5 - Clinical Cytogenetics Flashcards
(38 cards)
What are the three functional elements that chromosomes require for stability?
- Origin of replication
- Centromere
- Telomere
Describe the origin of replication of a chromosome?
Multiple locations on a chromosome where DNA replication can begin.
What is the function of the centromere?
Attachment point for spindle and thus is essential for chrom movement from equator during mitosis and meiosis.
Describe centromeres on human chromosomes?
Regional centromeres: their function resides in epigenetic marks provided by CENP histones.
Composed of tandemly repeated 171 bp AT-rich sequences called a-satellite DNA.
What does the alpha-satelite DNA contain? What else is at the centrosome?
A 1 7bp binding motif for CENP-B.
CENP-A replaces histone H3 at a small number of nucleosomes at the centromere.
Centromeric DNA supports assembly of kinetochore protein complex for spindle attachment.
What are telomeres?
Repeated TTAGGG sequence at the end of chromosomes.
Characteristic terminal loop.
Binds protein complex called shelterin that blocks access to DNA repair machinery, limiting
recombination.
What is the Hayflick limit?
The limited capacity that a somatic cell has to divide in its lifetime.
Differs by tissue.
How do cells in the germline and cancer cells differ from somatic cells?
They have telomerase, which can lengthen telemeres by adding TTAGGG hexamers.
What happens to cells as they approach the Hayflick limit? What else can occur to cells with very short telomeres?
Undergo growth arrest and they become post-mitotic.
Critically short telomeres stimulate p53-mediated arrest. They could also have damage that activates another type of tumor suppressor to undergo apoptosis.
What happens when a subset of cells escape the various protective mechanisms that should occur while approaching Hayflicks limit?
Senescence, a post-mitotic state that features resistance to apoptosis.
If they continue to divide, they undergo crisis. If they survive this, they are transformed and have high malignant potential.
What happens to acentric fragments of chromosomes during recombination?
Without a centromere, they don’t move from the equatorial plate at anaphase and are lost at high freq.
This leads to deletions of genes carried by them.
What happens to dicentric chromosomes during recombination?
They go through a breakage-fusion-bridge cycle.
At anaphase they may migrate to opposite poles, breaking the chrom between them. The free ends are recombinogenic and promote rearrangements. This is a common occurrence at crisis, when telomere insufficiency can initiate formation of a dicentric chrom.
What is a paracentric inversion?
An inversion that does not include the centromere and both breaks occur in one arm of the chromosome.
What happens if crossing over occurs within a paracentric inversion?
Then the recombinant chromosomes include a dicentric chromosome and an acentric chromosome.
What is a pericentric inversion?
An inversion that includes the centromere and there is a break point in each arm.
How can translocations be recognized in meiosis?
When the chromosomes fuse, you will see quadrivalents (four chrom fused together) if a translocation has occurred.
Normal karyotypes only form bivalents.
What are autosomal aneuploidies? What is the consequence?
An abnormal number of chromosomes in an autosomal cell.
Most autosomal aneuploidies, including autosomal monosomies and trisomies, are lethal in gestation.
What is down syndrome caused by? What are the characteristics? What is the incidence of down syndrome?
Most common autosomal aneuploidy, trisomy 21, typically from maternal non-disjunction.
Intellectual impairment, hypotonia, prominent epicanthic folds, simian palm. Increased risk of leukemia and short statues.
~1/700 live births
What is Edwards syndrome? What is the incidence? What are the characteristics?
Trisomy 18, incidence ~1/5000 live births (usually die within days of birth).
Microsomia, microcephaly, cardiac defects, microopthalmia (small jaw), overlapping digits.
What is Pateau syndrome? What are some associated characteristics? What is the incidence?
Trisomy 13, incidence ~1/15,000. Survival usually less than one year.
Midline defects: holoprosencephaly (undeveloped forebrain), cleft lip/palate, cardiac defects. Polydactyly, prominent heel.
How does a variable number of X chromosomes escape the dire consequences that accompany autosomal aneuploidy?
Most X-linked genes are subjected to dosage compensation.
Regardless of the number of X chrom, most X-linked genes are expressed at the same level because all X chrom except one are epigeneticallt silenced.
How are all but one X chromosomes silenced?
The chrom has an X inactivation center that includes the Xist locus.
Xist encodes non-coding RNA that can bind the X chromosome from the inactivation center and to the adjacent regions.
What does Xist binding to the X chromosome do?
Promotes stable epigenetic silencing of chromosome via specific DNA methylaton/demethylation, histone methylation/demethyl and histone acetylation/deacetylation.
What happens to the inactive X chromosome(S)? How does the number of X chromosomes compare to the number of barr bodies?
It stays in a concensed heterochromatin state and manifests as a barr body, a dense structure adjacent to the nuclear envelope.
Number of bass bodies is one less than the number of X chromosomes.
