Final Flashcards
(212 cards)
1
Q
What are some examples of genes responding to the environment?
A
- Insulin and insulin receptors respond to glucose levels
- Baldness and lactation are dependent on hormones
- Coat colour in rabbits is dependent on temperature
- Disease manifestation is determined by viral exposure
2
Q
What is the Waddington Hypothesis?
A
That biological processes such as development are finely tuned and perturbation of the process can produce a very different result.
3
Q
What is an example of the Waddington Hypothesis?
A
Poor nutrition can effect someone’s height so they might not meet the maximum height potential for their genes + optimal environment
4
Q
What is Mendelian Inheritance?
A
A dominant/recessive, autosomal/x-linked mode of gene inheritance that has predictable ratios
5
Q
What are some exceptions to biallelic expression?
A
Mitochondrial genes
Imprinted genes
UPD
6
Q
What is Polygenic Inheritance?
A
Each gene individually follows Mendelian rules but the genes act together on the same trait.
Multiple genes, multiple alleles, one trait
7
Q
What is multifactorial inheritance?
A
Polygenic inheritance with environmental factors.
8
Q
What happens when the number of genetic risk factors is increased in polygenic inheritance?
A
The number of possible phenotypic classes increases.
9
Q
True or False: Multifactorial traits can be demonstrated with models of Mendelian inheritance.
A
False. They’re too complex for that.
10
Q
What is the quantitative class of multifactorial disease?
A
A continuum which varies from one extreme through normal to another extreme, such as with height, BMI, IQ, BP, or cholesterol.
11
Q
What is the qualitative class of multifactorial disease?
A
Discrete, present or absent. Such as a heart attack, cancer, or rheumatoid arthritis.
12
Q
What is the quantitative trait model?
A
Measures an entity, such as height or blood pressure.
Varies continuously, typically with normal distribution.
When the trait is outside the normal range, a multifactorial disorder can be described, such as hypertension.
Monitors the accumulation of quantitative trait loci.
13
Q
What is regression or mediocrity?
A
Offspring are more likely to have a multifactorial trait that is closer to normal than their parent, especially if their parents are on one of the extreme ends because it is unlikely that all of the extreme genes will be passed on, although sufficient genes will be passed on that the offspring will not be the exact mean of the population.
14
Q
What is the Threshold of Liability Model?
A
It describes the complex pattern of inheritance of qualitative traits. A minimum number of liability factors must be present to have a disease.
15
Q
What is liability?
A
The genes and environmental factors that contribute to the likelihood of developing a disease
16
Q
If monozygotic twins are more concordant than dizygotic twins, what does that tell us?
A
That the difference in the trait is attributed to genetics.
17
Q
What is concordance?
A
If one twin is affected, how often is the other twin affected?
18
Q
True or False: Monozygotic and Dizygotic twin concordance rates are the same across all populations.
A
False, they differ.
19
Q
If monozygotic twins have a concordance rate of 0.72 for spina bifida, and dizygotic twins have a concordance rate of 0.33, what is the difference due to?
A
Genetics.
20
Q
What might you need to look out for in adoption studies?
A
Sometimes the prenatal environment has long lasting effects on an adopted child.
Adoption doesn’t always occur at birth.
21
Q
What might you need to look out for in twin studies?
A
Twins often share a room.
Siblings are raised in the same house, and would have the same environment.
22
Q
What is heritability?
A
The percentage of the population variation in a trait that is due to genes.
The proportion of the total variance of a trait caused by genetic factors.
23
Q
How is heritability calculated?
A
H = Variance (genetic) / Variance (population)
H = 100% for traits that are fully genetic.
H = 0% for traits that are fully environmental
Or
H = (C (MZ) - C (DZ)) / (1 - C (DZ)) in twins, where C is concordance rate for qualitative traits, and the correlation coefficient for quantitative traits.
24
Q
Diseases that are mostly genetic are:
A
Rare, simple (unifactorial), and have a high recurrence risk.
25
Diseases that are mostly environmental are:
Common, complex (multifactorial), and have a low recurrence risk.
26
What is ecogenetics?
The interaction between environmental factors and different human genotypes
27
True or False: multifactorial disorders are complex, while single gene disorders are simple.
False, single gene disorders can have genetic and environmental modifiers that make them complex.
28
What type of traits does the threshold liability model apply?
Qualitative/Discrete
29
What is an empiric risk?
Risks derived from direct observation of data from a large series of families with an affected individual. They're specific for each multifactorial disease and can vary from one population or geographic area to another.
30
True or False: Risk depends on degree of relatedness
True.
31
What are the three things that risk depends on?
1. Degrees of relatedness
2. Burden of disease in a family
3. Severity of the disease/condition
32
What is burden of disease in a family?
There is an increased risk of liability and risk factors in a family where there are more individuals affected.
33
If the affected proband is of the less commonly affected sex, what does that mean?
The overall risk is higher.
34
What is a proband?
An individual who presents with a genetic disorder or other specific characteristic that leads to the investigation of the individual's family
35
What five factors increase risk?
1. High heritability of disorder
2. Close relationship to proband
3. Multiple affected family members
4. Severity of the disease in proband
5. Proband of more rarely affected sex
36
True or False: Humans are distributed randomly across the world.
False. Humans are clustered into discrete populations
37
What is a population?
A local group of people sharing a common gene pool. They can be described by age structure, geography, birth and death rates, or allele frequency
38
What is a gene pool?
The set of genetic information (alleles of a gene) carried by the members of a sexually reproducing population.
39
What is population genetics?
The study of genetic variation and how genes and genotypes are maintained or change in populations, not individual matings
40
What is population diversity?
The idea that populations are more diverse than individuals because a group carries all the alleles for a trait, but individuals only have some.
41
What is allele frequency?
The frequency with which alternate forms of a particular gene are present in a population. It may change from generation to generation.
42
What is a potential outcome of a change in allele frequency?
A change in genotype frequency.
43
What is the difference between incomplete and complete dominant alleles?
Complete Dominance is when heterozygotes and homozygotes for the dominant variant allele have the same phenotype.
Incomplete Dominance is when homozygotes have a more severe phenotype than a heterozygote, which is only semi-dominant.
44
What is a co-dominant allele?
When both of the alleles of a pair are expressed in the heterozygous state.
45
What is the difference between a co-dominant allele and an incomplete dominant allele?
Incomplete dominance results in an entirely new phenotype, such as if you mixed red and blue paint, you'd get a purple paint.
Co-dominance results in both the dominant and recessive phenotypes being expressed at the same time, such as if you put a red block and a blue block next to each other.
46
How can one measure co-dominant allele frequencies?
Directly, by counting phenotypes since the phenotypes are equivalent to the genotypes.
47
What is the difference between genotype and phenotype?
Genotype is the combination of alleles you have (RR, Rr, rr)
Phenotype is the trait that is expressed as a result of the genotype (Blue eyes, green eyes, brown eyes)
48
If the MN blood group is co-dominant, what are the possible phenotypes?
M, N, MN
49
If in a study population of people, the phenotypes observed have a frequency of:
M blood type (MM genotype) 64/200
MN blood type (MN genotype) 120/200
N blood type (NN genotype) 16/200
Then what is the frequency of M, of N, and the what is the total number of alleles?
Frequency of M = 64 + 64 + 120 = 248 (62%)
Frequency of N = 120 + 16 + 16 = 152 (38%)
Total alleles = 248 + 152 = 400 (100%)
50
If in the study population of people, the phenotypes observed have a frequency of:
M blood type (MM genotype) 0.32
MN blood type (MN genotype) 0.60
N blood type (NN genotype) 0.08
What is the frequency of the allele N?
Frequency of N = 0.38
0.32 + 0.60 + 0.08 = 1.00
0.32 + 0.32 + 0.60 + 0.6 + 0.08 + 0.08 = 2.0
(0.60 + 0.08 + 0.08) / 2.0 = 0.38
51
Which types of allele frequencies can be measured directly and which cannot?
Co-dominant, incomplete, and homozygous recessive allele frequencies can be measured directly.
Complete dominant homozygous and heterozygous allele frequencies cannot.
52
How can we measure allele frequencies in populations?
Using the Hardy-Weinberg principle.
53
What is the Hardy-Weinberg Law?
The equilibrium relationship that exists between allele frequencies and genotype frequencies in a population.
Genotype frequencies can be calculated from allele frequencies because allele and genotype frequencies remain constant from generation to generation in an ideal population
54
What makes an ideal population in the context of the Hardy-Weinberg law?
The population is free from many complications that affect real populations.
55
What are the assumptions of the Hardy-Weinberg Law?
1. The population is large enough that there are minimal sampling errors in measuring allele frequencies.
2. All genotypes are equally able to reproduce
3. Mating in the population is random
4. No migration into or out of the population occurs
5. No new mutations are occurring
6. No matings between different generations are occurring
7. All matings produce the same number of offspring who are all equally fertile
56
What is the allele frequency formula for the Hardy-Weinberg Law?
For a population, p + q = 1
p is the frequency of the dominant allele A
q is the frequency of the recessive allele a
57
What is the genotype frequency formula for the Hardy-Weinberg Law?
p^2 + 2pq + q^2 = 1
p^2 is the frequency of the homozygous dominant genotypes.
q^2 is the frequency of the homozygous recessive genotypes
2pq is the frequency of the heterozygous genotypes
58
Why does the Hardy-Weinberg genotype frequency formula include the frequency of heterozygotes twice?
Because there are two parents so there are two ways to become a heterozygote. That is, Parent 1 gives A and Parent 2 gives a, or Parent 1 gives a and Parent 2 gives A.
59
In a population under ideal conditions, what is the frequency of all genotypes if bb genotypes have a 9% frequency?
9% = 0.09
q^2 = 0.09
q = sqrt(0.09) = 0.3
1 - 0.3 = 0.7
p = 0.7
p^2 + 2pq + q^2 = 1
(0.7)^2 + 2 * 0.7 * 0.3 + (0.3)^2 = 1
0.49 + 0.42 + 0.09 = 1
BB has a 49% frequency
Bb has a 42% frequency
bb has a 9% frequency
60
If there are 647 AA individuals, 134 Aa individuals, and 7 aa individuals, what is the total number of alleles?
647 + 134 + 7 = 788 * 2 = 1576 alleles
61
If there are 647 AA individuals, 134 Aa individuals, and 7 aa individuals, what is the allele frequency of A and what is the allele frequency of a?
A = [2(647) + (134)] / (647 + 134 + 7) = (1294 + 134) / 1576 = 1428 / 1576 = 0.906
a = [2(7) + (134)] / (647 + 134 + 7) = (14 + 134) / 1576 = 148 / 1576 = 0.094
62
What is genetic equilibrium?
When the allele frequency for a particular gene remains constant from generation to generation. Equilibrium in a population explains why dominant alleles do not replace recessive alleles
63
True or False: When a population is not in equilibrium, alleles frequencies and genotype frequencies fluctuate and change.
False. When not in equilibrium, allele frequencies stay the same, but the combinations of genotype frequencies do change.
64
If the parental generation has allele frequencies of A = 90.6% and a = 9.4%, and the new generation has 613 AA individuals, 152 Aa individuals, and 23 aa individuals, is there equilibrium in this population for these alleles?
No.
613 + 152 + 23 = 788 * 2 = 1576
A = 613 + 613 + 152 = 1378 / 1576 = 0.874 = 87.4%
a = 23 + 23 + 152 = 198 / 1576 = 0.126 = 12.6%
These are different from the previous generation's allele frequencies.
65
What is the Hardy-Weinberg Law used for in human genetics?
- Estimating frequencies of autosomal dominant and recessive alleles in a population
- Detecting when alleles frequencies are shifting in a population (evolutionary change)
- Measuring the frequency of heterozygous carriers of deleterious recessive alleles in a population
66
What is the formula for the frequency of genotype aa?
q^2
67
What is the formula for the frequency of the a allele in individuals with the homozygous recessive genotype aa?
sqrt(q^2) or q
68
What is the formula for the frequency of the dominant allele A in a population where you know the frequency of the homozygous recessive genotype aa?
p = 1 - q
69
What is the formula for the frequency of an X linked trait in males?
q
70
What is the formula for that frequency of an X linked trait in females?
q^2
71
What is the Hardy-Weinberg equation for the ABO blood types which have six different genotypes?
p^2 (AA) + 2pq (AB) + 2pr (AO) + q^2 (BB) + 2qr (BO) + r^2 (OO) = 1
72
What are the factors that disrupt Hardy-Weinberg Equilibrium?
1. Non-Random Mating
2. Genetic Drift
3. Migration and Gene Flow
4. Selection
73
What are the four types of non-random mating?
- Stratification: effectively separate breeding populations, such as whoever you're around most frequently.
- Assortative Mating: choosing a mate based upon their possession of a particular trait
- Consanguinity: related by descent from a common ancestor
- Inbreeding: mating of closely related individuals
74
What is an example of a population that has a higher than average rate of rare autosomal recessive traits?
Hutterites. They're genetically isolated and have an average degree of relatedness of ~2nd cousins
75
What is genetic drift and what are some more specific types of genetic drift?
Genetic Drift: Random fluctuations of allele frequencies from generation to generation that take place in small, isolated populations such as island populations or socioreligious groups. These chance occurrences, independent of genotype, have a significant effect on disease alleles frequency.
Founder Effect: A population starts with a small number of individuals (founders) or drastic reduction in population (bottle neck). The allele frequencies are established by chance in a population that is started by a small number of individuals
76
What is migration and gene flow?
The slow diffusion of genes across a barrier (geographic or social). A merger of a different "migrant" gene pool into the larger population with change in allele frequencies.
77
What is the primary force that leads to evolutionary divergence and the formation of new species?
Selection.
78
What is selection?
Natural selection acts on genetic diversity in populations and increases the reproductive success of certain genotypes.
79
What is natural selection?
Differential reproduction shown by some members of a population that is the result of differences in fitness. A measure of the relative survival and reproductive success of a specific individual or genotype.
80
What is the heterozygote advantage?
The high frequency of genetic disorders in some populations is the result of selection that often confers increased fitness on heterozygotes
81
What is an example of the heterozygote advantage?
A single sickle-cell allele confers resistance to malaria, but many recessive homozygotes die in childhood. Selection favours survival and differential reproduction of heterozygotes
82
True or False: allele frequency in a population is determined by drift, migration, selection, and mutations.
False, allele frequency in a population is determined by drift, migration, and selection. Mutation generates all new alleles but is not the reason for change in allele frequencies.
83
What results in cancer?
Dysregulated cell growth
84
What is neoplasia?
A new growth in a cell.
85
What is hyperplasia?
Too much growth in a cell.
86
What is dysplasia?
Incorrect growth in a cell.
87
What is metstasis?
Distant growth in a cell.
88
What is the difference between a benign growth and a malignant growth?
Benign is localized, malignant is uncontrolled.
89
What are the six basic capabilities of an invasive tumour cell?
1. Growth without external growth signals.
2. Insensitivity to external anti-growth signals
3. Ability to replicate indefinitely
4. Ability to avoid apoptosis
5. Ability of new cells to recruit new blood vessels
6. Ability to invade tissues and establish new tumour sites
90
What is a hit in the context of cancer?
The mutations that cause variants in the cells which accumulate and result in tumours.
91
What is the lifetime risk of cancer in humans?
33% - 55%
92
What is the most common cause of cancer?
Environmental factors.
Specifically, tobacco.
93
What are five environmental causes of cancer?
- Radiation
- Chemicals
- Viral infection
- Diet
- Lifestyle
94
For the following environmental causes, determine what type of environmental factor they belong to and what the most common type of cancer they each cause is:
- Sunlight
- Atomic Bombs
- X-rays
Radiation.
Sunlight = melanoma
Atomic bombs = leukemia
X-rays = lung cancer
95
For the following environmental causes, determine what type of environmental factor they belong to and what the most common type of cancer they each cause is:
- Asbestos
- Smoke soot
Chemicals
Asbestos = lung cancer
Smoke soot = scrotal cancer
96
For the following environmental causes, determine what type of environmental factor they belong to and what the most common type of cancer they each cause is:
- Hepatitis
- EBV
- HPV
- HIV
Viral infection
Hepatitis = liver cancer
EBV = Burkitt's lymphoma
HPV = cervical virus
HIV = lymphoma and Kaposi sarcoma
97
For the following environmental causes, determine what type of environmental factor they belong to and what the most common type of cancer they each cause is:
- Nitrite preservatives
- Alcohol
- Low fibre
Diet
Nitrite preservatives = liver cancer
Alcohol = liver cancer
Low fibre = colon cancer
98
For the following environmental causes, determine what type of environmental factor they belong to and what the most common type of cancer they each cause is:
- Smoking
- Prostitution
- Being a nun
Lifestyle
Smoking = lung cancer
Prostitution = cervical cancer
Being a nun = breast, ovarian, uterine cancer
99
What is a Retinoblastoma?
A retinal tumour of childhood.
It's seen in 1 / 20,000 children
The affected eye must be removed.
It's caused by hits/variants in the RB1 gene
It's a type of cancer
40% are inherited
100
What is the probability that an RB1 germline mutation is present in a parent with one retinoblastoma and a family history of retinoblastomas?
100%
101
What is the probability that an RB1 germline mutation is present in a parent with multiple retinoblastomas and a family history of retinoblastomas?
100%
102
What is the probability that an RB1 germline mutation is present in a parent with retinoblastomas in both eyes and a family history of retinoblastomas?
100%
103
What is the probability that an RB1 germline mutation is present in a parent with one retinoblastoma and NO family history of retinoblastomas?
15%
104
What is the probability that an RB1 germline mutation is present in a parent with multiple retinoblastomas and NO family history of retinoblastomas?
15% - 90%
105
What is the probability that an RB1 germline mutation is present in a parent with retinoblastomas in both eyes and NO family history of retinoblastomas?
90%
106
What is the Knudson Two Hit Hypothesis?
That either retinoblastomas are sporadic or inherited.
If it's inherited, one copy of a gene is mutated in every cell, making the first hit inherited, while the second hit in the second copy is acquired.
If it's sporadic, both copies of a gene are normal in every cell, and both hits are acquired.
107
What is the most common second hit in tumours?
Loss of heterozygosity.
108
What is loss of heterozygosity?
When a second hit happens in a tumour which results in one of four possibilities.
1. Nondisjunction, or duplication of the remaining chromosome
2. Sub-chromosomal deletion of the normal chromosome that was hit
3. Unbalanced reciprocal translocation of the normal chromosome that was hit
4. Somatic recombination of the normal chromosome that was hit
109
How many hits are required to have cancer?
Two
110
What are five features of inherited cancer syndromes?
- Autosomal dominant inheritance
- Early onset
- Same or linked forms of cancer in two or more close relatives
- Bilateral in paired organs
- Multiple primary tumours in an individual
111
What are oncogenes?
Genes that promote cell growth. They are responsible for tumour development.
112
What are tumour suppressor genes?
Genes that inhibit the cell cycle and promote apoptosis. They function to keep the behaviour of cells under control by slowing or stopping the cell cycle progression, maintaining integrity of the genome, or inducing apoptosis.
113
What are the two types of tumour suppressor genes?
Gatekeepers: prevent the cell cycle from getting out of control
Caretakers: fix DNA damage as it accumulates in the genome
114
What is Li-Fraumeni syndrome and what is it caused by?
A cancer causing mutation.
Causes cancers in connective tissue, bone, breast, brain, blood, and the adrenal glands
Caused by germline loss of function variant in TP53
TP53 activates transcription of genes involved in growth suppression, apoptosis, and DNA repair in response to DNA damage.
It's autosomal dominant
115
What is an obligate carrier?
Someone who is not affected and does not show signs or symptoms, but who must be a carrier as determined by analysis of a family tree.
116
What is familial adenomatous polyposis coli?
A variant in the APC gene that regulates cell division in the colon
Autosomal dominant inheritance
100 - 1000 polyps develop starting in the teens
Causes colon cancer in young adults with a 100% lifetime risk.
Has a 100% penetrance
117
What is penetrance?
The frequency, under given environmental conditions, with which a specific phenotype is expressed by those individuals with a specific genotype.
118
True or False: Mendelian breast cancer is common.
False, Mendelian breast cancer is rare, but breast cancer itself is common
119
If cancer can't be prevented, why do doctors still look for BRCA1/2 variants?
For treatment options for the patient, and for future surveillance.
And for surgical and lifestyle choices for family members, as well as surveillance for them.
120
What genetic syndromes are at increased susceptibility of cancer?
Constitutional aneuploidy, such as Trisomy 18 or 21, Klinefelter or Turner syndrome.
121
What is Xeroderma Pigmentosum?
An extreme skin sun sensitivity in 60% while the rest have freckle-like pigmentation
Causes eye problems from sun exposure that result in corneal clouding, eyelids turning in or out (or even falling off)
Has a high risk of skin cancer
Biallelic (AR) variants in one of six genes
Part of the mechanism to repair single nucleotide damage, especially from UV light
122
What is Ataxia Telangiectasia?
Biallelic (AR) variants in the ATM gene which controls cell cycle during DSB repair
Childhood onset of ataxia
Causes occular telangestasias
Causes lymphoid malignancies such as leukemia and lymphomas
Causes immunodeficiency
Very sensitive to ionizing radiation
123
What is Bloom Syndrome?
A pre and post natal growth deficiency that results in short stature
Reddening of the skin from sun exposure
Increased rate of sister chromatid exchange and gaps/breaks on karytoype
Biallelic (AR) variants in the BLM gene
Involved in the repair of DNA damage
124
Why do elephants rarely get cancer?
Because they have 20 copies of DNA repair genes, while humans only have 1 copy.
125
Which is more common: sporadic cancer or Mendelian cancer?
Sporadic cancer.
126
What are constitutional chromosome instability syndromes?
DNA repair disorders.
127
Name as many constitutional chromosome instability syndromes as you can. There are seven listed here.
1. Ataxia Telangiectasia
2. Bloom Syndrome
3. Nijmegen Breakage Syndrome
4. Fanconi Anemia
5. Werner's Syndrome
6. Xeroderma Pigmentosum
7. Rothmund-Thompson Syndrome
128
What is a proto-oncogene?
A normal gene that is involved in some aspect of cell division or proliferation. They may become activated to become an oncogene.
129
How are proto-oncogenes activated?
Through activating variants, gene amplification, translocation into active chromatin, or rearrangement creating novel fusion proteins.
130
What is an Oncogene Activating Mutation?
RET receptor mutations result in familial multiple endocrine neoplasia type 2.
They're heterozygous germline variants in RET
Causes a high risk of medullary thyroid cancer (95% - 100% risk).
50% will develop pheochomocytoma.
Autosomal dominant inheritance
Onset infancy to adulthood.
131
What is BRAF?
Another activating driver variant.
Is somatic.
Found in about 50% of melanoma cases, 90% of which are p.V600E, which is also present in thyroid cancer (45%) and colon cancer (10%)
Considered a driver, which are cells that have positive selection during tumourigenesis and drive tumour formation
132
What is NMYC in neuroblastomas?
Also known as MYCN.
Most common extra-cranial solid tumour in children (50% - 60% have metastases at diagnosis).
N-MYC is a transcription factor that promotes tumour progression.
Copy number correlates with state.
10 - 30 copes is low risk disease.
100 - 300 copies is high risk disease.
133
What is Burkitt Lymphoma?
A malignant B-cell cancer found in lymph nodes where they are undergoing maturation.
Predominantly found in children.
MYC gene is rearranged into Ig loci.
Has an endemic variant that is found in regions endemic with malaria, usually involves the jaw or facial bones, but can also involve the GI, ovaries, kidneys, or breasts.
Has a sporadic variant that is the most common form where malaria is not endemic, usually involves the ileocecal region.
Has an immunosupression-related variant that results in 2.5% of untreated HIV patient developing BL. Also more common in organ transplant recipients.
134
What is the cause of the novel fusion protein BCR:ABL1?
Rearrangement. Found in 95% of patients with chronic myeloid leukemia. It places the ABL1 Tyr kinase under the control of the BCR. A kinase that activates downstream targets for growth independent of external signals.
135
What is the cure for Chronic Myeloid Leukemia?
A $38,000/year therapy that about 50% will need lifelong. Increased the survival rate from 15% to 63%. 10-25% of patients will not respond or will develop resistance.
136
What is herceptin?
A breast cancer therapy that increases the 8 year disease free survival from 75% to 83% and costs $40,000 per treatment.
137
What is Precision Medicine?
An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. This practice is not currently in use for most diseases
138
What is Personalized Medicine?
Genomics + Medical Information + Technology + Patient Epowerment
139
What is Stratified Medicine?
Matching therapies with specific patient population characteristics using clinical biomarkers, such as with cancer therapy or pharmacogenomics.
140
What are Pharmacogenomics?
The study of how someone's combination of genotypes predicts how they respond to drug treatment.
For example, in a patient group, with the same diagnosis and the same prescription, there will be people for whom the drug is toxic but beneficial, for whom the drug is toxic and not beneficial, for whom the drug is not toxic and not beneficial, and for whom the drug is not toxic and beneficial.
141
True or False: Pharmacogenomics can predict adverse drug reactions?
True.
142
True or False: Predicting the effect of genetic variants in multifactorial traits is incredibly difficult but due to in depth analysis, are usually reliable.
False, predicting the effect of genetic variants in multifactorial traits is incredibly difficult and the results usually aren't right.
143
What are the five modalities of genetic disease therapy and what do they target?
1. Small molecule (DNA, RNA, Protein)
2. Protein replacement (Protein)
3. Antibody (Protein)
4. Oligonucleotide therapy (RNA)
5. Cell and gene therapy (DNA)
144
What is the origin of the mitochondria?
It evolved from free-living bacteria through a process known as endosymbiosis.
145
What is the structure of the mitochondria?
- Two phospholipid membranes: inner and outer, divides the mitochondria into two spaces (matrix and intermembrane space)
- Inner membrane has a higher protein/lipid ratio and forms a highly packed Cristae which contain the oxidative phosphorylation machinery, they increase the available surface for energy production.
- Inner boundary membrane: an inner membrane that does not protrude into the matrix and runs parallel to the outer membrane. Cristae and the IBM are connected via cristae junctions
146
What is the mitochondria's main function?
Energy production. It generates ATP via Oxidative Phosphorylation as well as through the Krebs cycle (citric acid) and through beta-oxidation of fatty acids.
147
What are the mitochondria's other functions aside from energy production?
Apoptosis
Cell signalling
Reactive Oxygen Species (ROS)
Urea cycle
Immunity
Ca++ homeostasis
Iron-sulphur clusters biosynthesis
Heme synthesis
148
What is the mitochondria?
A dynamic organelle that forms a complex network of tube-like structures (reticulum).
149
What is the purpose of fusion in the mitochondria?
It allows the organelles to share metabolites, proteins, and mtDNA.
150
What is fragmentation?
A process that causes mitochondrial dysfunction and cell death, but is also important in cell division and segregation of damaged portions of the reticulum
151
What is Mitchondrial DNA?
mtDNA
Present in 100s-1000s of copies per cell
Circular
Double stranded
Compact
NO INTRONS
Only one non-coding region called the D-loop
Codes for 37 genes.
Organized in nucleoid structure
Replication and expression are regulated by nuclear-encoded proteins.
Includes the H and L strands, OH and OL, and HSP1, HSP2, and LSP.
152
What are the differences between mtDNA and nDNA?
mtDNA:
- Circular
- 16.5 kb
- 100s - 1000s of copies per cell
- 37 genes
- Minimal non-coding
- No introns
- Codon usage
- Polycistronic
- Maternally inherited
- 10x mutation rate of nuclear DNA
- Lower repair rate than nuclear DNA
nDNA:
- Linear
- ~3.2 billion b
- Two sets of chromosomes
- ~20,000 genes
- Mostly non-coding
- Has introns
- Codon usage
- Monocystronic
- Not exclusively maternally inherited
153
What are the differences in codon usage between mtDNA and nDNA?
UGA codes for tryptophan in mtDNA and a STOP in nDNA.
AGA and AGG codes for a STOP in mtDNA and arginine in nDNA.
AUA codes for methionine in mtDNA and isoleucine in nDNA.
154
What are the four processes in mtDNA maintenance and expression?
Packaging
Replication
Transcription and Processing
Translation
155
What is relaxed replication in the context of mtDNA?
While nuclear DNA replicates once during the cell cycle, mtDNA turns over continuously. They replicate at random, making one or more copies at a time.
156
What is replicative segregation in the context of mtDNA?
mtDNA molecules sort randomly among mitochondria, which, in turn, are distributed randomly between the two daughter cells. This results in significant variability in the manifestations of mitochondrial disease among tissues and patients.
157
What is homoplasmy?
A pure population of wild type or mutant mtDNA.
158
What is heteroplasmy?
A mixture of wild-type and mutant mtDNA molecules. It's within and between cells and tissues/organs, so it can change over time.
159
What is the phenotypic expression of a mutation in mtDNA dependent on?
The relative proportion of mutant to wild-type mtDNA.
160
What is the threshold effect in mtDNA?
Once a certain proportion of mutant mtDNA is expressed, a new phenotype will be seen
161
What are the general characteristics of a mitochondrial disorder?
- 1:4,300 people
- Can present at any age
- Most common with neuromuscular symptoms
- Genetic heterogeneity
- Variable expression
162
True or False: Mitochondrial diseases and disorders are most commonly seen in a few specific organs.
False, they're seen in any organ at any age.
163
What is LHON?
- Lebers Hereditary Optic Neuropathy
- Blindness due to optic nerve degeneration
- Bilateral loss of central visual acuity onset between 15-33 years old
- Most common mito disease
- 3 primary mutation all in complex I that causes reduced activity
- Vast majority are homoplasmic
- Incomplete penetrance (10-50%)
- Smoking can trigger onset
- Unexplained sex bias for manifesting in males over females in Caucasian populations
164
What is MELAS?
- Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes
- A multisystem disorder
- Usually begins in first decade of life
- Muscle weakness
- Exercise intolerance
- Migraines
- Epileptic seizures
- Stroke-like episodes
- Hearing loss
- Visual deficits
- Diabetes mellitus
- Cardiac and gastrointestinal manifestations
- >80% of cases are from a mutation in mtDNA which impairs post-transcriptional modification of the first anti-codon position of the tRNA for leucine
- Caused by OXPHOS dysfunction
- Severity correlates with the proportion of mutated mtDNA
165
True or False: it's possible to have LHON and MELAS at the same time?
True. There are overlapping phenotypes that are associated with mtDNA point mutations in the structural ND5 gene of complex I
166
What is a disease model?
An animal, tissue, or cell that displays some or all pathological features of the actual disease in an experimental setting
167
What are the three criteria of validity for animal models in biomedical research?
1. Face: similar symptoms are observable in both the animal model and a patient
2. Construct: the molecular and cellular mechanisms of the disease are similar
3. Predictive: an animal's response to the pharmaceutical or behavioural testing is similar to humans
168
Who was Henrietta Lacks?
A woman who had cervical cancer, and while attempting to get medical treatment, had her cervical cancer cells taken without her consent by a doctor who had been taking cells without permission from those with cervical cancer for years. Her cells were able to double every 20-24 hours, which was unheard of. The cells were nicknamed HeLa cells and were used to study the effects of toxins, drugs, hormones, viruses, and treatments on the growth of cancer cells without the need to experiment on humans as well as the effects of radiation and poison, the study of the human genome, and more. They're still used today, such as in the development of the COVID 19 vaccine. Henrietta Lacks passed away from cancer never knowing that her cells had been taken.
169
What are the seven common disease models used today?
1. 2D cell cultures
2. C.elegans (worm-like organism)
3. D.melanogaster (flies)
4. D.rerio (zebrafish)
5. M.musculus (mouse)
6. PDX (patient derived xenograft on mice)
7. Human organoids
170
What is a 2D cell culture not suitable in?
An easy establishment of a system, recapitulation of developmental biology, and physiological complexity.
171
What is a PDX mouse model not suitable in?
recapitulation of developmental biology, genetic manipulation, and genome-wide screening
172
What is a mouse model not suitable in?
Genome-wide screening
173
Which disease models are the most suitable overall?
C.eleganis, D.melanogaster, and human organoids.
174
Sort the most common disease models from most to least experimentally pliable. Include a human test subject in the list.
Most: 2D cell cultures
Human organoids
C.eleganis (bacteria worms)
D.melanogaster (flies)
D.rerio (zebrafish)
M.musculus (mouse)
PDX (mouse)
Least: human test subject
175
Sort the most common disease models from most to least physiologically relevant. Include a human test subject in the list.
Most: human test subject
PDX (mouse)
M.musculus (mouse)
D.rerio (zebrafish)
D.melanogaster (flies)
C.eleganis (bacteria worms)
Human organoids
Least: 2D cell cultures
176
How should one go about choosing a disease model?
1. Look at the specific research objectives
2. Research the physiological context, the tissue type, the disease, etc.
3. Make sure the model of choice sufficiently mimics the disease under investigation
4. Make sure that genetic interventions are easy to introduce
5. Ideally, the model of choice should offer sufficient genetic tools
6. Experimental readouts are readily measurable and conclusive
7. Results expected from the study should match the cost
8. Continuous supply of biological material for you and your successors
9. Ethical approval must be obtained
177
What is developmental genetics?
The study of how the instructions encoded in genes control and coordinate the development of an organism, beginning with fertilization and ending with mature individuals capable of reproduction
178
Why is developmental genetics important?
Mutations in genes can hinder developmental processes, resulting in increased risk for birth defects, intellectual disability, and cancer.
179
What percentage of all live births worldwide have a major birth defect?
3%
180
What is the most common cause of birth defects?
Mutations in genes that control normal development, either alone or in combination.
181
What is aniridia?
Hypoplasia or aplasia of the iris. Abnormal development of the irises caused by mutation in Pax6
182
What are the pros and cons of a roundworm animal model?
Pros:
Fate of every cell is known.
Genome is well characterized
Easy to breed and maintain
Cons:
Alternative body plan compared to vertebrates
Tissues cannot be cultured
183
What are the pros and cons of a fruit fly animal model?
Pros:
Easy to breed
Large populations
Vast database of mutants
Feasible and affordable to do large screens
Cons:
Alternative body plan compared to vertebrates
Must be stored live, cannot be frozen
Pathology often different compared to humans
184
What are the pros and cons of a zebrafish animal model?
Pros:
Transparent embryos
Easy to maintain
Large populations
Feasible and affordable to do large screens
Cons:
Targeted gene modification is difficult
185
What are the pros and cons of a frog animal model?
Pros:
Transparent embryo is large and easy to manipulate
Cons:
Tetraploid genome makes genetic experiments difficult
186
What are the pros and cons of a chicken animal model?
Pros:
Easy to observe and manipulate embryo
Cons:
Genetic experiments are difficult
187
What are the pros and cons of a mouse animal model?
Pros:
Pathology similar to humans
Excellent tools for phenotypic characterization
Targeted gene modification is straightforward
Fully annotated genome available
Cons:
Relatively expensive to maintain
Manipulation of embryo is challenging
188
What are the pros and cons of a baboon animal model?
Pros:
Pathology and physiology similar to that of humans
Cons:
Very expensive to maintain
Small populations
Long generation time
Strong ethical concerns with the use of primates
189
What is the process of construction of an animal model?
1. Isolate the blascyst
2. Isolate the inner cell mass
3. Culture the cells
4. Use gene targeting or insertion of the transgene
5. Inject the genetically modified cells into the cavity of the blasocyst from a different mouse strain
6. Implant into the foster mother
7. Backcross the chimera baby mouse
190
What is genetic counselling?
The process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.
191
What information should be provided in genetic counselling?
- Medical diagnosis and its implications in terms of prognosis and possible treatment
- Mode of inheritance of disorder and the risk of developing and/or transmitting it
- Option of genetic testing including the pros, cons, limitations, and potential results
- Choices or options available for dealing with the risks
192
What are the six things that happen in a genetic counselling session?
- Contracting
- Information gathering
- Establishing/verifying diagnosis
- Risk assessment
- Information giving
- Psychosocial counselling
193
In genetic counselling, what is contracting?
Discussing why the person is here so you can determine what they're expecting or what they understand of why they're there.
194
What are the four ethical principles in genetic counselling?
1. Autonomy: the patient has the right to choose or refuse treatment
2. Beneficence: practitioner should act in the best interest of the patient
3. Non-Maleficence: do no harm
4. Justice: fair, equitable, and appropriate treatment of persons
195
There is a family with one son and one daughter. The son has Fragile X and is 6 years old. The daughter is clinically unaffected and is 7 years old. The parents want to test whether or not the daughter is a carrier for Fragile X. Walk through the four principles of ethics. Should you test the daughter?
Autonomy:
- The daughter has a right to decide for herself if she wants to know her carrier status
- 7 year olds cannot give informed consent
Beneficence:
- It may impact her ability to get insurance in the future from a decision she didn't make
- There are reproductive risks, but those are not relevant at this age
Non-Maleficence:
- Do no harm
You shouldn't test the daughter.
196
There is a family with one son and one daughter. The son has Fragile X and is 6 years old. The daughter is clinically unaffected and is 7 years old. The mother is pregnant and wants prenatal diagnosis. Walk through the four principles of ethics. Should you test the fetus?
Autonomy:
- The unborn child has a right to decide for themself if they want to know their carrier status
- Fetuses cannot give informed consent
- The mother also has a right to know since it might impact her decision to carry the baby
Beneficence:
- It may impact their ability to get insurance in the future from a decision they didn't make, especially if they are a carrier but aren't symptomatic
- There are reproductive risks, but those are not relevant
- There is also the possibility that the child will have Fragile X, in which case it would be in the best interest of the child that the parents know and are ready
Non-Maleficence:
- Do no harm
Hard to say
197
There is a family with one son. The son has cystic fibrosis F508/F508. The mother is a carrier F508. The father has no mutation. What are some possible causes of this event?
- Double non-disjunction resulting in the baby having both of the mother's chromosomes
- A trisomy saving event
- De novo mutation in the baby
- The father is not the father.
- Lab error
198
Walk through the four principles of ethics in the case of non-paternity.
Autonomy:
- The mother has the right to not have anyone know
- The father has a right to know
Beneficence:
- Have to act in the best interest of the patient, whichever person that might be
Non-Maleficence:
- Do no harm
199
What is an incidental finding?
Results that are not apparently relevant to the diagnostic indication for which sequencing was ordered.
200
What is a secondary finding?
Purposely analyzed as part of the test, but unrelated to the primary testing indication
201
Jane comes in wanting testing for a BRCA1 mutation that her aunt died of and that her grandmother has. Her mother, Barb, has never been tested and doesn't want to know if she has the mutation, but by testing Jane, you might also learn something about Barb. Walk through the four principles of ethics on this case.
Barb:
Autonomy: right not to know
Beneficence: information is of value to the patient
Non-Maleficence: psychological harm that may result
Jane:
Autonomy: right to know
Beneficence: information is of value to the patient
Non-Maleficence: could harm the relationship with her mom
202
What is an association study?
It compares the frequency of a risk in a patient population to a control population.
They require larger populations.
You want to match as many of the environmental factors as possible, such as age, sex, diet, exercise, stress, etc.
203
Given allele 1 on the patients as A, allele 2 on the patients as B, allele 1 on the controls as C, and allele 2 on the controls as D, what is the Odds Ratio for Disease Association?
AD/BC
It had a low success with candidate gene approach and the results were not often reproducible.
204
What is candidate gene approach?
It's used to identify plausible genes and to identify the genetic variants in the genes that alter gene expression. Candidate genes were selected from human models, animal models, biological knowledge, and positional cloning. The candidate gene gets screened to find variants which are then tested for association with the gene in question by genotyping cohorts of subjects with the specific gene variant in question, and controls.
205
What is coronary artery disease?
A common cause of heart disease.
Caused by atherosclerosis (narrowing of the coronary arteries)
Impeded blood flow leads to lack of oxygen and could cause a stroke
Risk factors include obesity, smoking, hypertension, elevated cholesterol levels, and a positive family history.
Genes associated with CAD are also associated with lipid metabolism, blood clotting, blood pressure, obesity, and diabetes.
206
What is GWAS?
Genome Wide Associate Studies
They have no hypothesis
They look for single nucleotide polymorphisms
Rely on statistical methods to identify association.
Greater frequency of a genetic variant in patients with trait/disease compare to unaffected people.
There is a risk of a false positive because you're testing millions of SNP.
SNPs on a microarray are rarely functional.
Doesn't identify the causal variant
Can produce different results in different populations
207
What is congenital malformations or birth defects?
Present in 2-3% of newborns
Over 4000 different ones
Most are considered multifactorial
Some are associated with monogenic syndromes or chromosomal disorders.
Some have environmental factors
208
Name some multifactorial disorders in adults.
- Atherosclerosis
- Breast Cancer
- Depression
- Epilepsy
- Neural Tube Defects
- Hyper Tension
- Obesity
- Asthma
- Ankylosing Spondylitis
- Parkinson's Disease
- Schizophrenia
- Osetoporosis
- Multiple Sclerosis
- Alzheimer's Disease
- Alcoholism
- Collagen-Vascular
- Crohn's Disease
- Dementia
- Sunburn
- Peptic Ulcers
- Psoriasis
209
What is cardiovascular disease?
A multifactorial disorder.
Heart disease
Leading cause of death worldwide
The most common underlying cause of heart disease is CAD.
Environmental risk factors include: age, sex, diet, smoking, stress, lack of exercise, high cholesterol, obesity, hypertension, diabetes.
Genetic risk factors include genes involved in: lipid metabolism, inflammation, blood clotting, hypertension, obesity, diabetes
210
What are the four steps involved in translating families with multifactorial disorders to clinical care?
1. Get information based on family history
2. Do risk assessment
3. Develop prevention/treatment plans/cures
4. Check for pharmacogenetic initiatives
211
Recurrence risks for multifactorial disorders are influenced by:
- Disease severity
- Degree of relationship
- Number of affected family members
- Heritability of disease
- Sometimes sex
212
What are four ways that genes and quantitative trait loci involved in a trait can be identified?
- Linkage: correlation between genomic regions and phenotype
- Affected sibling pairs: excess allele sharing
- Association studies: correlation between alleles and phenotype (GWAS)
- Animal models
