

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33
Q

Neanderthal DNA adds to

A

the variation in our genome that might be related to our phenotype

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34
Q

What percentage of the genome of modern day Melanesians is made up of variants that arose in Denisovans?

A

4-6%

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35
Q

What does the presence of Denisovan alleles in our genome suggest?

A

Homo sapiens mated with Denisovans (as well as mating with Neanderthals)

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36
Q

Comparing genomes within a species can help us identify

A

variants that might be related to the phenotype

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37
Q

Comparing genomes with another species can help us

A

identify variants that might be related to the biology or an organism

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38
Q

What are mutations?

A

Permanent changes to the DNA sequence

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39
Q

Mutations can be (2)

A

inherited or acquired

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40
Q

Mutations that are inherited are called _______ and are passed by the _______

A

germ-line mutations

gametes

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41
Q

Mutations can be acquired by somatic cells if

A

DNA gets damaged or is copied incorrectly

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42
Q

Can somatic mutations be passed onto the next generation?

A

no

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43
Q

Mutations are the driving force of

A

evolution

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44
Q

Mutations can be (3)

A

beneficial
harmfull
have no effect

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45
Q

The vast majority of mutations have

A

no effect

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46
Q

What does the outcome of the mutation depend on

A

environmental effects

other genes

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47
Q

What are some environmental effects that the outcome of a mutation depends on?

A

diet

exposure to toxins

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48
Q

Mutations can be _______ or __________ or give a

_________ or ________

A

dominant
recessive

loss of function
gain of function

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49
Q

A dominant mutation is one that causes the phenotype when

A

Heterozygous

only 1 copy of the mutant allele present

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50
Q

A recessive mutation is one that causes the phenotype when

A

Homozygous

2 copies of the mutant allele need to be present

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51
Q

What is a loss of function mutation?

A

A mutation that might break a gene

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52
Q

Loss of function mutations are often ______ (and why)

A

recessive because a normal copy of the gene exists on the other chromosome which can replace the lost function

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53
Q

What is a gain of function mutation?

A

When a mutation causes the gene to work too well, or to do something unexpected

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54
Q

Gain of function mutations are often _______ (and why)

A

dominant because having an allele that works too well will not be replaced by the other gene

55
Q

What is a monogenetic disease?

A

a disease caused by one gene

56
Q

What are some monogenetic diseases?

A
  • haemophilia
  • Huntington’s disease
  • Cystic fibrosis
57
Q

Describe haemophilia

A
  • blood clotting disorder
  • when you cut yourself, your blood starts to clot
  • this is a very finely balanced chemical reaction involving a bunch of proteins that detect when blood is flowing abnormally and you start forming that clot structure.
  • haemophilia A results from impairment or absence of clotting factor VIII
  • haemophilia B results from impairment or absence of clotting factor XI
58
Q

Describe the inheritance of haemophilia

A
  • caused by an inversion mutation on the X chromosome

- mutations are loss of function

59
Q

What is an inversion mutation?

A

A piece of DNA has popped out, turned around and gone back into the sequence. This scrambles the haemophilia protein so its doesn’t work anymore

60
Q

Because haemophilia affects the X chromosome, are males or females more likely to inherit the mutation? What are the chances?

A
  • Males are more likely to have haemophilia
  • Women have two X chromosomes and are rarely affected
  • Sons of women who are carriers have a 50% chance of inheriting the disease
61
Q

Describe Huntington’s disease

A
  • neurodegenerative disease
  • progressive tremors
  • involuntary movement
  • onset in midlife (30-50)
  • no effective treatment
62
Q

Describe the inheritance of Huntington’s disease

A
  • autosomal dominant inheritance
63
Q

Describe the genetic cause of Huntington’s disease

A
  • mutation of HTT gene in chromosome 4
  • caused by the expansion of CAG triplet repeat in the HTT gene
  • In HTT, there is a patch of CAG repeats and CAG encodes glutamine in the protein
  • the protein therefore has a long polyglutamine tract
  • the protein become unstable and it fragments, clumping together in nerve cells and damaging them
64
Q

How can you test for Huntington’s disease?

A
  • putting a primer at each end of the CAG region
  • do PCR to determine how far apart the primers are which can tell you how long the CAG region is
  • the length of the CAG region can affect the chances of getting Huntington’s
65
Q

How many CAG triplets affect the chances of getting Huntington’s disease?

A

10-35 copies: normal

40+ copies: disease develops

66
Q

What are some symptoms of Cystic fibrosis? (4)

A
  • lung infections
  • pancreatic insufficiency
  • congenital absence of vas diferens in males
  • salty tasting skin
67
Q

The inheritance of Cystic fibrosis is

A

autosomal recessive

68
Q

What is the mutation that causes Cystic fibrosis?

A
  • three base pair deletion in the CTFR gene
  • the protein is abnormally processed and degraded because it goes to the wrong part of the cell
  • this causes thickening of cells secretions
69
Q

How can you find potential disease genes?

A
  1. sequence the genome
  2. compare this with the human reference genome and determine what is different
  3. eliminate the variants in common (because they are not causing the disease)
  4. look at the different variants
  5. eliminate the ones that are not predicted to be harmful
  6. validate and test the variants that are predicted to be harmful
70
Q

What are polygenetic diseases?

A
  • diseases that involve many genes acting together or environmental factors interacting with genes
71
Q

What are some examples of polygenetic diseases?

A 
obesity
diabetes
gout
bipolar disorder
rheumatoid arthritis
72
Q

How can you find a polygenetic disease?

A
  1. compare the genomes of cases (ie. people with the disease) with a control (people without the disease)
  2. identify variations between the two groups
  3. of these variations, determine the shared variations within the cases group
  4. validate and test these variants
73
Q

Most genetic disorders are ________ not _________

A

probabilistic not deterministic

74
Q

What does “most genetic disorders are probabilistic not deterministic” mean?

A

it means that for most genes, having disease related variation does not mean you will get the disease because the diseases come about through a combination of variants and the environment

75
Q

Where gene change alters the phenotype, it gives a clue to the

A

gene function

76
Q

If we can find or create mutants in the related genes in other animals, we may learn

A

what the functions of those genes are in humans

77
Q

How do we use genetic techniques to find out what a gene does?

A

Using functional molecular genetics

78
Q

Describe the process of functional molecular genetics

A
  1. study organisms that are naturally occurring for that gene
  2. increase the rate of mutation by intensive breeding or chemicals
  3. select for a phenotype of interest and sequence the genome to identify the mutation (genetic screen)
  4. once you have a gene you are interested in, you can insert it into another organism using transgenesis or genetic engineering
  5. you can also break a particular gene to see what happens using targeted mutation, gene knockout or reverse genetics
79
Q

What are some model organisms can be used to make mutants?

A

Mice
Zebrafish
Drosophila

80
Q

Why can some organisms be used to make mutants?

A

Because we share many of our genes with them and because these model organisms can easily raised in a controlled environment and are easy to manipulate genetically

81
Q

Mutants can be made by treatment of gametes with mutagens such as

A

X - rays

Chemicals

82
Q

What is the purpose of transgenesis?

A

To understand how genes work / what a gene does.
To engineer useful protein products (synthetic biology).
For gene therapy approaches.
To study the effect of making a foreign protein or of making a protein in the wrong cells.

83
Q

What is transgenesis?

A

Where we add DNA from a different organism to a genome to make a new protein or to replace a defective gene

84
Q

What is gene therapy?

A

Delivery of a good copy of the gene to sick cells so they have a good copy of the gene to make a good protein from

85
Q

What do you need for trangenesis?

A

regulatory sequence and the coding part of the gene that you want

86
Q

What is the purpose of the regulatory sequence?

A

A regulatory sequence is something to make the gene work in the organism you are putting it in because it controls how that gene is deployed (moved into action)

87
Q

Give an example of trangenesis and explain how it works

A

Putting the fluorescent jellyfish gene into mice
You can inject a mouse embryo after fertilisation and inject the DNA that you want. The DNA will therefore become part of the DNA of the mouse

88
Q

Give examples of how transgenesis can help humans

A
  • Factor IX for haemophilia B in hamster cells
  • spider silk produced by transgenic goats, in their milk
  • human insulin produced by bacteria for treatment of type 1 diabetes
  • Brewer’s yeast modified to produce cannabinoids
89
Q

How can you find out whether a variant is pathogenic?

A
  1. Sequence the genome
  2. Map and compare it to the human reference
  3. Rule out the common variants
  4. Of the novel variants, rule out those predicted to be benign
  5. Of the variants that are predicted to be harmful, validate and test them
90
Q

How can we test whether a variant gene is pathogenic?

A
  • we can damage, or modify, the gene we are interested in by genetically modifying an organism or cell line
  • by examining the organism, we should be able to work out what that gene normally does
91
Q

What is one method of modifying/damaging the gene?

A

CRISPR - Cas9

92
Q

What is Cas-9

A

associated protein 9

93
Q

What is Cas9 and what is its purpose?

A

It is a nuclease that cuts double stranded DNA molecules

94
Q

Explain how CRISPR-Cas9 works

A
  • Cas9 protein contrains active sites that can cut DNA
  • a guide RNA binds with the Cas9 protein forming a complex that is allowed to then be introduced into the cell
  • In the nucleus, the complementary sequence of the RNA binds to part of the target gene
  • the active site of the Cas 9 protein cut the DNA on both strands
  • this results in a cut in the target gene
  • the broken strands of DNA are “repaired” by the the cell in two different ways
95
Q

What is the purpose of the guide RNA?

A

It guides the Cas9 protein to a target gene that only binds to the gene of interest

96
Q

Describe the structure of the RNA that is used in CRIPSR-Cas9?

A

There is a complementary sequence that can bind to the target gene
The RNA also binds to itself in a structure called a hairpin which makes the RNA stable and it also means that it can fit nicely into the cas-9 enzyme.

97
Q

What are the two different ways in which the cell “repairs” the broken DNA after Cas9 broke the strands?

A
  1. no template is provided and repair enzymes insert and/or delete random nucleotides (InDels) making the gene non-functional or mutated
  2. if a repair template is provided, it is possible to use this to “edit” the DNA sequence at the cut site (“gene editing”)
98
Q

What are the two types of genetic disease?

A

Somatic diseases

Germline diseases

99
Q

Describe a somatic disease

A
  • the target cells or organs are affected
  • does not affect the next generation
  • often single gene diseases caused by loss of function mutations
100
Q

What are some methods of fixing somatic diseases?

A

Gene therapy

CRISPR-Cas9 is also being explored as an example

101
Q

What’s an example of a somatic disease and how can it be fixed?

A
  • Cystic fibrosis
  • caused by mutations that alter the function of the Cl- ion channel encoded by the CFTR gene
  • gene therapy can be used to fix it
102
Q

Describe how gene therapy can be used to help Cystic fibrosis

A

Delivering DNA with a functional copy of the CFTR gene to lung epithelial cells via nebuliser (drug delivery device used to administer medication in the form of a mist inhaled into the lungs). The extra copy of the DNA makes good CFTR protein, restoring function into some cells.

103
Q

What are some ways to fix germline diseases?

A
  • preimplantation genetic diagnosis
  • three parent babies
  • CRISPR gene “edited” babies
104
Q

Describe preimplantation genetic diagnosis

A

IVF can be used to make embryos from the parents egg and sperm. These embryos can be tested before implantation, and only healthy embryos implanted

105
Q

Describe three parent babies

A

Important genes are found in the mitochondria which is inherited from the mother. If these are faulty, a donor egg with good mitochondria can be used. Therefore the baby had DNA from 3 parents: sperm from the dad, nucleus from the egg from the mum, and the mitochondria from the egg of another women

106
Q

What is the purpose of CRISPR-Cas9?

A

It is one method to break or modify a gene replicate a possible disease causing variant in a model organism, to see if the disease develops as a result

107
Q

What does totipotent mean?

A

The cells have the potential to make any cell in the whole body including the placenta and embryo

108
Q

What does pluripotent mean?

A

The cells that have the potential to make any cell in the whole body but not the placenta and embryo

109
Q

What are the stages of embryo development?

A
  1. an 8 cell stage
  2. a cell polarisation
  3. compaction
  4. the inner, apolar cells are cut off
  5. forms a blastocyst
110
Q

Describe cell polarisation

A

There is an inside and an outside forming. The outside makes microvilli and nucleus moves towards inside

111
Q

Describe compaction

A

Cells are tightly stuck together

112
Q

Describe the process where the inner, apolar cells are cut off

A

The 8 cells divide in the plane which means that the inner cells are cut off from the outside environment (intrauterine environment)
This makes them do completely different things

113
Q

Cells become more __________ and less __________ during embryo development, except for ______ _______ and ________ __________ (______ and _______)

A

specialised
flexible
stem cells
germ cells (egg and sperm)

114
Q

Describe the blastocyst

A

There is the inner cell mass (ICM) and the trophectoderm

115
Q

What is the ICM?

A

Is it the inner cell mass that is formed from the division of apolar cells that have been cut off
These continue to divide to form you

116
Q

What is the trophectoderm?

A

The embryos contribution to the placenta.

117
Q

What is a stem cell?

A

A relatively unspecialised cell that can both reproduce itself indefinitely and, under appropriate conditions, differentiate into specialised cells of one or more types

118
Q

Summarise why the human genome was sequenced

A

To find all the human genes and to identify the types and extent of variation in the human population

119
Q

Knowledge of variation can be used to (4)

A
  1. diagnose genetic disease
  2. determine which drugs will work best in a patient
  3. determine out closest relatives
  4. determine out species origins
120
Q

The embryo begins as a small number of naïve, __________ cells

A

totipotent

121
Q

Embryonic stem cells can give rise to all cell types except

A

trophectoderm

122
Q

Embryonic stem cells are not

A

differentiated

123
Q

Embryonic stem cells are an example of

A

pluripotent cells

124
Q

What are pluripotent cells?

A

Cells that are capable of giving rise to many different cell types

125
Q

What is cell differentiation?

A

When cells become specialised in structure and function

126
Q

Define totipotent, pluripotent and multipotent

A

Totipotent:
such as a fertilised egg which is able to give rise to all cell types via cell division (including the placenta)

Pluripotent:
such as embryonic stem cells can become any cells of the human body

Multipotent:
stem cells that give rise to both stem cells and cells that will differentiate into one or more (but not all) types of functional tissue cells. Examples include adult stem cells such as those from blood or the bone marrow

127
Q

Describe genomic equivalence

A

differentiated cells contain all the DNA required to build an entirely new organism

128
Q

Embryonic stem cells are harvested from the

A

inner cell mass

129
Q

Umbilical cord stem cells are _________ as they are _________ _________ _______ __________

A

multipotent

immature blood stem cells

130
Q

What are haemotopoietic stem cells?

A

Blood stem cells that are found in the bone marrow and can be used for transplants

131
Q

What is gene editing?

A

A type of genetic engineering in which genomic DNA is altered, removed or replaced

132
Q

What is an iPSC?

A

Induced Pluripotent Stem Cell: a laboratory technique that “deprogrammes” differentiated cells through manipulation, restoring them to a pluripoent state

133
Q

What is a stem cell?

A

Any relatively unspecialised cell that can produce, during a single division, two identical daughter cells or two more specialised daughter cells that can undergo further differentiation, or one cell of each type

CELS 191 (5 decks)

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