Genetics Post-Midterm Flashcards
(195 cards)
1
Q
Alpha thalassemia
A
Alpha: Multiple globin genes in clusters on Ch. 11 & 16; Sites arose due to duplications in evolutionary past. Ch 16 w/ alpha-cluster. Because of repetitive structure of alpha-structure, deletions are common diseases causing mechanism for alpha-thalassemia
2
Q
Beta thalassemia
A
Beta: decreased or absent beta-globin protein; decreased HbA (HbF = 2 alpha, 2 gamma); leads to RBC destruction
3
Q
Fragile X Syndrome
A
CGG repeat; more methylation because more GC-islands
*Decreased expression of FMR1 gene
4
Q
3 major methods of duplications in the genome
A
- STR/VNTR
- Transposons (Alu – SINES/LINES)
- Pseudogenes – vestigal, duplicated, processed
5
Q
What are pseudogenes? What are the 3 types?
A
Pseudogenes are dysfunctional relatives of genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell
- Vestigal
- Duplicated, unexpressed
- Processed
6
Q
What are processed pseudogenes?
A
Introns removed, normal poly-A tail. Reverse transcription yields pseudogene w/o introns
7
Q
Most repetitive DNA in genome is __________________________ sequence
A
Transposon (LINES, SINES)
- Jumping genes: can integrate in critical spot in genome, disrupt gene and cause disease
- Can lead to misalignment during meiosis
8
Q
How does red-green color blindness happen?
A
Unequal intragenic recombination between pairs of X chromosomes during meiosis
9
Q
What are the 3 different DNA microarray methods?
A
CGH
SNP
cDNA
10
Q
What is haplotype?
A
Combinations of alleles at different loci on chromosomes that are transmitted together
11
Q
What is an example of a vestigal gene?
A
Vitamin C
12
Q
What is the HapMap? What is the key research question?
A
Looks for genetic variation in individuals without sequencing entire individual genomes
i.e. What markers segregate with this disease phenotype?
13
Q
What is the transcriptome?
A
All the mRNA produced in a particular cell under a particular condition; isolate mRNA, label with cDNA, hybridize to expression microarray
14
Q
What is proteomics?
A
Attempt to look at protein fingerprint of a cell; genes with multiple start sites, RNA editiong, modified protein complexes
15
Q
What is the major challenge to proteomics?
A
Difficult to ID proteins at very low concentrations
16
Q
What are the two main tools of proteomics?
A
2D-gel electrophoresis
Mass spectometry
17
Q
What is epigenomics?
A
Studying DNA methylation patterns on CG repeat islands
18
Q
T/F Chromosomal abnormalities account for a large number of spontaneous abortions
A
True
19
Q
What are the 2 categories/types of chromosomal abnormalities?
A
- Numerical
2. Structural
20
Q
What are the 2 major numerical -ploidy of chromosomal abnormalities?
A
- Euploidy / multiples of 23 (incompatible with life)
2. Aneuploidy (+/- chromosomes, i.e. monosomy, trisomy)
21
Q
What is an exception to the rule that monosomy results in death?
A
Turner syndrome (45, X)
22
Q
Differentiate between tripolidy and trisomy.
A
Triploidy (69, XXY)
Trisomy (47 chromosomes)
23
Q
Differentiate between sex-chromosome aneuploidy and autosomal aneuploidy.
A
Sex: Turner (X), Klinefelter (XXY)
Autosome: Trisomy 21 (Down), 18 (Edward), 13 (Patau)
24
Q
Nondisjunction can cause 5 major diseases
A
Trisomy 12, 18, 21
Turner, Klinefelter
25
Nondisjunction is most common in MI/MII in males/females
MI, females
26
An increasing risk of what disorder results with increasing maternal age?
Trisomy 21: Down Syndrome
27
Trisomy 21
Down syndrome
*Most common, short, intellectual disability, single palmar crease, congenital heart defect, Alzheimers, depressed nasal bridge
28
Trisomy 18
Edward
| *Clenched fist, rocker bottom feet, heart, micro
29
Trisomy 13
Patau
| *Polydactly, cleft lip, cardiac
30
Turner Syndrome
45,X -- female mosaics!
| Short, webbed neck, amenhorrea, streak ovaries, gonadal dysgenesis
31
Klinefelter Syndrome
47, XXY
32
Klinefelter Syndrome will not happen in MI/M2 males/females
M2 males
33
XXX phenotype will not occur in M1/M2 males/females
M1 males
34
What is the effect of inversions during crossover in meiosis?
Duplication or deletion of genetic material
| Acentric (no centromere) or Dicentric (2 centromeres) are not viable
35
A radiation worker lose genetic material at the terminal ends of her chromosomes and they fused to form a...
Ring chromosome
36
What is an isochromosome?
Loss of 1 arm and duplication of other arm (2p's or 2q's)
37
X-isochromosome i(X)
Can occur in children with Turner; 2 long arms of X chromosome
38
What are the two types of inversions in a chromosome?
Pericentric: involves centromere
Paracentric: does not involve centromere
39
Differentiate between reciprocal and Robertsonian translocation.
Reciprocal: genetic exchange between non-homologs
Robertsonian: acrocentric chromosomes 13,14,15,21,22
Alternate (Balanced) or Adjacent (unbalanced)
40
2 large deletion genetic conditions
1. Wolf-Hirschorn 4p
| 2. Cri du Chat 5p
41
With what tests can you examine for a microdeletion?
FISH or CGH
42
4 microdeletion syndromes
1. Angelman (15q11)
2. Prader-Willi (15q11)
3. DiGeorge (22q11)
4. WAGR syndrome (11) Wilms tumor, aniridia, GU, retardation
43
Philadelphia chromosome
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML). It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t(9;22)(q34;q11)
44
The t(8,14) translocation is associated with...
Burkitt's Leukemia
45
Which are the acrocentric chromosomes?
13,14,15,21,22
46
What are the 4 major types of genetic disorders?
1. Single gene
2. Chromosomal
3. Mitochondrial
4. Complex: genes + environment
47
Explain additive alleles.
Number of dominant alleles determine the phenotype
48
Describe the polygenic theory of quantitative traits.
What you see in "real life"; a normal distribution
49
The more genes that control a trait may determine...
The extent of the phenotype observed
| * More genes = broader range of phenotypes
50
What percentage of height is genetically determined?
20%
51
Describe the genetic liability model.
A discontinuous phenotype (affected/not affected) in the context of continuous variation
* All factors that contribute to the disease = liability
* Genes and environment
52
For a family with "bad" genes, the distribution of the liability-threshold model is right/left shifted?
Right shifted
53
Within a family, who (first, second, third-degree) relatives has a greater familial relative risk? The risk drops by ____ in every succeeding degree
First-degree relatives
| * Risk drops by 1/2
54
What is lambda t (familial aggregation/relative risk)? The larger lambda T...
Freq in family/Freq in general population; greater the risk in the family
55
Can the genetic liability model be used to identify recurrence risk in families?
Yes
56
What are features of complex/multifactorial inheritance diseases?
- Non-Mendelian
- Aggregates in families
- Close relatives
- Multiple genes
57
For a multifactorial disease, can risk change for children?
Yes -- more first degree relatives, greater risk
58
Is pyloric stenosis more common in boys or girls?
Boys
59
For women to have CVD pre-menopause, they have more/less contributing factors than do men.
More
60
Identifying the genetic component of a complex disease will determine the ________________ of the disease.
Heritibility
61
What are the tools to study genetic and environmental factors of a complex disease?
Migration studies, family, twin, adoption, association studies
62
A higher heritibility, a greater/lesser contribution of genetics?
Greater
63
With monozygotic twins, the greater the discordance, the lesser/greater environmental input?
Greater
64
With respect to concordance, a condition with high concordance in monozygotic and dizygotic twins has a greater environmental or genetic role?
Environmental
65
Heteroplasmy
Characteristic of mitochondrial inheritance
66
How can we identify genes that contribute to multifactorial inheritance?
1. Allele sharing (siblings, families)
| 2. Population-based association studies
67
What is IBD, or identical-by-descent?
Allele-sharing methods involve testing whether affected relatives inherit the same genomic regions (called identical by descent) more often than expected under Mendelian segregation.
Affected sibling pairs -- normally share 50% of genes, but analysis of affected pairs may reveal that a trait-causing gene is present >50% of time, highlighting the importance of this gene in the phenotype
68
T/F Population-based association studies are case-control studies
True
69
What is the caveat with population-based associated studies?
They give only correlation between the presence of a marker and the occurrence of the disease
70
What is the objective of genome-wide-association studies?
Compare genomes of people with illness to unaffected people
| * Look for relationships between SNP's and disease phenotype
71
With respect to common disease, rare variant hypothesis, rare variants have arisen more recently or ancient?
More recently
72
On what chromosome is the APOE4 gene?
```
Chromosome 19 (Alzheimers)
*Involved in lipoprotein metabolism; binds beta-amyloid and reduces its solubility
```
73
What are the prevailing arguments about neural tube defects being genetic/environmental?
Genetic: 3% risk of having a second child with NTD
Environmental: folate reduces risk by 70% & down to 1% for a second child
74
Who is at highest risk for obesity?
Non-hispanic blacks
75
Differentiate between DNA damage and mutation.
Damage is repaired before replication
| Mutation is incorporated, not fixed, and replicated
76
Describe the 2 major classes of spontaneous mutation
1. Error of replication (S phase)
| 2. Spontaneous lesion (resting cell)
77
What are the 2 major classes of DNA mutation
1. Spontaneous
| 2. Induced
78
How is DNA repaired?
By 3' 5' DNA polymerase exonuclease activity
79
What are the 3 major types of spontaneous lesions (as a subclass of spontaneous mutations)?
1. Depurination
2. Deamination
3. Oxidative damage
80
Where is a mutational hotspot?
5-methyl-cytosine deaminated to thymidine
81
What is a mutagen?
Increases frequency of normal mutation (mismatches, depurination, etc.)
82
True or False: Ionizing radiation can cause many types of cellular damage and lead to heritable mutations
True
83
Which of the following is the most common error in DNA? Depurination, deamination, methylation
Depurination
84
Differentiate between nucleotide excision, base excision, mismatch repair
Nucleotide: up to 30 bases (i.e. UV damage)
Base excision: single base (i.e. methylation)
Mismatch repair: mismatched bases (i.e. tautomers)
85
Excision repair involves 3 steps
1. Recognition
2. Removal (glycosylase and then endonuclease)
3. Replacement (ligase seal)
86
What is the AR disorder that involves extreme sun sensitivity?
Xeroderma pigmentosum
87
Mismatch repair is pre- or post- replicative?
Post-replicative
88
What type of DNA repair is important for triplet repeat expansion disorders?
Mismatch repair
89
How does the cell know which DNA is the correct one to repair? (Proks and Euks)
Proks: methylated strand
Euks: methylation +/- host machinery
90
A mutation of mismatch repair genes MSH2 and MLH1 can result in...
Hereditary nonpolyposis colon cancer
91
Which gene is central to a large number of repair processes, including damage sensor, chromatin remodeling, bloom helicase, MMR, cell cycle control, regulation of apoptosis?
BRCA1
92
Longterm consequences of DNA damage
Aging and cancer
93
Ataxia telangrectasia
| Louis-Bar syndrome
A-T is caused by a defect in the ATM gene, which is responsible for managing the cell’s response to multiple forms of stress including double-strand breaks in DNA. In simple terms, the protein produced by the ATM gene recognizes that there is a break in DNA, recruits other proteins to fix the break, and stops the cell from making new DNA until the repair is complete
94
2 disorders associated with chromosomal breaks
```
Bloom syndrome (15q26.1)
Fanconi Anemia (N8)
```
95
Term for the ability of chemicals to exist as mixtures of 2 inconvertible isomers
Tautomerism
96
DNA repair can involve 3 processes
1. Nucleotide excision
2. Base excision
3. Mismatch repair (MMR)
97
Does the threshold model apply for cancer?
No
98
Tumor progression results from waves of __________ followed by ______________.
Mutation; clonal expansion
99
There are several alterations in malignant transformation. What are they?
1. Increased survival and growth
2. Metastasis (loss cell-to-cell adhesion)
3. Increased mutation rate (breakdown host DNA repair)
4. Energy supply (angiogenesis)
100
Are cancers derived from a single cell?
Most no (polyclonal); some are monoclonal
101
What is the story behind X-inactivation and cancer?
All cancer cells have the same X-inactivated
102
How can we monitor the effetiveness of cancer therapy?
Look at cells pre- and post- treatment to see if they still contain the chromosomal abberation
103
Multiple myeloma is a malignancy of the ____ cell. All myeloma cells in a patient produce ___________.
B cell
| Same antibody molecule
104
What are the 3 major categories of cancer causing genes?
1. Proto-oncogenes
2. Tumor suppressor genes
3. Repair genes
105
Match the following:
Gain of function/Loss of function
Proto-oncogenes; tumor suppressor genes
Gain: proto-oncogenes
Loss: tumor suppressor genes
106
What is the mutant form of proto-oncogenes?
Oncogenes
107
Mutant oncogene or production of large amount of a protein that stimulates cell division can lead to:
Cancer
108
Oncogenic activation by translocation can result in (2)
1. Chronic myeloid leukemia
| 2. Burkitt lymphoma
109
What is the genetics of chronic myeloid leukemia?
Philly chromosome translocation: t(9,22)
| * Unregulated tyrosine kinase
110
The nuclear protein responsible for stimulating cell cycle at the G1/S transition
MYC
111
What is the genetics of Burkitt Lymphoma?
Overproduction of MYC (rapid cell division); t(8.14)
112
The MAP kinase pathway, which is stimulated by growth factors....
Results in phosphorylation of serine and threonine, which drives cell division
113
Constitutive activity of a proto-oncogene can result from:
point mutation; truncation/deletion
114
Match:
Chromosome 9, 22
BCR; ABL
Ch. 9: ABL
| Ch. 11: BCR
115
Imatinib mesylate
A powerful inhibitor of tyrosine kinase
| * Effective against BCR/ACL fusion protein
116
Oncogenesis depends on RAS over/under-activity
| * RAS is a _______-involved in cell proliferation
Hyperactivity
| GTP-ase
117
RAS-GTP vs. RAS-GDP
Active vs. inactive
118
What is double minutes?
Extra-chromosomal fragments of DNA containing an amplified region of the chromosome
119
EGFR is seen in advanced....
gliomas
* EGFR is amplified as double minute chromosome (extra-chromosomal fragments of DNA containing an amplified region of the chromosome)
120
Example of an autosomal dominant cancer
Wilms' tumor
* Results from loss of function in the WT1 gene on chromosome 11, which encodes for a transcription factor important in the control of cell growth/differentiation
121
What is the two-hit hypothesis?
Need to lose 2 tumor suppressor genes for cancer to develop
122
Differentiate between sporadic/familial cancers for the 2 hit hypothesis.
Sporadic: 2 hits
Familial: 1 hit (b/c 1 is inherited)
123
The second hit (in a familial cancer is not a simple mutation, but a......
Loss of heterozygosity
124
Recently, it has been discovered that the "second hit" can result from.....
Aberrent methylation
125
HER2
Amplification
126
MYC
Overexpression IgH
127
BCR/ABL
Translocation/tyrosine kinase
128
RAS
Mutation
129
BRCA
Mutation
130
APC
Familial adeomatous polyposis (bowel ca) (TSG)
131
VHL
Von Hippel-Lindau syndrome (hemangioblastoma, pheo, renal cell carcinoma) (TSG)
132
TP53
Li-Fraumeni Syndrome (Soft tissue sarcoma) (TSG)
133
NF1/2
Neurogibromatosis 1/2 (schwannoma, meningioma) (TSG)
134
TSC1/2
Tuberous sclerosis complex (TSG)
135
WT1
WAGR (Wilms tumor, aniridia, GU, growth) (TSG)
136
MSH1/2, PMS1/2
Hereditary non-polyposis colon cancer (TSG)
137
MEN1
Multiple endocrine neoplasia (TSG)
138
A loss of Rb or a mutant Rb leads to...
Inability of Rb to bind to E2F and hence, unregulated cell growth (G1/S)
139
Rb is normally bound to _________ which stimulates/prevents cell growth.
E2F; prevents
140
Describe the effect of phosphorylating Rb
Inactivates it; allows E2F to stimulate cell divison
141
Differentiate between sporadic and Mendelian retinoblastoma.
Mendelian: Requires a second hit; Bilateral, early, multi-tumor (30%)
Sporadic: 2 somatic mutations; unilateral, later onset, single tumor
142
The 4 genes that regulate the phosphorylation of Rb
1. p16
2. CLND
3. CDK4
4. Rb/E2F
143
p16
CDK inhibitor (Rb)
144
CLnD/CDK4 complex
Inactivates Rb by phosphorylation
145
p53 is a _________________________ that controls both _______________ and __________________
Tumor supressor gene
| Cell growth; cell death
146
Why is a mutation of p53 bad?
Uncontrolled cell growth & greater mutation (cancer progression)
147
LiFraumeni syndrome
Inherited mutation of p53
* 1st hit: mom
* 2nd hit: LOH/somatic
* * Childhood cancer -- breast, bone, brain
148
p53 regulates the intrinsic apoptosis pathway in 3 ways:
1. pro-apotosis BCL-2
2. FAS receptor/CD95
3. IGFBP-3 (sequesters insulin growth factor and prevents it from interacting with receptor)
149
What what pathway is APC associated? What is a disease associated with this mutation?
Fam adenomatous polyposis
* APC normally degrades beta-catenin which inhibits growth (WNT signalling pathway)
* Without APC, unregulated growth (B-catenin -- TCF4 pathway)
150
Yes WNT signal
| No WNT signal
Yes -- growth
| No -- no growth (because of APC)
151
RAS: tumor suppressor or proto-oncogene?
Proto-oncogene
152
Which disease progresses more rapidly: FAP or HNPCC
HNPCC
153
Which is the gate-keeper and which is the caretaker? APC, MMR genes
Gatekeeper: APC
Caretaker: MMR genes
154
What cancer is associated with microsatellite instability?
HNPCC
155
T/F BRCA1 demonstrates allelic heterogeneity.
True
156
How do you best describe the heterogeneous relationship between BRCA1 and 2
Locus heterogeneity
157
What treatment is effective for Her2+ breast cancer?
Herceptin // prevents HER2- epidermal growth factor interaction
158
What is the role of microRNA mutations in cancer?
Not enough -- enhanced oncogenes
| Too much -- suppression of tumor suppressors
158
Differentiate between inherited/sporadic cancers with respect to age of onset, multiplicity, paired organs, types of tumors, family pattern, markers, degree of risk
Inherited -- earlier, manu tumors, bilateral, familial associations
159
Differentiate between inherited/sporadic cancers with respect to age of onset, multiplicity, paired organs, types of tumors, family pattern, markers, degree of risk
Inherited -- earlier, manu tumors, bilateral, familial associations
161
Imatinib mesylate can be used to treat
Philadelphia + CML
162
HIV
"Facilitated apoptosis"
| Inactivation of BCL-2; FAS pathway, viral proteins inducing apoptosis (tat, nef, epr)
163
Differentiate between BCL-2 and BAX/BAK
BCL-2: anti-apoptosis
| BAX/BAK: pro-apoptosis
164
Which process requires energy: necrosis or apoptosis?
Apoptosis
165
Differentiate between the intrinsic and extrinsic pathways of apoptosis (objective and caspases)
Intrinsic: genotoxic damage (caspase 9, 2)
Extrinsic: unwanted cells during development, virally infected cells (caspase 8, 10)
166
What are the steps/key players of the intrinsic apoptosis pathway?
1. p53 phosphorylation
2. BAX, p21
3. Cytochrome c (mito)
4. APAF-1 (binds apoptosome)
5. Procaspase --> Caspase
167
What are the steps/key players of the extrinsic apoptosis pathway?
1. T-killer cell expresses FAS
2. Bind to FAS death receptor
3. Adaptor molecules
4. Procaspase -- DISC
5. Caspase
168
The 3 major components of the apoptosis pathway
1. Regulators -- BCL2 (anti); BAK, BAX (pro)
2. Adaptors -- bind to procaspase
3. Effectors -- caspases (laminins, DNA repair)
169
The 3 methods to look for apoptosis in vivo
1. DNA ladder / fragmentation
2. Change in membrane structure (Ab- Annexin 5 translocated to outer cell membrane)
3. Caspase assay
170
What can you use to detect DNA fragmentation in situ?
TUNL (terminal transferase dUTP nick end labeling)
171
Extracellular survival factors (up or down) regulate apoptosis
Down
172
Too much apoptosis leads to...
Alzheimers, HIV
173
Too little apoptosis leads to...
cancer
174
Pyknosis
Condensation of chromatin (apoptosis)
175
Karyorrhexis
Discontinuous nuclear envelope (apoptosis)
176
What are the 2 types of genetic screening?
1. Targeted (carriers, late penetrance conditions)
| 2. Population (prenatal, neonatal)
177
Prenatal screening is done to test for 3 conditions
Trisomy 21, 18, neural tube defects
178
What are the 2 major types of prenatal screening?
1. Non-invasive -- Maternal serum, ultrasound
| 2. Invasive -- CVS, Amnio
179
Trisomy 21 on pre-natal screening
High B-HCG, inhibin A
180
Trisomy 18 and 13 on pre-natal screening
All lower
181
NTD on pre-natal screening
High AFP
182
At what week can an ultrasound reveal nuchal translucency?
18 weeks
183
Which can you do first: CVS or Amnio?
CVS
184
To test for CF in the blood, what types of test do you do?
Immuno-reactive trypsinogen
185
BCHE gene defect
AR
| -Succinylcholine metabolism
186
Toxicity associated with n-acyltransferase
Isoniazid - neuropathy, hepatotoxicity
Hydralazine (HTN), procainamide (arrhythmia) SLE
Sulfonamides hemolytic anemia, SLE
187
CYP2D6 deficiency
CYP450 superfamily
| * Anti-depressants, antiarrhythmic, analgesics
188
Thiopurine s-methyltransferase polymorphism
Low TPMT toxicity and myelosuppression when treated with standard doses of thiopurine, i.e. azathioprine, mercaptopurine (anti-cancer drugs)
189
Warfarin
-S- Warfarin more potent than R-Warfarin
CYP2C9 metabolizes S-Warfarin
Underactive CYP2C9 -- lower doses of warfarin, higher dose risk of bleeding
* Also Vit K epoxide reductase deficiency -- normally this enzyme is inhibited by Warfarin
190
Malignant hyperthermia
AD
Defect in RYR1 - Ryanodine receptor
Elevated release of Ca2+ from SR of skeletal muscle following inhalation anesthesia (halothane)
191
Differentiate between somatic cell nuclear transfer and induced pluripotent stem cells
SCNT: correct mutation in vitro, nucleus transferred to egg or embryonic stem cells
IPPSC: reprogram a somatic cell to become an embryonic stem cell
192
What signal can send something to a lysosome?
Mannose
193
With what is urea cycle treated?
Sodium benzoate (diverts ammonia to glycine and excretion of hippurate)
194
What is PEGylation?
adds stability to a protein
195
With what can PKU1 be treated?
Sapropterin -- pharmacologic doses of BH4
