01: Introduction to Genetics Flashcards
What is CHEK2?
Human gene which, if mutated, increases risk of breast cancer. Deletion (S428F) increases risk 2-fold (vs. BRCA1/2, which increases risk 10-fold).
Describe the two types of changes which may occur to DNA.
Constitutional: Via the germ line; affects every cell.
Somatic: Mutation over time
What is gene expression profiling?
A measurement of the activity (the expression) of thousands of genes at once, to create a global picture of cellular function.
Example: Microarrarys
What is Long QT Syndrome? What are the different types, their causes, and their genetically-based treatments?
Autosomal dominantly inherited predisposition to cardiac arrhythmias and sudden death.
Genetically heterogenous syndrome (phenotype/genetic disorder may be caused by any one of a multiple number of alleles locus mutations). Due to a mutation in a single gene.
For KCNQ1 & KCNH2 (LQT1): triggered by exercise; mutation in rapid potassium channel; administer beta blockers (beta adrenergic antagonists suppress sympathetics).
For KCNH2 (LQT2): triggered by unexpected sound during sleep; mutation in slow potassium channel; avoid hypokalemia (reduced potassium repolarizing current; more potassium necessary).
SCN5A (LQT3): triggered by unexpected sound during sleep; mutation of sodium channel (failure to remain inactive); administer mexiletine (avoid tachyarrhythmic events induced by bradycardia).
Gene-specific pharmacology!
What is the utility of susceptibility testing?
Allows us to tailor preventative medicine via:
- Lifestyle modification
- Risk avoidance
- Preventative pharmacotherapy
- Increased surveillance
What is hypertrophic cardiomyopathy? What is the genetic basis of prognosis?
Disease in which the heart muscle becomes abnormally thick , making it harder for the heart to pump blood.
Caused by a mutation of cardiac troponin T. If mutation is Val606Met, high survival. If mutation is Arg92Gln, low survival, therefore pacemaker necessary.
This information is shown on a Kaplan-Meier survival curve.
What are genetic modifiers?
Genes that have small quantitative effects on the level of expression of another gene; when acting together, may cause disease (e.g., RAAS signaling pathway polymorphisms).
What is malignant hyperthermia? What is its genetic predisposition/putative environmental trigger?
Autosomal dominantly inherited disorder (mutation in RYR1) which results in a fast rise in body temperature and severe muscle contractions when the affected person gets general anesthesia.
Describe aneuploidy:
- Definition
- Difference from polypoidy
- Most common types
- Gender & age effects
- An abnormal number of chromosomes (extra or missing) within a cell; a type of chromosome abnormality.
- Polyploidy occurs due to altering set of chromosome number such as 2n, 3n, 5n, whereas aneuploidy occurs due to altering particular chromosome or part of a chromosome such as 2n-1(monosomic).
- Trisomy 16 most common, followed by Trisomy 21 & 22.
- Mostly in oogenesis, with maternal meiosis I errors being more common than maternal meiosis II errors. Incidence in 1-2% of sperm, 20-30% of oocytes. Down syndrome incidnece approaches 35% in women >40 years of age.
Name and describe the stages of mitosis.
Describe meiosis, including the difference between the genders.
- Occurs only in ovaries and testes (in gamete cells).
- Reduces number of chromosomes from diploid (2n=46) to haploid (n=23).
- Male meiosis:
- Begins at puberty & continues throughout life
- Spermatocytes continually replaced by mitosis
- Sperm maturation involves loss of histones and highly condensed DNA
- Each cycle from spermatocyte to sperm takes ~40 days
- Each complete (I&II) meiotic division produces 4 sperm
- Female meiosis:
- All oocytes are formed during fetal life, continually lost by apoptosis throughout life
- Meiotic prophase begins at 14 weeks of gestation
- Meiosis I arrested after diplotene and resumes only at time of ovulation
- Meiosis II completed only after fertilization
- Cell division is asymetrical, producing one large egg and three nonfunctional polar bodies.
What are the several substages of meiosis and what occurs in each?
Meiosis I: Prophase I, Metaphase I, Anaphase I, Telophase I
Prophase I further subdivided:
- Leptotene (committment of cell to meiosis)
- Zygotene (pairing of homologous chromosomes)
- Pachytene (crossing/recombination occurs)
- Diplotene (homologous chromosomes repel each other)
- Diakinesis (greatest level of contraction)
At what stage do most meiotic errors occur?
Metaphase/Anaphase I
What are the meiotic error mechanisms, and what occurs in each?
- True non-disjunction: Homologues travel together to same pole (disomic gamete/trisomic embryo & nullisomic gamete/monosomic embryo)
- Achiasmate non-disjunction: Homologues that have failed to pair and/or recombine travel independently to the same pole (no recombination; disomic gamete/trisomic embryo & nullisomic gamete/monosomic embryo)
- Premature (precocious) separation of sister chromatids PSSC): chromatids rather than homologues segregate from one another (disomic game/trisomic embryo & nullisomic gamete/monosomic embryo AND normal gamete/normal embryo & normal gamete/normal embryo)
PSSC is more frequent than whole-chromosome non-disjunction
What most often causes aneuploidy, and what are its mechanisms?
Altered recombination causes aneuploidy. Reduce/abolished recombination can result from meiotic arrest, abnormalities in chromosome segregation (achiasmatic segregation), and increased levels of non-disjunction.
Describe the function and characters involved in “hotspots.”
Hotspots are regions where recombination most often occur. Contain degenerate DNA sequence of 13 nucleotides. PRDM9 (zing finger protein) binds here (three types: A, B, I). During cell division, sister chromatid cohesion facilitated by cohesin (has 4 subunits: 2 SMC, one SA, one Kleisin). During meiosis I, cohesin complexes removed during MI-AI transition, allowing segregation of recombined homologues to opposite poles (cohesin remains at centromere). Cohesin complexes released by separase; this enzyme is inhibited by securin until ubiquitinated by anaphase promoting complex/cyclosome (APC/C).
What is the link between advanced maternal age and aneuploidy?
Female aging characterized by depletion of cohesin; thus, chiasmata are destabilized and induces a loss of tight association between sister centromeres (leads to major anaphase I defects).
What is the process of normal mitotic chromosome segregation?
Bi-orientation of sister kinetochores and attachment to microtubules emanating from opposite poles (amphitelic orientation) causes tension between sister kinetochores that stabilizes microtubule attachment.
What are the types of aberrant kinetochore orientation in mitosis, and what lineages do they generate?
- Monotelic: Unoccupied microtubule attachment sites on unattached kinetochores accumulate mitotic checkpoint proteins –> create signal that keeps process moving forward.
- Syntelic: Both kinetochores attach on same side; mitotic checkpoint still active (prevent moving forward).
- Merotelic: Attachment of single kinetochore to microtubules from both spindle poles rather than one; does not activate mitotic checkpoint due to tension.
1 & 2 will generate mosaicism with two or three cell lineages (normal, trisomy or monosomy); 3 will generate mosaicism with two cell lineages (normal or monosomy)
Describe the components and functions of the cell-cycle control system.
Coordinates the events of the cell cycle by cyclically switching on/off appropriate machinery.
Depends on a set of protein kinases composed of cyclin (regulatory subunit) and cyclin-dependent protein kinase (Cdk; catalytic subunit).
Different cyclin-Cdk complexes trigger different steps of the cell cycle: M-Cdk (mitosis), G1-Cdk (G1), G1/S-Cdk & S-Cdk (S phase)
Can be halted by two mechanisms:
1) Cdk inhibitor proteins
2) Components can stop being made
What is the mitotic spindle checkpoint and how does it work?
Surveillance mechanism that regulates metaphase-to-anaphase transition.
Proteins localize to unattached kinetochores and generate a “wait anaphase signal.”
Monotelic and syntelic orientations are converted to bipolar attachments under this checkpoint.
