Cytogenetic Principles Flashcards
What is cytogenetics?
The study of chromosome abnormalities (number and structure)
Which is more common: cytogenetic abnormalities or single gene mendellian disorders?
Cytogenetic abnormalities are more common than all single gene mendellian disorders combined
Most chromosome abnormalities lead to what?
93.7% of chromosomal abnormalities lead to spontaneous abortions
How does the percentage of live births between unbalanced rearrangements and balanced rearrangements?
Unbalanced rearrangements result in many more still births (95.7%) than balanced rearrangements (16%)
What type of cell is most frequently used for cytogenetic analysis?
White blood cell T-lymphocytes
What are the three different types of chromosomes and how do they differ?
Metacentric: has centromere in the middle with equal length p and q arms
Submetacentric: has off center centromere with either p>q or q>p
Acrocentric: has centromere nearly at one end of the chromosome, with satellite stalks on the shorter end
What do the satellites from acrocentric chromosomes code for?
They contain hundreds of copies of rRNA coding genes
What does an ideogram show?
Ideograms show the G-banding patterns for human chromosomes
Allows us to visualize the location of bands of coding/noncoding portions of DNA and helps to identify which chromosome is which
How does the chromosome numbering system work? Where can c18p22 be found?
The chromosome number is listed first, followed by the designation of short (p) or long (q) arm
The arms are subdivided into regions which are further subdivided into bands.
c18p22 is the second band of the second region on the short arm of chromosome 18
How can higher resolution bands be seen in a giemsa stained chromosome?
Staining the chromosome in a less condensed state than metaphase such as prometaphase or prophase
On Giemsa staining, what do the dark and light bands correspond with?
Dark bands (G bands) correspond with AT-rich regions that condense early during the cell cycle and replicate late. These regions are gene poor and Alu poor but LINE rich
Pale bands (R bands) correspond with GC rich regions that condense late during the cell cycle, but replicate early. These regions are gene rich and LINE poor but Alu rich
Other than Giemsa staining, what are other chromosome staining methods?
Q-banding with fluorescence microscopy (fluorescent bands correspond exactly with G bands)
R-banding: reverse pattern as G banding
Fluorescence R-banding: fluorescent bands correspond with R bands
High resolution banding: obtain banding at earlier stage than metaphase
How prevalent are live births with autosomal monosomies?
Autosomal monosomies are incompatible with liver births
What are the three autosomal trisomies that result in live births?
Trisomy 13: Patau syndrome
Trisomy 18: Edward syndrome
Trisomy 21: Down syndrome
What are the most common sex chromosomal aneuploidies in females?
Turner syndrome: monosomy X (45, X)
Trisomy X: (47, XXX)
Total: 1/580 female births
What are the most common sex chromosomal aneuploidies in males?
Klinefelter syndrome (47, XXY and 48, XXXY)
47, XYY syndrome
Total: 1/360 male births
What is the most frequent cause of aneuploidy?
Meiotic nondisjunction: when homologs or sister chromatids do not properly separate during meiosis I or meiosis II
What happens when nondisjunction occurs in meiosis I?
Both homologs will stay together for the first division.
Two gametes will each contain one maternal and one paternal copy of the chromosome.
The other two gametes will be empty
What happens when nondisjunction occurs in meiosis II?
The first division occurs properly, but in the second division, one of the sister chromatids does not separate from the other.
This results in two normal gametes, and one gamete that contains both copies of either the maternal or paternal chromosome, as well as one empty gamete
What happens during an unbalanced rearrangement?
A portion of one chromosome is either duplicated (leading to a partial trisomy) or removed (leading to a partial monosomy)
What is an isochromosome?
The p-arm of one homolog is lost.
The q-arms from each sister can act as one long chromatid, which can be replicated to form a homolog with 4 q arms
Two gametes will be normal and two will contain the isochromosome (q-q)
How can a ring chromosome form from an unbalanced arrangement?
Material is lost from both ends, and the cell corrects the free ends by ligating them together into a ring.
This ring can be replicated, but often becomes problematic during cell division and gets torn apart randomly between the progeny
What are the two types of balanced rearrangements and how do they differ?
Paracentric and Pericentric
Paracentric rearrangements occur when a portion of the chromosome on one arm is inverted (this does not affect the centromere location)
Pericentric inversions occur when a portion of the chromosome, spanning the centromere, is inverted
Following a balanced rearrangement, how do homologous chromosomes line up? What complications can arise from this?
They form an inversion loop.
If chromosomes cross over in the looped conformation, inviable chromosomes can be produced that contain 2 centromeres or 0 centromeres (from a paracentric inversion)
Pericentric inversions result in viable chromosomes, but with gain or loss of information
Are carriers of balanced translocations phenotypically abnormal? What about their offspring?
Carriers of balanced show no clinical phenotype, but their offspring are at a risk for unbalanced combinations of chromosomes.
The chromosomes can segregate properly (2:2 segregation) or incorrectly (3:1 segregation) which can result in many different unbalanced chromosome combinations
What is a Robertsonian translocation?
In acrocentric chromosomes, proximal short arms of two different chromosomes can be exchanged and lost.
The long arms from each chromosome are then joined together
Following meiosis, gametes can have extra or missing copies of the chromosomes involved
This can result in monosomy or trisomy in zygotes following fertilization by a normal gamete
What is an example of a microdeletion disorder? How does this occur?
Prader-Willi and Angelman syndromes are a result of a 15q11-q13 deletion
This occurs when there is unequal crossing over within repetitive sequences
How is FISH useful for detecting aneuploidies in interphase chromosomes?
By staining for the presence of specific chromosome(s), you can discern whether or not there are normal quantities of each chromosome in the cell.
How does comparative genome hybridization work and what is it used for?
CGH is used to detect insertions or deletions
This works by comparing patient and control DNA using a microarray
Patient and control DNA compete to attach or hybridize to the microarray, and a scanner measures the fluorescent signals
If equal hybridization–> YELLOW
If DNA dosage lost —> RED
If DNA dosage gained —> Green
In a healthy female, compared to a healthy male, what result would a CGH microarray analysis show you?
A CGH microarray analysis would show you that the female has a double dosage of the X-chromosome, compared to the male, and a half dose of the Y-chromosome compared to the male.
The autosomal chromosomes should all have mean ratios near 1
What result would a CGH microarray analysis of an individual with trisomy 18 yield?
The mean ratio of the diseased individual will be equal to 1.5 (3/2 ratio) for chromosome 18, and equal to 1.0 for the other autosomal chromosomes
How do Prader-Willi syndrome and Angelman syndrome occur?
Genetic imprinting occurs.
Imprinting causes only one copy of the gene to be functional, so if there is a deletion in the good copy, then a disease state will occur.
