Cytogenetic Principles

Question 1

What is cytogenetics?

Answer 1

The study of chromosome abnormalities (number and structure)

Question 2

Which is more common: cytogenetic abnormalities or single gene mendellian disorders?

Answer 2

Cytogenetic abnormalities are more common than all single gene mendellian disorders combined

Question 3

Most chromosome abnormalities lead to what?

Answer 3

93.7% of chromosomal abnormalities lead to spontaneous abortions

Question 4

How does the percentage of live births between unbalanced rearrangements and balanced rearrangements?

Answer 4

Unbalanced rearrangements result in many more still births (95.7%) than balanced rearrangements (16%)

Question 5

What type of cell is most frequently used for cytogenetic analysis?

Answer 5

White blood cell T-lymphocytes

Question 6

What are the three different types of chromosomes and how do they differ?

Answer 6

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

Question 7

What do the satellites from acrocentric chromosomes code for?

Answer 7

They contain hundreds of copies of rRNA coding genes

Question 8

What does an ideogram show?

Answer 8

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

Question 9

How does the chromosome numbering system work? Where can c18p22 be found?

Answer 9

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

Question 10

How can higher resolution bands be seen in a giemsa stained chromosome?

Answer 10

Staining the chromosome in a less condensed state than metaphase such as prometaphase or prophase

Question 11

On Giemsa staining, what do the dark and light bands correspond with?

Answer 11

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

Question 12

Other than Giemsa staining, what are other chromosome staining methods?

Answer 12

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

Question 13

How prevalent are live births with autosomal monosomies?

Answer 13

Autosomal monosomies are incompatible with liver births

Question 14

What are the three autosomal trisomies that result in live births?

Answer 14

Trisomy 13: Patau syndrome

Trisomy 18: Edward syndrome

Trisomy 21: Down syndrome

Question 15

What are the most common sex chromosomal aneuploidies in females?

Answer 15

Turner syndrome: monosomy X (45, X)

Trisomy X: (47, XXX)

Total: 1/580 female births

Question 16

What are the most common sex chromosomal aneuploidies in males?

Answer 16

Klinefelter syndrome (47, XXY and 48, XXXY)

47, XYY syndrome

Total: 1/360 male births

Question 17

What is the most frequent cause of aneuploidy?

Answer 17

Meiotic nondisjunction: when homologs or sister chromatids do not properly separate during meiosis I or meiosis II

Question 18

What happens when nondisjunction occurs in meiosis I?

Answer 18

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

Question 19

What happens when nondisjunction occurs in meiosis II?

Answer 19

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

Question 20

What happens during an unbalanced rearrangement?

Answer 20

A portion of one chromosome is either duplicated (leading to a partial trisomy) or removed (leading to a partial monosomy)

Question 21

What is an isochromosome?

Answer 21

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)

Question 22

How can a ring chromosome form from an unbalanced arrangement?

Answer 22

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

Question 23

What are the two types of balanced rearrangements and how do they differ?

Answer 23

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

Question 24

Following a balanced rearrangement, how do homologous chromosomes line up? What complications can arise from this?

Answer 24

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

Question 25

Are carriers of balanced translocations phenotypically abnormal? What about their offspring?

Answer 25

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

Question 26

What is a Robertsonian translocation?

Answer 26

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

Question 27

What is an example of a microdeletion disorder? How does this occur?

Answer 27

Prader-Willi and Angelman syndromes are a result of a 15q11-q13 deletion

This occurs when there is unequal crossing over within repetitive sequences

Question 28

How is FISH useful for detecting aneuploidies in interphase chromosomes?

Answer 28

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.

Question 29

How does comparative genome hybridization work and what is it used for?

Answer 29

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

Question 30

In a healthy female, compared to a healthy male, what result would a CGH microarray analysis show you?

Answer 30

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

Question 31

What result would a CGH microarray analysis of an individual with trisomy 18 yield?

Answer 31

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

Question 32

How do Prader-Willi syndrome and Angelman syndrome occur?

Answer 32

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.