Final (cumulative) Flashcards
(275 cards)
1
Q
What is stratification? What effect does it have on genotype frequencies? Also provide an example
A
A form of non-random mating, effectively separating breeding populations. It increases homozygosity and decreases heterozygosity. Ex: sickle cell disease is higher frequency in African Americans than in the US general population.
2
Q
What is assortative mating and an example of this?
A
A form of non-random mating. Choosing a mate based upon their possession of a particular trait
- people tend to mate with people who resemble themselves
3
Q
What is consanguinity? What is inbreeding?
A
A form of non-random mating
Consanguinity: related by descent from a common ancestor
Inbreeding: mating of closely related individuals
4
Q
Who are the hutterites? What is seen with their allele frequencies?
A
Genetic isolate, small religious group that tends to marry within their families. Average degree of relatedness is 2nd cousins.
- Some autosomal recessive rare alleles are common
5
Q
What is genetic drift?
A
Random fluctuations of allele frequencies from generation to generation that take place in small, isolated populations such as island populations or socioreligious groups
- Chance occurrences, independent of genotype, have significant effect on disease allele frequencies
6
Q
What is the founder effect? Provide an example
A
A type of genetic drift. A population starts with a small number of individuals (founders) or drastic reduction in population (bottleneck)
- Allele frequencies established by chance in a population that is started by a small number of individuals could be higher than expected
Ex: French Canadians have a high frequency of certain disorders, such as Leigh syndrome
7
Q
Explain how migration and gene flow disrupt HWE
A
Slow diffusion of genes across a barrier (geographic or social). This merges different “migrant” gene pools into the larger population causing changes in allele frequencies.
8
Q
Explain how selection can disrupt HWE
A
Wallace and Darwin identified selection as the primary force that leads to evolutionary divergence and the formation of new species.
- Natural selection acts on genetic diversity in populations and is the major force in driving evolution
- Selection increases the reproductive success of certain genotypes
9
Q
What is fitness?
A
Differential reproduction shown by some members of a population that is the result of differences in fitness
- A measure of relative survival and reproductive success of a specific individual or genotype
10
Q
Mutations generate new alleles, but has little impact on allele frequency in a population. Why?
A
Lots of mutations are lethal and get eliminated from the population right away
11
Q
If the mutation rate for a gene is known, what can be calculated?
A
The change in allele frequency resulting from new mutations in each generation can be calculated
12
Q
How does the Duchenne muscular dystrophy (DMD) allele maintain in a population? Describe the mutation rate of DMD and how it is balanced within a population.
A
In heterozygous form, because if present in homozygous state, it is lethal.
The mutation rate for DMD is (relatively) high, introducing more DMD alleles.
- The frequency of the DMD allele in a population is balanced between alleles introduced by mutation and those removed by deaths
13
Q
What is heterozygote advantage and two examples of it?
A
The high frequency of genetic disorders in some populations is the result of selection that often confers increased fitness on heterozygotes. This can disrupt HWE.
- A single sickle-cell allele confers resistance to malaria
- A single Tay-Sachs allele confers resistance to tuberculosis
14
Q
True or false: Many sickle-cell anemia recessive homozygotes die in childhood
A
True
15
Q
What is the chi-square formula?
A
χ²= sum of (observed-expected)^2/expected
16
Q
How to find degrees of freedom for chi-squared test?
A
df=n-1 (n= the number of genotypes)
17
Q
If your calculated chi-square sum is greater than the critical value, what does this mean?
A
The difference between observed and expected frequencies is statistically significant, suggesting that the population is likely not in HWE
18
Q
If your calculated chi-square sum is less than or equal to the critical value, what does this mean?
A
There is not a statistically significant difference, suggesting the population is in HWE
19
Q
Define disease model
A
An animal, tissues or cells that display some or all pathological features of the actual disease in controlled, experimental setting
20
Q
What are the 3 validity criteria for animal models?
A
- Face
- Construct
- Predictive
21
Q
Describe the “face” validity criterion
A
Similar symptoms are observable in both the animal model and a patient
22
Q
Describe the “construct” validity criterion
A
The molecular and cellular mechanisms of the disease are similar in both the animal and patient
23
Q
Describe the “predictive” validity criterion
A
An animal’s response to pharmaceutical or behavioural testing is similar to humans
24
Q
What is a basic experiment model still used today?
A
Immortalized cell lines, following the discovery of HeLa cells
25
What are 4 things that HeLa cells specifically helped discover due to their immortality and growth?
1. Polio vaccine
2. HPV role in cervical cancer
3. HIV identification
4. Telomerase activity
26
Describe the following for 2D cell culture models (e.g. HeLa cells and cancer cell lines):
- Ease of establishing system
- Ease of maintenance
- Recapitulation of developmental biology
- Duration of experiments
- genetic manipulation
- genome-wide screening
- Physiological complexity
- Relative cost
- Recapitulation of human physiology
- Ease of establishing system: meh/no (i.e. getting new ones is difficult)
- Ease of maintenance: yes (main advantage)
- Recapitulation of developmental biology: no (starting with an already developed cell)
- Duration of experiments: yes (don't have to wait for the reproduction cycle)
- genetic manipulation: yes
- genome-wide screening: yes
- Physiological complexity: no (no connection to a living system)
- Relative cost: yes
- Recapitulation of human physiology: meh (still has the human genome so still partly useful?)
27
Describe the following for C. elegans models:
- Ease of establishing system
- Ease of maintenance
- Recapitulation of developmental biology
- Duration of experiments
- genetic manipulation
- genome-wide screening
- Physiological complexity
- Relative cost
- Recapitulation of human physiology
- Ease of establishing system: yes
- Ease of maintenance: yes
- Recapitulation of developmental biology: yes (gametes are very accesible)
- Duration of experiments: yes (quick reproductive cycle)
- genetic manipulation: yes (simple genomes that are well understood)
- genome-wide screening: yes
- Physiological complexity: yes (within a living organism)
- Relative cost: yes
- Recapitulation of human physiology: meh (lots of differences between C. elegans and humans)
28
Describe the following for D. melanogaster models:
- Ease of establishing system
- Ease of maintenance
- Recapitulation of developmental biology
- Duration of experiments
- genetic manipulation
- genome-wide screening
- Physiological complexity
- Relative cost
- Recapitulation of human physiology
- Ease of establishing system: yes
- Ease of maintenance: yes
- Recapitulation of developmental biology: yes
- Duration of experiments: yes
- genetic manipulation: yes
- genome-wide screening: yes
- Physiological complexity: yes
- Relative cost: yes
- Recapitulation of human physiology: meh (lots of differences between D. melanogaster and humans)
29
Describe the following for zebrafish models:
- Ease of establishing system
- Ease of maintenance
- Recapitulation of developmental biology
- Duration of experiments
- genetic manipulation
- genome wide screening
- Physiological complexity
- Relative cost
- Recapitulation of human physiology
- Ease of establishing system: meh
- Ease of maintenance: meh
- Recapitulation of developmental biology: yes
- Duration of experiments: yes
- genetic manipulation: yes (embryos are very accessible)
- genome-wide screening: yes
- Physiological complexity: yes
- Relative cost: meh
- Recapitulation of human physiology: yes (have more similarity to the human system)
30
Describe the following for M. musculus models:
- Ease of establishing system
- Ease of maintenance
- Recapitulation of developmental biology
- Duration of experiments
- genetic manipulation
- genome-wide screening
- Physiological complexity
- Relative cost
- Recapitulation of human physiology
- Ease of establishing system: meh
- Ease of maintenance: meh
- Recapitulation of developmental biology: yes
- Duration of experiments: yes
- genetic manipulation: meh
- genome-wide screening: no (more complex and difficult)
- Physiological complexity: yes
- Relative cost: meh
- Recapitulation of human physiology: yes (have more similarity to the human system)
31
What is the main advantage seen with using models like zebrafish and mice as models for human disease?
More complex organisms have more similarity to the human system
32
Describe the following for patient-derived xenograft models:
- Ease of establishing system
- Ease of maintenance
- Recapitulation of developmental biology
- Duration of experiments
- genetic manipulation
- genome-wide screening
- Physiological complexity
- Relative cost
- Recapitulation of human physiology
- Ease of establishing system: meh
- Ease of maintenance: meh
- Recapitulation of developmental biology: no (studying disease at a certain stage)
- Duration of experiments: yes
- genetic manipulation: no (not really the goal)
- genome-wide screening: no
- Physiological complexity: yes
- Relative cost: meh
- Recapitulation of human physiology: yes
33
Describe the following for human organoid models (an artificially grown mass of cells or tissue that resembles an organ):
- Ease of establishing system
- Ease of maintenance
- Recapitulation of developmental biology
- Duration of experiments
- genetic manipulation
- genome-wide screening
- Physiological complexity
- Relative cost
- Recapitulation of human physiology
- Ease of establishing system: yes (grown in cell culture)
- Ease of maintenance: yes
- Recapitulation of developmental biology: yes (can be studied from initial study point)
- Duration of experiments: yes (grow pretty quick and aren't reliant on the reproductive system of an animal)
- genetic manipulation: yes
- genome-wide screening: yes
- Physiological complexity: meh (isolated organ with no connection with other organs, only characteristics of a single organ)
- Relative cost: yes
- Recapitulation of human physiology: yes
34
Describe the interplay between experimental pliability and physiological relevance when using advanced models
More experimentally pliable models (able to do a lot with the model and have more control) aren't as physiologically relevant. And vice versa, the less experimentally pliable mode share increased physiological relevance (these models are less able to be controlled)
- e.g. 2D cell cultures, human organoids, and C. elegans are less physiologically relevant but have greater experimental pliability, while D.melanogaster, zebrafish (D. zerio), mice and patient-derived xenografts (PDX) have greater physiological relevance but less experimental pliability
35
True or false: intestinal organoid models represent the human intestine very well (is very physiologically relevant)
False; the intestinal organoid model is just an enclosed spherical model of lumen. So dead cells and waste get trapped in lumen and can't be carried away like what usually happens in the intestine
- But is still helpful because the stem cells are still produced in the crypts of the organoid like seen in the intestine
36
What is an advantage of using a zebra fish model over a 2D cell culture model?
a) zebrafish are easier to genetically manipulate than 2D cell culture
b) zebrafish better model physiological complexity than 2D cell cultures
c) zebrafish are less costly than 2D cel culture
d) zebrafish are easier to maintain than 2D cell culture and never jump out of their tanks
B
37
What are 3 things that researchers do to increase the physiological relevance of organoid models?
1. Alter the morphology so that it recapitulates human organs
2. Increase vascularization (because organs within the body are connected using vascularization)
3. Add organ systems
38
What is an example that we looked at of how researchers change the morphology of organoids to have increased physiological relevance
Researchers directed organoid morphogenesis for intestines using a growth matrix (rather than allowing the organoids to grow freely in a suspension, which usually leads to them developing a spherical shape). This growth matrix contained channels that ensures that the cells grew into elongated, structured shapes rather than random spheres (basically they directed morphogenesis of this organoids, aka controlling where the cells grow, and allowing for the model to grow in a way that better recreates a natural human intestine)
- This decreased the build-up of dead cells and waste within the lumen, and allowed for less maintenance of the lumen. Also mimics natural intestinal architecture, making it useful for studying tissue behaviour
39
True or false: researchers have used monolayer models containing intestinal stem cells and other intestinal cell types to study the regulation of stem cell differentiation, proliferation and maintenance
True
40
What are three ways that we can increase the vascularization of organoids to increase their physiological relevance?
1. Manipulating cell differentiation
2. Manipulating the physical environment of the organoids
3. Utilizing orthotopic transplantation
41
How have researchers manipulated cell differentiation to increase the vascularization of organoids?
They started with human pluripotent stem cells that were given specific reagents/growth media which allowed for them to develop into intestinal organoids (but different cell types within the organoid). They then grouped cell types together based on similar transcriptomes with early stage intestinal organoids. They were able to identify a small endothelial population (vascularized cells). The growth of these endothelial cells were then emphasized and sustained throughout the development of the intestinal organoids which increased overall vascularization.
Summary: Directed differentiation allowed for the development of intestinal organoids with vasculature present)
42
Describe how researchers increased the vascularization of kidney organoids through manipulation of the physical environment
The researchers grew kidney organoids under a high pressure flow system environment (they engineered a fluid chip that allowed for flow over the media and they were trying to recreate the high pressure seen in the filtration system of the nephron)
- High flow increased vascularization of the kidney organoids, having that pressure moving on top of them allowed for a better development of the vasculature of the kidney organoids
- There was also an increase in the presence of podocyte cells (highly specialized epithelial cells that wrap around the capillaries of the kidney's glomeruli, forming the glomerular filtration barrier)
Summary: the physical environment allowed for development of vasculature as well as development of specialized kidney cell types
43
What is an orthotopic transplantation?
Taking cells from a specific organoid and then putting it within the organ that it came from into a model organism
44
Describe how researchers increased vascularization of neural organoids
Researchers implanted a pre-made neural organoid into the brain tissue of a mouse which allowed for the formation of vasculature within the transplanted organoids
- Organoid tissue tagged with GFP in order to differentiate between the mouse brain tissue and the tissue originating from the organoid
45
What theoretical idea describes how we could make organoid models more physiologically relevant by incorporating whole organ systems?
Organ systems-on-chip, a theoretical idea that hasn't been done yet. Describes that if we were able to grow organoids from tissues all somehow connected, we could increase the physiological relevance of organoid tissues.
46
What is a patient-derived xenograft?
Transferring human tissue to a mouse model (often cancer cells are injected below the skin of mice to allow for growth of a subcutaneous tumour)
47
What is an orthotopic xenograft?
Transferring of human cancer to the same organ in mice as the organ from which it came from in the human patient
48
Why are patient-derived xenografts still used if orthotopic xenografts are typically better models?
It's simpler and more feasible to carry out patient-derived xenografts (orthotopic xenografts carry many more considerations)
49
How did researchers compare and validate organoids within patient-derived xenografts with parental tumours? What did they find?
Extracted parental tumours and extracted organoids from patient-derived xenografts and compared them to parental tumours using different analysis. They found that organoids production from patient biopsies is a valid method of mimicking tumour evolution and can be used to study drug responses, offering a valuable tool for precision cancer medicine research.
50
Explain how CRISPR-Cas9 was used to screen for the tumorigenic potential of genes commonly found to be mutated in colorectal cancer
Pools of gRNAs to target these "candidate genes". This generated engineered organoids with these specific mutations, and then observed the ability of these organoids to form tumours and metastasize when transplanted orthotopically into mouse intestines.
- Compared this ability between different pools of mutated organoids
51
Describe how patient-derived xenografts can be used to determine treatment for colorectal cancer
First generate patient-derived organoids. Then, inject these organoids into mice forming a xenograft, and administer treatment to the xenografts. Measure effecitveness of treatment by measuring tumour size.
52
What are 9 things to consider when choosing a disease model?
1. Figure out your specific research objectives
2. Do homework; figure out the physiological context needed, tissue type and disease that you're trying to model
3. Model of choice must sufficiently mimic the disease under investigation
4. Ensure that genetic interventions are easy to introduce into the model
5. Ideally, model of choices should offer sufficient genetic tools to carry out genetic manipulation (different options to actually carry out that genetic manipulation when we need it
6. Experimental readouts need to be readily measurable and conclusive
7. Results expected from the study should match the cost of the model
8. Continuous supply of biological material should be available for you and your successors
9. Ethical approval must be obtained (if applicable)
53
What is genetics counselling?
The process of helping people to understand and adapt to the medical, psychological and familial implications of genetic contributions to disease
54
True or false: genetics counsellors can diagnose
False; this is the role of the geneticist (MD)
55
What 4 pieces of information should be provided by genetics counsellors to patients?
1. Medical diagnosis and its implications in terms of prognosis and possible treatment
2. Mode of inheritance of disorder and the risk of developing and/or transmitting it
3. Option of genetic testing including pros, cons, limitations and potential results
4. Choices or options available for dealing with the risks
56
What 6 things are done in a genetic counseling session?
1. Contracting (understand why patient is meeting with counselor and what their expectations are for the session)
2. Information gathering (taking history)
3. Establishing/verifying diagnosis
4. Risk assessment (risk of inheritance or passing on condition, explaining what certain screens provide in terms of information, etc)
5. Information giving (e.g. inheritance patterns, options for patient)
6. Psychosocial counseling (dealing witht he diagnosis)
57
Does genetics counselling focus on directive or non-directive approaches? How and why?
Non-direective: there is a universal agreement that genetics counsellors will be non-coercive with no attempt to direct patient along a course of action.
- Have to be non-judgemental, even if the decision is ill-informed
- Consideration should be given to consequences of each possible course of action
58
Define ethics
Moral principles that govern a person's or group's behaviour, the moral correctness of a specified conduct
59
What are the 4 ethical principles?
1. Autonomy
2. Beneficence
3. Non-maleficence
4. Justice
60
Explain the autonomy ethical principle
The patient has the right to choose or refuse treatment/testing (this can be based on personal opinions and beliefs)
61
Explain the beneficence ethical principle
Practitioner should act in the best interest of the patient
62
Explain the non-maleficence ethical principle
Do no harm
63
Explain the justice ethical principle
Fair, equitable and appropriate treatment of persons (treating all people fairly and equitably, regardless of their background or characteristics)
64
Is carrier testing of asymptomatic minors typically done?
No, because we should respect the patient's autonomy for knowing if they're a carrier when they're an adult (if being a carrier doesn't affect their childhood and there's no implications for their own health)
65
Is prenatal diagnostic testing typically done
Yes, because the diagnosis could impact the child's health and could present termination options to mother if she wants them
66
Is prenatal carrier testing typically done?
No, same reasons as carrier testing of asymptomatic minors
67
Is prenatal testing for the BRCA mutation typically done?
No, because BRCA1 mutation has incomplete penetrance. But there's always exceptions
68
How does insurability affect decisions on carrying out genetics testing?
Laws might change when the tested individual is an adult so not testing them before they're an adult protects them from lack of insurance
69
Is predictive testing recommended in minors?
Predictive testing should OPTIMALLY be deferred until the individual has the capacity to weigh the associated risks, benefits and limitations of this information, taking his/her circumstances, preferences and beliefs into account to preserve his/her autonomy and right to an open future.
70
What was the genetic non-discrimination act (GNA) put into law for?
Protects individuals from the use of genetic test results in areas outside of medical care and research, such as insurance and employment
71
What should genetics counsellors do if they encounter a potentially non-paternity result in a test?
Informed consent (non-paternity should be covered in pre-test counselling)
- Tell parents that they're both expected to be carriers
Need to consider non-maleficence and beneficence when informing the parents
72
Should secondary findings in whole exome sequencing be reported to patients?
Only if they sign a separate consent form for reporting of secondary findings
73
How do you balance the conflicting "rights" of two family members? e.g. if daughter wants to know if she has a BRCA mutation but mother doesn't
Daughter will have the right to testing (autonomy) but counsellor should discuss what she will do if the test comes back as positive (e.g. will she tell her mom?)
- Non-maleficence: trying to avoid harm to their relationship
- Beneficence: information is of value to patients
74
What is Peto's paradox?
Peto's paradox is the observation that large, long-lived animals don't have a higher cancer incidence than smaller, shorter-lived animals, despite the expectation that more cells and cell divisions would lead to more mutations and thus, more cancer.
75
Define neoplasia
New growth
76
What is hyperplasia?
Too much growth
77
What is dysplasia?
Incorrect growth
78
What is benign growth?
Localized growth (doesn't spread)
79
What is malignant growth?
Uncontrolled growth
80
What is metastatic growth?
Distant growth
81
Why does cancer in the lungs, brain and liver cause the most metastasis?
Higher blood flow through the capillaries (cancer cells travel through the capillaries)
82
True or false: Malignant carcinomas can travel via lymph vessels to other places in the body
True
83
What are the 6 basic capabilities of invasive tumours?
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
84
What does cancer result from in general?
An accumulation of somatic variants
85
What describes the clonal evolution of tumours?
The fact that not all tumour cells have the same mutation
- Mutations keep happening until you get a metastatic tumour (so will find different hits in different tissues)
86
How many independent variants are requierd for a normal epithelial cell to become a metastatic cancer?
6 independent hits in the same cell
87
What is most cancer caused by?
Environmental factors
88
What type of cancer can sunlight (UV) cause?
Melanoma
89
What type of cancer can an atomic bomb (IR) cause?
Leukemia
90
What type of cancer does previous X-rays cause?
Lung cancer
91
What type of cancer does asbestos cause?
Lung cancer
92
What type of cancer does smoke soot cause?
Scrotal cancer
93
What type of cancer does hepatitis cause?
Liver cancer
94
What type of cancer does EBV (virus) cause?
Burkitt's lymphoma
95
What type of cancer does HPV cause?
Cervical cancer
96
What type of cancer does HIV cause?
Lymphoma and Kaposi sarcoma
97
What type of cancer does drinking too many nitrites cause?
Liver cancer
98
What type of cancer does drinking too much alcohol cause?
Liver cancer
99
What type of cancer does a low fibre diet cause?
Colon cancer
100
What type of cancer does smoking cause?
Lung cancer
101
What type of cancer is seen more often in prostitutes? Why?
Cervical cancer, due to increased exposure to HPV
102
What 3 types of cancer is seen more often in nuns? Why?
Breast, ovarian, uterine cancer
- because they never go through pregnancy and there's something about pregnancy hormones that prevents these cancers
103
What is retinoblastoma in general? What gene is mutated?
Retinal tumour of childhood, variants (hits) in RB1 gene
- Tumour is in the eye that doesn't reflect red from flash (tumour fills up entire eye)
104
The presence of bilateral multifocal tumours (increases/decreases) the risk of offspring being a carrier
- Explain why
Increases
- These tumours have characteristics of a germline variant
105
What causes the multiple numbers of independent second hits in the RB1 gene leading to retinoblastoma?
A large number of retinoblasts undergoing rapid proliferation
106
What is the penetrance of an RB1 variant?
>99%
107
Describe Knudson's two hit hypothesis for germline and somatic mutations
Germline mutation (Inherited Disease): one copy is already mutated in every cell (first hit is inherited) and second hit is acquired (so it is much more likely that a second hit will be acquired through lifetime)
Somatic mutation (Sporadic disease): Both copies are acquired
108
What is the most common second hit in tumours? What 4 things usuallty cause a second hit?
Loss of heterozygosity (LOH)
1. Nondisjunction, leading to duplication of the hit in the remaining chromosome
2. Sub-chromosomal deletion of the normal chromosome
3. Unbalanced reciprocal translocation of the normal chromosome
4. Somatic recombination, leading to two copies of the hit
109
What are 5 characteristics of inherited cancer?
1. Multiple primary tumours in an individual
2. Bilateral in paired organs
3. Early onset (20s-30s)
4. Autosomal dominant inheritance usually
5. Same or linked forms of cancer in two or more close relatives
110
What are 3 characteristics of sporadic cancer?
1. Single tumours (e.g. unifocal)
2. Unilateral in paired organs
3. Later onset (60s-90s)
111
Mutations in what 4 types of genes results in cancer?
1. Oncogenes
2. Tumour suppressor genes
3. Caretaker genes (AD, AR; a type of tumour suppressor)
4. Gatekeeper genes (a type of tumour suppressor)
112
What are tumour suppressors in general?
Function to keep the behaviour of cells under control
- Slow or stop cell cycle progression, maintain integrity of the genome or induce apoptosis
113
What is a caretaker tumour suppressor protein?
Fixes DNA damage as it accumulates in the genome
114
What is a gatekeeper tumour suppressor protein?
Prevents the cell cycle from getting out of control
115
What mutation is Li-Fraumeni syndrome caused by?
Germline loss of functino variants in TP53 (a gatekeeper tumour suppressor)
116
What 6 cancers are associated with Li-Fraumeni syndrome?
1. Connective tissue
2. bone
3. Breast
4. Brain
5. Blood
6. Adrenal
117
What is the inheritance pattern for Li-Fraumeni syndrome?
Autosomal dominant inheritance
118
Why do women have a greater penetrance with Li-Fraumeni syndrome?
Because they have more mammary tissue (and the syndrome causes breast cancer)
119
What mutation is Familial adenomatous polyposis coli (FAP) caused by?
Variants in the APC gene, a gatekeeper tumour suppressor that regulates cell division in the colon
120
What is the inheritance pattern for Familial adenomatous polyposis coli (FAP)?
Autosomal dominant inheritance
121
What is the penetrance in Familial adenomatous polyposis coli (FAP)?
100%
122
What is familial breast cancer? How is it different from Mendelian breast cancer?
Inheriting several mutations that can increase the risk of getting cancer (but not actually inheriting a cancer gene, this is Mendelian breast cancer)
123
True or false: familial breast cancer is multifactorial
True
124
True or false: breast cancer is common, but Mendelian breast cancer is rare
- explain
True; most breast cancer cases are sporadic (2 hits are acquired in BCRA genes throughout lifetime)
125
Variants in BRCA 1/2 account for __% of Mendelian breast cancer (__% total)
20, 2
126
What % of breast cancer cases are sporadic?
70
127
What % of breast cancer cases are familial or multifactorial?
20
128
What % of breast cancer cases are Mendelian?
10
129
Hereditary breast and ovarian cancer results from variants in...
BRCA 1/2
130
What do BRCA 1/2 function in repairing?
Double stranded DNA breaks
131
BRCA 1/2 inheritance pattern?
Autosomal dominant
132
True or false: BRCA 1/2 mutations are only penetrant in women
False
133
If we can't prevent cancer, why look for BRCA 1/2 variants?
- Explain for the patient with cancer
- Treatment: therapy choice (radiation vs surgery), adjunct therapy, propholaxis (action to prevent disease, e.g. removing both breasts)
134
If we can't prevent cancer, why look for BRCA 1/2 variants?
- Explain for the family members of the patient
1. Propholactic surgical and lifestyle options (action to prevent disease, e.g. removing both breasts just in case)
2. Surveillance frequency and type
135
True or false: cancers can be found in other genetic syndromes and there's a link between constitutional aneuploidy and cancer susceptibility
True
136
What are constitutional chromosome instability syndromes (aka DNA repair disorders) caused by?
Complete loss of function variants in DNA repair genes, aka the caretakers
137
What is xeroderma pigmentosum? What causes it?
Extreme sun sensitivity and high risk of skin cancer in any sun exposed area. Caused by biallelic (AR) variants in one of six genes involved in NER which are caretaker tumour suppressors (so it's a constitutional chromosome instability syndrome/DNA repair disorder caused by
138
What is Ataxia Telangiectasia?
Childhood onset of ataxia (uncoordinated movement) due to biallelic (AR) variants in the ATM gene (a caretaker gene involved in cell cycle control during DSB repair)
- Very sensitive to ionizing radiation
139
What is Bloom syndrome caused by?
Biallelic (AR) variants in the BLM gene, which is a caretaker tumour suppressor involved in the repair of DNA damage (especially DSB)
140
True or false: Mendelian cancer syndromes are related
True
141
Why do elephants rarely get cancer, despite Peto's paradox?
They have 15-20 copies of TP53 and for cancer to progress, all of these need to be mutated.
142
What is an oncogene? How it is different from a proto-oncogene?
A proto-oncodgene is a normal gene involved in some aspect of cell division or proliferation. May become activated (SNV or other mechanism) to become an oncogene (DOMINANT GOF VARIANT IN PROTO-ONCOGENE = ONCOGENE)
143
What are some examples of proto-oncogenes?
Growth factors, receptor Tyr-kinases, transcription facotrs, telomerase, anti-apoptotic proteins, etc
144
What are 4 ways that proto-oncogenes are activated?
1. Activating variant
2. Gene amplification (and all of the copies are active)
3. Rearrangement creating novel fusion protein
4. Translocation into active chromatin (i.e. proto-oncogene goes under the control of a different promoter)
145
RET receptor mutations lead to...
Familial multiple endocrine neoplasia type 2 (Autosomal dominant)
146
Describe how RET receptor mutations (oncogenes) lead to cancer
Heterozygous germline variants in RET, usually involving a mutation in Cys, so receptors cause disulfide bonds and receptors them cross-phosphorylate even in the absence of GDNF (signalling protein)
147
Describe how BRAF mutations (oncogenes) lead to cancer
Somatic activating variants in BRAF are found in 50% of melanoma cases, causes constitutive activation of a downstream signaling cascade that leads to proliferation, survival and differentiation
148
Describe how N-MYC (aka MYCN) mutations (oncogenes) lead to cancer
Gene amplification in N-MYC (a transcription factor that promotes tumour progression)
- Copy number correlates with stage
149
Where do amplified genes tend to reside?
Extrachromosomal structures (extra genes that somehow acquire a centromere, and that replicate with the cell cycle due to pseudocentromeres)
150
Describe how MYC mutations (oncogenes) lead to cancer
MYC gene (different from NMYC) rearranged into being after immunoglobulin promoter in lymph nodes (very high transcription)
- Leads to Burkitt lymphoma
151
Describe the endemic variant of Burkitt lymphoma
Found in regions endemic with malaria
152
Describe the sporadic variant of Burkitt lymphoma
Most common form where malaria is not endemic
153
True or false: Burkitt lymphoma is immunosupression-related
True; 2.5% of untreated HIV patients will develop Burkitt lymphoma
154
Describe how the BCR:ABL1 fusion gene causes cancer
Rearrangement of chromosome 9 and 22 places the ABL1 Tyr kinase under the control of the BCR (breakpoint cluster region gene of unknown function) which is highly expressed in bone marrow
- Is present in 95% of patients with chronic myeloid leukemia (CML)
155
What is BCR:ABL1?
A kinase that activates downstream targets for growth independent of external signals
156
What is a drug that functions against the BCR:ABL1 fusion gene?
Imatinib, which prevents the binding of ATP to BCR-ABL1 kinase, so phosphorylation/activation of the growth signals is inhibited
157
Describe how herceptin (Trastuzumab) can be used to treat breast cancer
ERBB2 (HER2) is a receptor involved in the activation of the cell cycle that is amplified in 20-30% of invasive breast cancers (mutations cause ligand-independent activation of HER2)
- Herceptin binds to HER2 and prevents it from dimerizing
158
Describe how olaparib can be used to treat BRCA1/2/ATM-deficient metastatic cancers
PARP is a protein involved in ssDNA breaks. Olaparib is a PARP inhibitor that prevents the repair of ssDNA breaks. In the S phase, this increases the frequency of dsDNA breaks. BRCA1/2/ATM-deficient cells can't properly repair DSBs, so this kills the cancer cells but not the normal cells (since normal cells still have a copy of functional BRCA 1/2)
159
Mutations causing transformation are usually ____ mutations
- Provide the exception
Usually somatic mutations, exception is germline variants in RET gene
160
Define precision medicine
Emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person.
161
True or false: While some advances in precision medicine have been made, the practice is not currently used for most diseases
True
162
Define personalized medicine
Genomics + medical information technology + patient empowerment (Rare genetic disease identification; direct to consumer testing e.g. 23 and me)
163
Define stratified medicine
Matching therapies with specific population characteristics using clinical biomarkers (cancer therapy; pharmacogenomics)
164
What is pharmacogenomics?
The study of how someone's combination of genotypes predicts how they respond to drug treatment (same diagnosis, same prescription)
165
A 7 day old baby shows signs of lethargy and troubles breast feeding. Baby was found dead at day 13. Toxicology report found morphine levels at 70 ng/mL (normal <2). Mom had been taking Tylenol 3 since delivery; breast milk concentration of 87 ng/mL (normal <20). What happened?
Codein is metabolized into morphine by the cytochrome family of enzymes in the liver. These enzymes vary in activity between individuals. Mom is an ultra-metabolizer (has more than two functional alleles for CYP2D6 enzyme). She was able to tolerate the high morphine doses because she's bigger, but baby couldn't tolerate these morphine doses (because it's not the normal amount suitable for a baby)
166
Describe an example of how pharmacogenomics can predict adverse drug reactions
HLA-B*1502 in Han Chinese are 2500X more likely to develop SJS/TEM with exposure to carbamazepine (take the drug then your skin starts to boil off)
167
True or false: Drug labels recommend pharmacogenetics testing for >90 drugs
True
168
Describe how every tumour from each patient is unique, and how drug companies are trying to develop targeted therapies to unique tumours
Tumours are made of different driving pathways so drug companies try to determine all the pathways involved in a single tumour and try to give it targeted therapy for that tumour
169
How do you identify tumour variants for targeted therapy?
Sequence the tumour and the unaffected tissue, then determine which variants are present in the tumour but not the healthy tissue
170
True or false: the genetics of complex traits is easy to develop personalized meidicne for
False
171
True or false: predicting the effect of genetic variants in multifactorial traits is incredibly difficult and the results aren't usually right
True
172
Describe lysosomal storage disease
One of the enzymes in the lysosome involved in degradation is non-functional so molecules accumulate in the lysosome
173
Describe how bone marrow transplants work for treating lysosomal storage disease
Makes functional macrophages (if this is where the issue arised). Macrophages contain some of the enzymes involved in lysosomal degradation
174
Describe how enzyme replacement therapy works for treating lysosomal storage disease (and what the replacing enzyme requires)
Enzyme-replacement therapy in the blood via injection, can inter cells and lysozymes ONLY IF IT HAS A MONO-6-PHOPSHATE to actually target the lysozyme
175
Describe how chaperone therapy works for treating lysosomal storage disease
If an enzyme gets misfolded and is then targeted for lysosome, you can create a chaperone for it to properly fold
176
Describe how gene therapy works for treating lysosomal storage disease
Still on trial, but replace the DNA in the bone marrow with functional enzyme genes
177
Describe the cause of spinal muscular atrophy
Genomic arrangement of the SMA locus. WT has 2 copies of SMN1 and SMN2 (two different genes). SMN1 not in SMA patients. SMN2 contains a variant in exon 7 that results in its exon skipping.
- Individuals with SMN2 only have 10% of copies with exon 7 (functional copies) which isn't enough for proper function
178
What are two potential therapies for SMA? Which is more expensive?
1. Oligonucleotide binds to intronic splice silencer, leading to inclusion of exon 7 (converting SMN2 into SMN1). Hundreds of thousands of dollars.
2. Infect cells with viral DNA containing SMN1 in kids <2y or before onset of symptoms. 2.1 million dollars.
179
Describe the Milasen treatment
Example of a targeted therapy for one individual with Batten disease (a lysosomal strorage disease)
- Retrotransposon was inserted between exon 6 and 7, contains a stop codon so caused a nonsense variant in MFSD8 was being produced.
- Researchers created an antisense of all the nucleotides over the acceptor site of this retrotransposon, allowing for normal splicing to occur on this allele and to make a normal protein
180
What is a monogenic disorder?
A single gene disorder, where pathogenic variant(s) in a single gene are sufficient to cause the trait
181
What is a polygenic disorder? How does it differ from locus heterogeneity?
Variant(s) in multiple genes are needed to cause the trait
- Different from locus heterogeneity in single gene disorders, bc polygenic disorders need multiple variants in different genes to be present at the same time
182
What is a multifactorial disorder?
A complex disorder, variant(s) in multiple genes and environmental factors (lifestyle, chemical exposures, etc) are needed to cause the trait
183
Monogenic disorders are (rare/common), while multifactorial disorders are (rare/common)
Rare, common
184
What % of individuals experience genetic disorders by age 5?
5%
185
What % of individuals experience genetic disorders throughout their lifetime? What is the vast majority caused by?
67%, vast majority comes from multifactorial
186
What are three ways that genes work together?
1. For the appropriate expression of genes (e.g. transcription and translation require the coordination of multiple proteins)2
2. In forming functional complexes (e.g. hemoglobin)
3. In a pathway (e.g. ETC, TCA) - proteins act as substrates/products in pathways and enzymes
187
What are 5 examples of how genes respond to the environment?
1. Genes respond to glucose levels (code for insulin and insulin receptors)
2. Genes respond to hormones (e.g. results in baldness, lactation)
3. Genes respond to temperature (e.g. results in a change in coat colour)
4. Genes respond to teratogens (which influences fetal development)
5. Genes respond to viral exposure (which impacts disease manifestation, e.g. COVID 19 causes no symptoms while it was lethal in others)
188
What is Weddington's hypothesis? Provide an example
Biological processes such as development are finely tuned. Perturbation of the process can produce a very different result
- e.g. Tall genes and an optimal environment cause you to have maximum height potential. Poor nutrition causes you to fall slightly off of the optimal pathway, resulting in slightly short stature. A growth hormone deficiency causes completely short stature (doesn't matter if you have poor nutrition or not)
189
True or false: mechanisms leading to multifactorial diseases are less understood
True
190
Albinism is a (single gene/multifactorial) disease, while the skin colour continuum is a (single gene/multifactorial) trait
Single gene, multifactorial
191
True or false: the combination of genes resulting in the skin colour continuum is known
False; it is unknown
192
The additive effects of many genetic environmental factors produces a...
- Explain this
Continuous spectrum
Each gene individually follows mendelian rules. Genes act together on the same trait. So if theres multiple genes with small effects acting on a phenotype, and you add in environmental factors, the spectrum of phenotypes appears continuous (there is variation around a given genotype)
193
Increasing the number of genetic risk factors (multiple alleles at one or multiple genes) (increases/decreases) the number of possible phenotypic classes
Increases
194
Height, BMI, IQ, BP and cholesterol levels are (qualitative/quantitative)
- explain this
Quantitative
- A continuum; varies from one extreme through normal to another extreme
195
Heart attacks, cancer and rheumatoid arthritis are (qualitative/quantitative)
- explain this
Qualitative
- Discrete; present or absent
196
What model describes quantitative multifactorial disease?
Quantitative trait model (Basic model): accumulation of quantitative trait loci (QTLs)
197
What model describes qualitative multifactorial disease?
Threshold model: accumulation of liability/risk factors beyond a certain threshold (so you have the disease past a certain number of accumulated risk factors)
198
Describe the quantitative trait model
Varies continuously, typically a normal distribution.
- Outside the "normal" range, multifactorial disorders can be described (start to see more individuals with particular conditions)
- Normally distributed range of measurements due to the additive effects of many genes
- so accumulation of alleles increases trait (e.g. accumulation of tall genes increases height)
199
Describe the regression to mediocrity (mean) and provide an example
Parents are unlikely to pass on all their multifactorial genes to their offspring, but their offspring will still have more genes than the average individuals in the population
- e.g. very tall people give birth to shorter people because it is unlikely that tall parents will pass on all tall genes to their children
200
Describe the threshold model
Liability/risk factors are genes and environmental factors that contribute to the likelihood of developing a disease. A minimum number of liability factors (threshold) must be present to have the disease. Once you pass the threshold, the accumulation of risk factors you have a higher predisposition to certain diseases
201
Describe how you can predict the risk for single gene disorders
Can predict easily if its Mendelian inheritance or even if it's non-Mendelian inheritance (mitochondrial genes, imprinted genes, uniparental disomy aka getting both chromosomes from one parent and dynamic expansion disorders)
- In other words, SINGLE GENE DISORDERS HAVE A PREDICTABLE PATTERN OF INHERITANCE
202
What are 4 complications of predicting the risk for single gene disorders?
1. Incomplete penetrance
2. Phenocopies (non-genetic explanation for manifesting the same features)
3. Genetic heterogeneity
4. Variable expressivity
203
In multifactorial disorders, all risk factors are unknown, precise genotypes are unknown and environmental effects are variable. How do we predict risk for these diseases?
- provide an example of this
Empirical risks are derived from direct observation of data from large cohorts and families with an affected individual
- e.g. 2-3% of siblings of neural tube defects also have a neural tube defect; thus the recurrence risk of parents who have had one child with a neural tube defect is 2-3%
204
True or false: empirical risks are specific for each multifactorial disease and can vary from one population or geographic area to another
- explain why or why not
True; gene frequencies differ between populations and different populations are exposed to different environments
205
The closer an individual is related to an individual with the multifactorial trait, the (more/less) likely the individual will inherit more of the genetic risk factors segregating in the family
- explain what else could be influencing this
True
- Similarly, first degree relatives are more likely to share the same environment
206
More liability/risk factors are demonstrated in families with (more/less) individuals affected
More
- Think of the family with more affected individuals as having a "big bad" of genetic risk factors
207
Provide an example of a qualitative trait that demonstrates gender differences
pyloric stenosis is more common in males than in females. Males need fewer risk factors to develop the disease (so there's more affected males in the population)
208
Is the probability of passing on pyloric stenosis to offspring higher for females or males? Explain
Higher for females because they have more risk factors to pass on
209
Describe the distribution of offspring for pyloric stenosis from male probands
Liability curve slightly shifts right, threshold for disease is still lower for male offspring than female offspring so females are less affected
210
Describe the distribution of offspring for pyloric stenosis from female probands
Liability curve shifts way more to the right, threshold for disease is still lower for male offspring than female offspring so females are less affected
211
If sex alters the liability threshold, the risk of inheriting the disease is higher if...
The affected proband is of the less commonly affected sex
- so if mom is proband (female=less commonly affected sex), male children are at higher risk
212
How do the number of risk factors correlate with the disease severity in the proband?
Increased severity is often the result of more liability/risk factors
213
Describe how twin studies work
Monozygous share the same genotype and "same" environment, while dizygous twins have different genotypes and the "same" environment. So differences between MZ twins can be attributed to the environment.
- If MX twins are more concordant than DZ (both twins share the same trait), then the difference is attributed to genetics
214
The greater the difference in concordance between MX and DZ twins, the (lower/higher) the genetic contribution
Higher
215
In twin studies, the ___ rate is compared between MZ and DZ twins for qualitative traits while the ____ rate is compared between MZ and DZ twins for quantitative traits
Concordance, intraclass correlation
216
What does heritability measure?
Heritability (H^2) measures the proportion of total variance of a trait that is caused by genetic factors
217
A heritability of 100% means...
Traits that are fully genetic
218
A heritability of 0% means...
Traits that are fully environmental
219
Heritability ranges between __ and __, and (is/is not) population specific
0, 100, is
220
Disorders with high heritability have (lower/higher) risks to relatives
Higher
221
Describe adoption studies
Compare birth parents and biological siblings vs adopted parents and non-biological siblings.
- More similar to birth parents and biological siblings = genetic contribution
- More similar to adopted parents and non-biological siblings = environmental contribution
222
What are 3 reasons for why caution is needed when interpreting twin studies?
1. Shared environment between MZ twins and DZ twins may not be equally similar (MZ twins are often treated more similarly than DZ twins)
2. All MZ twins do not share the same prenatal environment (two amnions and two chorions, two amnions and one shared chorion, or one shared amnion and one shared chorion)
3. MZ twins do not have identical genomes; similarity decreases with time due to somatic and epigenetic changes
223
What are 2 reasons for why caution is needed when interpreting adoption studies?
1. Prenatal environment may have long lasting effects on an adopted child
2. Adoption doesn't always occur at birth, providing time for effects of a shared environment
224
A trait may be influenced by the combination of both a single gene with large effects and a...
- Provide an example
Multifactorial background in which additional genes and environmental factors have smaller individual effects
- Different pathogenic alleles of the CFTR gene correlate with pancreatic insufficiency, but lung disease does not correlate with allelic heterogeneity.
- In cystic fibrosis, two modifying loci are candidates for the severity of pulmonary disease: MBL2 and TGF1
- These modifying genes don't influence whether you have cystic fibrosis or not, they influence the manifestation of the disease
225
True or false: even "purely" genetic or "purely" environmental traits are influenced by genetic and environmental modifiers
True
226
Lets say you have a female proband (disease has a lower threshold in males). Do her male or female relatives have a greater risk of carrying the disease allele?
Males, since the females have a lot of risk factors to pass on and the males have a lower threshold
227
Lets say you have a male proband (disease has a lower threshold in males). Do his male or female relatives have a greater risk of carrying the disease allele?
Males, since they have a lower threshold.
228
What are 5 factors that increase the risk to relatives for acquiring a multifactorial disease?
1. High heritability
2. Close relationship to proband (if risk doesn't decrease by 50% as you go out, this is a hint that the disorder is multifactorial)
3. Multiple affected family members
4. Severity of the disease in the proband
5. Proband of more rarely affected sex (pass on more risk factors)
229
In general for multifactorial diseases, what happens to the effect size as allele frequency increases?
Effect size decreases
230
What types of variants contribute to most multifactorial diseases
Rare variants with small effects
231
Describe how multifactorial diseases are caused by genetic heterogeneity
e.g. if there's 30 at-risk alleles and 9 of these alleles are required to develop the disease, each patient will carry a different combination of 9 or more risk factors
232
What are 3 benefits of finding genetic risk factors for multifactorial diseases?
1. Better understanding of the underlying biology of the disease
2. Identify biological markers to improve risk assessment
3. Identify targets for intervention to prevent or improve outcomes of disease
233
What are the 5 challenges of finding genetic risk factors?
1. Locus heterogeneity
2. Interaction of multiple genes
3. Incomplete penetrance
4. Age-dependent onset (many multifactorial diseases have late onset)
5. Phenocopies (non-genetic reasons causing diseases that are similar to genetic diseases)
234
How can we use linkage analysis to find genetic risk factors?
Look for markers that segregate with the disease allele and calculate the LOD scores. Disease-causing gene will lie near the marker with a large LOD score (this shortens the search space for us)
235
How can we use affected sib pair analysis to find genetic risk factors?
Look at large number of individuals in a family that are affected. Assumption is that two affected siblings will share marker alleles in the region containing the genetic risk factor.
- Genotype DNA from each individual for markers and if the proportion of alleles shared by affected sibling pairs is >50%, there is evidence in favour of a genetic risk factor locus nearby
236
How do you increase the power of sib pair analysis?
Select sib pairs with an extreme phenotype
237
What is discordant sib pair analysis?
Looking at sibling pairs where one individual exhibits the trait or phenotype of interest
- Look at the proportion of affected sib pairs, and if its <50% this is evidence in favour of a genetic risk factor locus nearby shared markers
238
What are 3 advantages of affected sib pair analysis?
1. No assumption necessary about mode of inheritance
2. No effect of reduced penetrance
3. No effect of age of onset
239
What is a disadvantage of affected sib pair analysis?
Large sample size required
240
What are association studies aka case-control studies and how to they help with identifying genetic risk factors for multifactorial diseases?
- What is required to carry out this test?
Compare the frequency of risk factors in a PATIENT population to a control population. The probability of identifying a risk factor is proportional to its contribution to the disease and its frequency in the population (power)
- Use chi-square test to determine if the frequency of alleles differs between the groups
- Have to match as many of the environmental factors as possible (age, sex, diet, exercise, etc)
241
Typically, for multifactorial disorders, what is the odds ratio for disease association? What does this mean?
~1.1-1.5 (OR=1 means that patients and controls have the same risk so risk factors are statistically showing a small contribution to the disease)
242
What is the candidate gene approach in determining genetic risk factors for multifactorial disease? Is it successful?
The candidate gene approach is a method in genetics that focuses on studying specific genes that are hypothesized to be involved in a disease or trait. Instead of a broad genome-wide search, this approach selects genes based on prior knowledge of their function and potential role in the disease.
- Low success
243
Why is the candidate gene approach often not successful? (2 reasons)
Results are often not reproducible:
- Different populations carry different risk factors
- Frequency of alleles differ in different populations
244
Describe genome-wide association studies (GWAS) for finding risk factors associated with multifactorial disease
A hypothesis- free method that uses a SNP array (high throughput genotyping) using patients and controls
- If variant is higher in frequency in patient cases than controls, likely that this SNP is associated with the disease (there's a certain threshold where we consider statistically significant binding in the SNP array)
245
What is a pro and con of GWAS?
Pro: biological pathway does not have to be known
Con: Does not always provide insight into biology
246
What does GWAS rely on? What is a risk of this?
Statistical methods to identify association (there's a greater frequency of a genetic variant in patients with trait/disease compared to unaffected people)
- Risk: False positive may occur due to testing 1 million SNVs (so you need to set a low p value)
247
GWAS (does/does not) identify the causal variant
- Explain this
Does not
- The assumption is that the causal variant is in linkage disequilibrium with the identified variant
- SNPs on a microarray are rarely functional
248
What do GWAS studies identify in general?
A region on a chromosome to further investigate to search for the causative gene and variant
249
What 3 techniques can be used as an alternative to SNP microarray genotyping (GWAS)?
1. RNAseq - looks for a change in mRNA expression for a gene near a GWAS finding
2. Looks for methylation signatures that are common between cases and not controls
3. Whole genome sequencing is an alternative to SNP microarray genotyping
250
What is are two advantage of using whole genome sequencing as an alternative to GWAS?
1. Detects all types of variation, not just SNPs and non-coding variants that may regulate gene expression (regulatory variants)
2. N=1 studies are successful (but still need to compare SNPs to other individuals with the same phenotype just to confirm)
251
What are 3 advantage for doing animal studies to look at multifactorial diseases?
Can manipulate matings, control genetic background and the environment (e.g. diet, exercise, etc)
252
Explain how we can use animal models in general to study multifactorial diseases
Can control matings and then sequence the mice genomes using whole genome sequencing like we would do in humans
253
Explain how GWAS was used during COVID19
Did SNP microarrays for hospitalized COVID patients (cases) and normal COVID patients (control) to find some risk factors in hospitalized patients
254
What % of newborns have congenital malformations/birth defects?
2-3
255
Most congenital malformations/birth defects are considered...
Multifactorial
256
What are two genetic causes for congenital malformations/birth defects?
Some are associated with monogenic syndromes or chromosomal disorders
257
Describe the congenital anomalies surveillance system
Began in 1963 in response to malformations caused by thalidomide in late 1950s
- Registry on structural congenital anomalies, as well as physical and neurodevelopmental disabilties
- Used to establish prevalence rates for the different anomalies, watch trends over time
- Used for planning and policy decisions and evaluating prevention strategies
258
True or false: the congenital anomalies surveillance system had a real time response to emerging threats such as Zika virus
True
259
What happened in 1998 in terms of the congenital anomalies surveillance system? What happened as a response?
Folic acid fortification of white flour, pasta and cornmeal became mandatory in Canada because folic acid was found to prevent congenital malformations. This significantly decreased the rate of congenital malformations
260
What is the most common underlying cause of heart disease?
Coronary artery disease (CAD), which is caused by artherosclerosis (a narrowing of the coronary arteries resulting from the formation of lipid-laden lesions)
- Heart eventually dies from lack of oxygen, leading to a heart attack
- and/or low O2 in the brain leads to stroke
261
What are some of the risk factors for CAD and what increases the risk?
Risk factors for CAD include obesity, cigarette smoking, hypertension, elevated cholesterol level and positive family history
- Risk increases if more relatives are affected (only need one more hit in the chromosome is you've already inherited one), affected relative is female and age of onset in the affected relative is early
262
What are 2 gene types that are associated with coronary artery disease (CAD)?
1. Lipid metabolism/transport
2. Inflammation, inflammatory response
263
What does familial hypercholesterolemia (FH) result from?
Heterozygous pathogenic variants in the LDLR gene (autosomal dominant condition) which is involved in lipid metabolism/transport
264
Other than heterozygous pathogenic variants in the LDLR gene, elevated choelsterol is also seen in individuals with defective...
ApoB100
265
Describe how understanding the defects leading to FH (a CAD) has led to treatments
Led to:
1. Dietary reduction in cholesterol intake
2. Drugs/resins that bind to cholesterol in circulation and are excreted
3. Drugs that reduce cholesterol synthesis
266
What causes coronary artery disease in general, based on the candidate gene approach?
Variants in genes identified using this approach (with smaller effects), when combined together and with environmental risk factors are responsible for the MF disease
267
What is cardiomyopathy and the cause of it in general?
Abnormality of heart muscle typically caused by single gene disorders
- e.g. hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome
268
Inherited forms of heart conditions have provided valuable insight into...
Mechanisms of disease and thus potential targets for treatment
269
What is a polygenic risk score?
A score that determines your risk of developing a multifactorial condition. Higher score= higher risk of developing the condition
270
What are 4 pieces of information that is provided by direct-to-consumer genetic testing like 23andme?
1. Disease risk stratification
2. Carrier status for autosomal recessive disorders
3. Drug response
4. Nutrition
271
Inherited forms of multifactorial disorders tend to have (earlier/later) age of onset
Earlier
272
More severe multifactorial disease are more likely to have what effect on families?
More likely to cluster in families (have increased cases in families)
273
(genetic/environmental) risk factors often contribute less to a multifactorial disorder than (genetic/environmental) risk factors
Genetic, environmental
274
True or false: Identification of pathogenic variant(s) causing familial forms of multifactorial diseases allows for identification of family members at higher risk, and early screening, potentially drug treatment
True
275
Constitutional chromosome instability syndromes are also known as...
DNA repair disorders
