Lecture 24

Question 1

What is polyploidy usually due to?

Answer 1

Usually due to a meiosis I failure.

Question 2

What occurs during aneuploidy?

Answer 2

• The chromosomes do not separate properly between two cells. Usually happens when cytokinesis (division of the cytoplasm) begins while karyokinesis (division of the nucleus) is underway.
• This is the most common type of clinically significant chromosome abnormality.

Question 3

Which are more deleterious monopolies or trisomies?

Answer 3

Monosomies.

Question 4

what is the difference between euploid and aneuploid?

Answer 4

euploid is an exact multiple of the haploid chromosome number while aneuploid is any other chromosome number.

Question 5

which monosomies are still viable?

Answer 5

only monosomy X

Question 6

which trisomies are viable?

Answer 6

trisomies on chomosomes 13, 18, 21, X and Y
- 13, 18, and 21 have the lowest number of genes on them so it is presumed that the lethality of the trisomy increases with the amount of genes on the chromosome.

Question 7

what are the two types of inversions and what is the level of abnormal risk associated with both?

Answer 7

• Pericentric inversions are when the centromere is included in the inversion. The risk of abnormalities increases with size of the inversion.
• Paracentric inversions do not include the centromere in the inversion and have a very low risk of abnormal phenotype.

Question 8

what is the most common cause of triploidy?

Answer 8

fertilization by two sperm (dispermy). Failure of one of the meiotic divisions resulting in a diploid egg or sperm.

Question 9

what is the most common type of trisomy?

Answer 9

trisomy 21, seen in 95% of patients with Down Syndrome

Question 10

what is the only case in which monosomy for an entire chromosome is still viable?

Answer 10

monosomy for the X chromosome.

Question 11

explain nondisjunction.

Answer 11

it is the failure of a pair of chromosomes to disjoin properly during one of the two meiotic divisions. usually during meiosis I.

Question 12

What is the consequence of nondisjunction during meiosis I?

Answer 12

the result is two gametes with a copy from each parental chromosome (disomic) and two gametes with no chromosomes from either parent (nullisomic). (4 gametes total)

Question 13

when was down syndrome first described and by whom?

Answer 13

• first described in 1866 by John Langdon Down but first understood by Jerome Lejeune about a century later in 1959.

Question 14

what are the three common sex chromosomal abnormalities identified in 1959 and why are they almost never phenotypically active?

Answer 14

• 47, XXY
• 47, XXX
• 47, XYY
• they are usually not active because X-inactivation via XIST proteins help control gene expression, however there is only enough to inactivate one X.

Question 15

what the prenatal indications of an aneuploidy?

Answer 15

• history of spontaneous abortion
• maternal age over 35
• family history of mental retardation/developmental delay
• fetal anomalies on ultrasound

Question 16

how do you prepare a karyotype?

Answer 16

• culture amniocytes for 7-10 days
• grow them then arrest mitotic chromosomes at metaphase
• stain amniocytes with giemsa dye (G-banding allows for distinctive banding patterns based on G:C concentration)
• visualize g-banding on a microscope and observe deletions, rearrangements, aneuploidies, etc. (can’t see very small changes)

Question 17

what is FISH and what is it good for?

Answer 17

• Fluorescence in situ hybridization
• allows you to see individual gene deletions and duplications that are too small to be observed via karyotype visualization.

Question 18

how is a FISH performed?

Answer 18

• take chromosomes
• hybridize these chrommosomes on a slide in situ (in place) with a fluorescently labeled piece of DNA from the gene of interest (must know beforehand).

Question 19

what are the advantages and disadvantages of FISH?

Answer 19

A) allows for visualization of small microdeletion syndroms such as DiGeorge which can’t be seen on a karyotype.
A) you can identify contiguous gene syndromes like Prader-Willi
A) you can perform it on amniocytes that are in interphase (as opposed to metaphase in karyotypes)
A) you have rapid diagnosis compared to karyotyping
A) you can look at the end of chromosomes, inside telomeres where there are often subtelomeric regions rich in genes.
A) you can see amplified oncogenes and deleted tumor suppressor genes
D) you can only detect abnormalities based on the specific hybrid probe you’ve injected so it requires prior knowledge since the whole genome is not being scanned.

Question 20

how many mutations must a cell undergo in order for it to become a cancerous cell?

Answer 20

• 10 to 12 mutations

Question 21

what are 1/3rd of breast tumors due to and how is it treated?

Answer 21

• 1/3rd of breast tumors are due to overexpression of the Her-2-neu oncogene.
• this is treated usiong Herceptin which reduces the exression of this gene which can be visualized using FISH.

Question 22

what type of chromosomal aberrations is most likely to result in a phenotypic change and why not the others?

Answer 22

• deletion because during inversions or translocations there is still the correct amount of gene dosage only reorganized, while in deletions you are permanently losing genetic material.

Question 23

What is the difference between an intrachromosomal recombination and an interchromosomal recombination?

Answer 23

• an inter-chromosomal event occurs when two homologous chromosomes misalign during meiosis and there is unqual crossing over. Sometimes due to two non-homologous chromosomes pairing and misaligning. Results in a deletion gamete and a duplication gamete.
• an intra-chromosomal event occurs when homologous sequences align on the same chromosome when they shouldn’t forming a loop of DNA within one parental chromosome. If there is no centromere in this loop then the loop and all genes in the loop will dissociate from the chromosome and be lost forever via degradation. Results in only a deletion gamete, no duplication gamete but can result in an inversion.

Question 24

what are two inviable gametes?

Answer 24

• ones with 0 or 2 centromeres.

Question 25

GO OVER PERICENTRIC AND PARACENTRIC INVERSIONS.

Answer 25

NOW.

Question 26

What is a recipricol translocation?

Answer 26

a balanced trade between two different derivative chromosomes. The majority of one chromosome with its centromere (1st derivative chromosome) recombines with a smaller portion of the 2nd derivative chromosome. The remaining majority of the 2nd derivative chromosome with its centromere recombines with the smaller portion of the 1st chromosome.

Question 27

what is a robertsonian translocation?

Answer 27

There are five acro-centric (barely any p-arm) chromosomes which has a small nub of a p-arm containing ribosomal genes on them. What happens is the small p-arms from two different acro-centric chromosomes basically fuse together forming one long chromosome, losing some of the ribosomal genes in each p-arm but being mostly phenotypically normal. (chromosome 14 + chromosome 21 = chromsome 14, 21).

Question 28

what are the five acro-centric human chromosomes?

Answer 28

chromosomes 13, 14, 15, 21, and 22

Question 29

how do chromsomes that have undergone recipricol translocation line up with their normal homologous chromosome and how can the pairs be segregated?

Answer 29

• in a cross formation.
  1) Alternate: the two normal chromosomes can segregate together into one gamete resulting in a completely normal gamete. And the two remaining alternate chromosomes will segregate into the other gamete and it will still be balanced.
  2) Adjacent 1: results in trisomy and monosomy
  3) Adjacent 2: results in trisomy and monosomy in the opposite manner as Adjacent 1

Question 30

how do chromosomes that have undergone robertsonian translocation line up with their normal homologous chromomes and how can the pairs be segregated?

Answer 30

• in a triangular formation.
  1) Alternate: generates one normal and one balanced gamete.
  2) Adjacent 1 and 2: generates two unbalanced gametes (opposite but both unbalanced, usually lethal).