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.
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)
