Genetics Post-Midterm Flashcards
Alpha thalassemia
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
Beta thalassemia
Beta: decreased or absent beta-globin protein; decreased HbA (HbF = 2 alpha, 2 gamma); leads to RBC destruction
Fragile X Syndrome
CGG repeat; more methylation because more GC-islands
*Decreased expression of FMR1 gene
3 major methods of duplications in the genome
- STR/VNTR
- Transposons (Alu – SINES/LINES)
- Pseudogenes – vestigal, duplicated, processed
What are pseudogenes? What are the 3 types?
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
What are processed pseudogenes?
Introns removed, normal poly-A tail. Reverse transcription yields pseudogene w/o introns
Most repetitive DNA in genome is __________________________ sequence
Transposon (LINES, SINES)
- Jumping genes: can integrate in critical spot in genome, disrupt gene and cause disease
- Can lead to misalignment during meiosis
How does red-green color blindness happen?
Unequal intragenic recombination between pairs of X chromosomes during meiosis
What are the 3 different DNA microarray methods?
CGH
SNP
cDNA
What is haplotype?
Combinations of alleles at different loci on chromosomes that are transmitted together
What is an example of a vestigal gene?
Vitamin C
What is the HapMap? What is the key research question?
Looks for genetic variation in individuals without sequencing entire individual genomes
i.e. What markers segregate with this disease phenotype?
What is the transcriptome?
All the mRNA produced in a particular cell under a particular condition; isolate mRNA, label with cDNA, hybridize to expression microarray
What is proteomics?
Attempt to look at protein fingerprint of a cell; genes with multiple start sites, RNA editiong, modified protein complexes
What is the major challenge to proteomics?
Difficult to ID proteins at very low concentrations
What are the two main tools of proteomics?
2D-gel electrophoresis
Mass spectometry
What is epigenomics?
Studying DNA methylation patterns on CG repeat islands
T/F Chromosomal abnormalities account for a large number of spontaneous abortions
True
What are the 2 categories/types of chromosomal abnormalities?
- Numerical
2. Structural
What are the 2 major numerical -ploidy of chromosomal abnormalities?
- Euploidy / multiples of 23 (incompatible with life)
2. Aneuploidy (+/- chromosomes, i.e. monosomy, trisomy)
What is an exception to the rule that monosomy results in death?
Turner syndrome (45, X)
Differentiate between tripolidy and trisomy.
Triploidy (69, XXY)
Trisomy (47 chromosomes)
Differentiate between sex-chromosome aneuploidy and autosomal aneuploidy.
Sex: Turner (X), Klinefelter (XXY)
Autosome: Trisomy 21 (Down), 18 (Edward), 13 (Patau)
Nondisjunction can cause 5 major diseases
Trisomy 12, 18, 21
Turner, Klinefelter
Nondisjunction is most common in MI/MII in males/females
MI, females
An increasing risk of what disorder results with increasing maternal age?
Trisomy 21: Down Syndrome
Trisomy 21
Down syndrome
*Most common, short, intellectual disability, single palmar crease, congenital heart defect, Alzheimers, depressed nasal bridge
Trisomy 18
Edward
*Clenched fist, rocker bottom feet, heart, micro
Trisomy 13
Patau
*Polydactly, cleft lip, cardiac
Turner Syndrome
45,X – female mosaics!
Short, webbed neck, amenhorrea, streak ovaries, gonadal dysgenesis
Klinefelter Syndrome
47, XXY
Klinefelter Syndrome will not happen in MI/M2 males/females
M2 males
XXX phenotype will not occur in M1/M2 males/females
M1 males
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
A radiation worker lose genetic material at the terminal ends of her chromosomes and they fused to form a…
Ring chromosome
What is an isochromosome?
Loss of 1 arm and duplication of other arm (2p’s or 2q’s)
X-isochromosome i(X)
Can occur in children with Turner; 2 long arms of X chromosome
What are the two types of inversions in a chromosome?
Pericentric: involves centromere
Paracentric: does not involve centromere
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)
2 large deletion genetic conditions
- Wolf-Hirschorn 4p
2. Cri du Chat 5p
With what tests can you examine for a microdeletion?
FISH or CGH
4 microdeletion syndromes
- Angelman (15q11)
- Prader-Willi (15q11)
- DiGeorge (22q11)
- WAGR syndrome (11) Wilms tumor, aniridia, GU, retardation
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)
The t(8,14) translocation is associated with…
Burkitt’s Leukemia
Which are the acrocentric chromosomes?
13,14,15,21,22
What are the 4 major types of genetic disorders?
- Single gene
- Chromosomal
- Mitochondrial
- Complex: genes + environment
Explain additive alleles.
Number of dominant alleles determine the phenotype
Describe the polygenic theory of quantitative traits.
What you see in “real life”; a normal distribution
The more genes that control a trait may determine…
The extent of the phenotype observed
* More genes = broader range of phenotypes
What percentage of height is genetically determined?
20%
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
For a family with “bad” genes, the distribution of the liability-threshold model is right/left shifted?
Right shifted
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
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
Can the genetic liability model be used to identify recurrence risk in families?
Yes
What are features of complex/multifactorial inheritance diseases?
- Non-Mendelian
- Aggregates in families
- Close relatives
- Multiple genes
For a multifactorial disease, can risk change for children?
Yes – more first degree relatives, greater risk
Is pyloric stenosis more common in boys or girls?
Boys
For women to have CVD pre-menopause, they have more/less contributing factors than do men.
More
Identifying the genetic component of a complex disease will determine the ________________ of the disease.
Heritibility
What are the tools to study genetic and environmental factors of a complex disease?
Migration studies, family, twin, adoption, association studies
A higher heritibility, a greater/lesser contribution of genetics?
Greater
With monozygotic twins, the greater the discordance, the lesser/greater environmental input?
Greater
With respect to concordance, a condition with high concordance in monozygotic and dizygotic twins has a greater environmental or genetic role?
Environmental
Heteroplasmy
Characteristic of mitochondrial inheritance
How can we identify genes that contribute to multifactorial inheritance?
- Allele sharing (siblings, families)
2. Population-based association studies
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
T/F Population-based association studies are case-control studies
True
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
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
With respect to common disease, rare variant hypothesis, rare variants have arisen more recently or ancient?
More recently
On what chromosome is the APOE4 gene?
Chromosome 19 (Alzheimers) *Involved in lipoprotein metabolism; binds beta-amyloid and reduces its solubility
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
Who is at highest risk for obesity?
Non-hispanic blacks
Differentiate between DNA damage and mutation.
Damage is repaired before replication
Mutation is incorporated, not fixed, and replicated
Describe the 2 major classes of spontaneous mutation
- Error of replication (S phase)
2. Spontaneous lesion (resting cell)
What are the 2 major classes of DNA mutation
- Spontaneous
2. Induced
How is DNA repaired?
By 3’ 5’ DNA polymerase exonuclease activity
What are the 3 major types of spontaneous lesions (as a subclass of spontaneous mutations)?
- Depurination
- Deamination
- Oxidative damage
Where is a mutational hotspot?
5-methyl-cytosine deaminated to thymidine
What is a mutagen?
Increases frequency of normal mutation (mismatches, depurination, etc.)
True or False: Ionizing radiation can cause many types of cellular damage and lead to heritable mutations
True
Which of the following is the most common error in DNA? Depurination, deamination, methylation
Depurination
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)
Excision repair involves 3 steps
- Recognition
- Removal (glycosylase and then endonuclease)
- Replacement (ligase seal)
What is the AR disorder that involves extreme sun sensitivity?
Xeroderma pigmentosum
Mismatch repair is pre- or post- replicative?
Post-replicative
What type of DNA repair is important for triplet repeat expansion disorders?
Mismatch repair
How does the cell know which DNA is the correct one to repair? (Proks and Euks)
Proks: methylated strand
Euks: methylation +/- host machinery
A mutation of mismatch repair genes MSH2 and MLH1 can result in…
Hereditary nonpolyposis colon cancer
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
Longterm consequences of DNA damage
Aging and cancer
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
2 disorders associated with chromosomal breaks
Bloom syndrome (15q26.1) Fanconi Anemia (N8)
Term for the ability of chemicals to exist as mixtures of 2 inconvertible isomers
Tautomerism
DNA repair can involve 3 processes
- Nucleotide excision
- Base excision
- Mismatch repair (MMR)
Does the threshold model apply for cancer?
No
Tumor progression results from waves of __________ followed by ______________.
Mutation; clonal expansion
There are several alterations in malignant transformation. What are they?
- Increased survival and growth
- Metastasis (loss cell-to-cell adhesion)
- Increased mutation rate (breakdown host DNA repair)
- Energy supply (angiogenesis)
Are cancers derived from a single cell?
Most no (polyclonal); some are monoclonal
What is the story behind X-inactivation and cancer?
All cancer cells have the same X-inactivated
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
Multiple myeloma is a malignancy of the ____ cell. All myeloma cells in a patient produce ___________.
B cell
Same antibody molecule
What are the 3 major categories of cancer causing genes?
- Proto-oncogenes
- Tumor suppressor genes
- Repair genes
Match the following:
Gain of function/Loss of function
Proto-oncogenes; tumor suppressor genes
Gain: proto-oncogenes
Loss: tumor suppressor genes
What is the mutant form of proto-oncogenes?
Oncogenes
Mutant oncogene or production of large amount of a protein that stimulates cell division can lead to:
Cancer
Oncogenic activation by translocation can result in (2)
- Chronic myeloid leukemia
2. Burkitt lymphoma
What is the genetics of chronic myeloid leukemia?
Philly chromosome translocation: t(9,22)
* Unregulated tyrosine kinase
The nuclear protein responsible for stimulating cell cycle at the G1/S transition
MYC
What is the genetics of Burkitt Lymphoma?
Overproduction of MYC (rapid cell division); t(8.14)
The MAP kinase pathway, which is stimulated by growth factors….
Results in phosphorylation of serine and threonine, which drives cell division
Constitutive activity of a proto-oncogene can result from:
point mutation; truncation/deletion
Match:
Chromosome 9, 22
BCR; ABL
Ch. 9: ABL
Ch. 11: BCR
Imatinib mesylate
A powerful inhibitor of tyrosine kinase
* Effective against BCR/ACL fusion protein
Oncogenesis depends on RAS over/under-activity
* RAS is a _______-involved in cell proliferation
Hyperactivity
GTP-ase
RAS-GTP vs. RAS-GDP
Active vs. inactive
What is double minutes?
Extra-chromosomal fragments of DNA containing an amplified region of the chromosome
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)
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
What is the two-hit hypothesis?
Need to lose 2 tumor suppressor genes for cancer to develop
Differentiate between sporadic/familial cancers for the 2 hit hypothesis.
Sporadic: 2 hits
Familial: 1 hit (b/c 1 is inherited)
The second hit (in a familial cancer is not a simple mutation, but a……
Loss of heterozygosity
Recently, it has been discovered that the “second hit” can result from…..
Aberrent methylation
HER2
Amplification
MYC
Overexpression IgH
BCR/ABL
Translocation/tyrosine kinase
RAS
Mutation
BRCA
Mutation
APC
Familial adeomatous polyposis (bowel ca) (TSG)
VHL
Von Hippel-Lindau syndrome (hemangioblastoma, pheo, renal cell carcinoma) (TSG)
TP53
Li-Fraumeni Syndrome (Soft tissue sarcoma) (TSG)
NF1/2
Neurogibromatosis 1/2 (schwannoma, meningioma) (TSG)
TSC1/2
Tuberous sclerosis complex (TSG)
WT1
WAGR (Wilms tumor, aniridia, GU, growth) (TSG)
MSH1/2, PMS1/2
Hereditary non-polyposis colon cancer (TSG)
MEN1
Multiple endocrine neoplasia (TSG)
A loss of Rb or a mutant Rb leads to…
Inability of Rb to bind to E2F and hence, unregulated cell growth (G1/S)
Rb is normally bound to _________ which stimulates/prevents cell growth.
E2F; prevents
Describe the effect of phosphorylating Rb
Inactivates it; allows E2F to stimulate cell divison
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
The 4 genes that regulate the phosphorylation of Rb
- p16
- CLND
- CDK4
- Rb/E2F
p16
CDK inhibitor (Rb)
CLnD/CDK4 complex
Inactivates Rb by phosphorylation
p53 is a _________________________ that controls both _______________ and __________________
Tumor supressor gene
Cell growth; cell death
Why is a mutation of p53 bad?
Uncontrolled cell growth & greater mutation (cancer progression)
LiFraumeni syndrome
Inherited mutation of p53
- 1st hit: mom
- 2nd hit: LOH/somatic
- Childhood cancer – breast, bone, brain
p53 regulates the intrinsic apoptosis pathway in 3 ways:
- pro-apotosis BCL-2
- FAS receptor/CD95
- IGFBP-3 (sequesters insulin growth factor and prevents it from interacting with receptor)
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)
Yes WNT signal
No WNT signal
Yes – growth
No – no growth (because of APC)
RAS: tumor suppressor or proto-oncogene?
Proto-oncogene
Which disease progresses more rapidly: FAP or HNPCC
HNPCC
Which is the gate-keeper and which is the caretaker? APC, MMR genes
Gatekeeper: APC
Caretaker: MMR genes
What cancer is associated with microsatellite instability?
HNPCC
T/F BRCA1 demonstrates allelic heterogeneity.
True
How do you best describe the heterogeneous relationship between BRCA1 and 2
Locus heterogeneity
What treatment is effective for Her2+ breast cancer?
Herceptin // prevents HER2- epidermal growth factor interaction
What is the role of microRNA mutations in cancer?
Not enough – enhanced oncogenes
Too much – suppression of tumor suppressors
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
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
Imatinib mesylate can be used to treat
Philadelphia + CML
HIV
“Facilitated apoptosis”
Inactivation of BCL-2; FAS pathway, viral proteins inducing apoptosis (tat, nef, epr)
Differentiate between BCL-2 and BAX/BAK
BCL-2: anti-apoptosis
BAX/BAK: pro-apoptosis
Which process requires energy: necrosis or apoptosis?
Apoptosis
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)
What are the steps/key players of the intrinsic apoptosis pathway?
- p53 phosphorylation
- BAX, p21
- Cytochrome c (mito)
- APAF-1 (binds apoptosome)
- Procaspase –> Caspase
What are the steps/key players of the extrinsic apoptosis pathway?
- T-killer cell expresses FAS
- Bind to FAS death receptor
- Adaptor molecules
- Procaspase – DISC
- Caspase
The 3 major components of the apoptosis pathway
- Regulators – BCL2 (anti); BAK, BAX (pro)
- Adaptors – bind to procaspase
- Effectors – caspases (laminins, DNA repair)
The 3 methods to look for apoptosis in vivo
- DNA ladder / fragmentation
- Change in membrane structure (Ab- Annexin 5 translocated to outer cell membrane)
- Caspase assay
What can you use to detect DNA fragmentation in situ?
TUNL (terminal transferase dUTP nick end labeling)
Extracellular survival factors (up or down) regulate apoptosis
Down
Too much apoptosis leads to…
Alzheimers, HIV
Too little apoptosis leads to…
cancer
Pyknosis
Condensation of chromatin (apoptosis)
Karyorrhexis
Discontinuous nuclear envelope (apoptosis)
What are the 2 types of genetic screening?
- Targeted (carriers, late penetrance conditions)
2. Population (prenatal, neonatal)
Prenatal screening is done to test for 3 conditions
Trisomy 21, 18, neural tube defects
What are the 2 major types of prenatal screening?
- Non-invasive – Maternal serum, ultrasound
2. Invasive – CVS, Amnio
Trisomy 21 on pre-natal screening
High B-HCG, inhibin A
Trisomy 18 and 13 on pre-natal screening
All lower
NTD on pre-natal screening
High AFP
At what week can an ultrasound reveal nuchal translucency?
18 weeks
Which can you do first: CVS or Amnio?
CVS
To test for CF in the blood, what types of test do you do?
Immuno-reactive trypsinogen
BCHE gene defect
AR
-Succinylcholine metabolism
Toxicity associated with n-acyltransferase
Isoniazid - neuropathy, hepatotoxicity
Hydralazine (HTN), procainamide (arrhythmia) SLE
Sulfonamides hemolytic anemia, SLE
CYP2D6 deficiency
CYP450 superfamily
* Anti-depressants, antiarrhythmic, analgesics
Thiopurine s-methyltransferase polymorphism
Low TPMT toxicity and myelosuppression when treated with standard doses of thiopurine, i.e. azathioprine, mercaptopurine (anti-cancer drugs)
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
Malignant hyperthermia
AD
Defect in RYR1 - Ryanodine receptor
Elevated release of Ca2+ from SR of skeletal muscle following inhalation anesthesia (halothane)
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
What signal can send something to a lysosome?
Mannose
With what is urea cycle treated?
Sodium benzoate (diverts ammonia to glycine and excretion of hippurate)
What is PEGylation?
adds stability to a protein
With what can PKU1 be treated?
Sapropterin – pharmacologic doses of BH4
