Chromosomal Instability

Question 1

What is Chromosomal Instability (CIN)?

Answer 1

describes the rate (cell-to-cell) of gain or loss of whole chromosomes or fractions of chromosomes

Question 2

What is Genomic instability?

Answer 2

includes CIN & other forms of presently known genomic instabilities, like microsatellite instability (MIN)

Question 3

What are CIN syndromes?

Answer 3

a group of rare inherited disorders that make a person more likely to develop CIN, either on their own or when exposed to cancer-causing agents.

Question 4

What are causes of CIN syndromes?

Answer 4

defects in proteins or enzymes essential for DNA repair & chromosomal maintenance → leads to higher risk of different pathologies including certain cancers

Question 5

How are CIN syndromes diagnosed?

Answer 5

requires genetic testing & evaluation of chromosomal breakage

Question 6

What is Ataxia-telangiectasia (Louis-Bar syndrome)?

Answer 6

CIN syndrome: lack of coordination and dilated blood vessels; caused by mutations in the ATM gene (crucial for NA repair & cell cycle control)

Question 7

What is Bloom syndrome?

Answer 7

CIN syndrome: a genetic condition that causes skin sensitivity to sunlight, weakens the immune system, and leads to a higher risk of multiple cancers and chromosomal instability.

Question 8

What is Fanconi anemia?

Answer 8

CIN syndrome: due to mutation in FANCA gene, leading to genomic instability and an increased risk of cancer

Question 9

What is Nijmegen breakage syndrome?

Answer 9

CIN syndrome: genetic disorder caused by mutations in the NBS1 gene, leading to microcephaly (small head size), growth retardation, weakened immune system, and an increased risk of cancer

Question 10

What is a Microsatellite?

Answer 10

short, repetitive sequences of DNA found throughout the genome

Question 11

What do microsatellites consist of?

Answer 11

short repeating units of 1-9 base pairs & can be highly variable in length among individuals

Question 12

How does microsatellite variation make them useful for genetic studies?

Answer 12

Genetic mapping: help identify location of genes associated with specific traits or diseases
Population genetics: used to study genetic diversity and relationships within and between populations
Forensic analysis: used for DNA fingerprinting to identify individuals

Question 13

What is the evolutionary origin of microsatellites?

Answer 13

duplication errors during mitosis –> microsatellites have a higher mutation rate compared to other DNA regions

Question 14

How likely are human microsatellites of viral origin?

Answer 14

Unlikely

Question 15

What are the putative roles of microsatellites?

Answer 15

modulation of:
Transcription factor binding
Spacing between promoter elements, enhancers
Cytosine methylation
Alternative splicing
mRNA stability
Selection of transcription start and termination sites in alternative splicing
Nucleosome positioning and modification and higher order chromatin structure
Noncoding RNA
Meiotic recombination hot spots

Question 16

Describe the variation in the human genome

Answer 16

> 99.5% of the human genome does not vary. Within the variant areas are the special polymorphic sequences used in forensic applications

Question 17

Where are Polymorphic DNA sequences used for forensic typing are derived from?

Answer 17

chromosome regions that do not control any known traits & have no known functions (i.e. STRs)

Question 18

What is trisomy?

Answer 18

genetic disorder in which a person has 3 chromosomes instead of the usual 2

Question 19

What is the most well-known trisomy?

Answer 19

Down-syndrome (trisomy 21)

Question 20

What are the effects of trisomy?

Answer 20

can range from few/no symptoms - severe birth defects that make life & pregnancy unsustainable

Question 21

What does Canadian prenatal screening focus on the most?

Answer 21

Trisomy 21, 18, 13 represent 0.2% pregnancies (most frequent chromosomal anomalies)

Question 22

What is Chorionic villus sampling?

Answer 22

tiny projections of placental tissue matching the fetus’ genetic material

Question 23

What is Karyotyping through Chorionic villus sampling?

Answer 23

process used to analyze the chromosomes of a fetus to detect genetic abnormalities

Question 24

What is Karyotyping?

Answer 24

(standard procedure for 50+ years) Cells are halted in the G phase of mitosis to allow for standard chromosome banding. Chromosomes are then collected, stained, and examined under a microscope

Question 25

What does SKY (special karyotyping)-labeled human chromosomes do?

Answer 25

Offers enhanced and simplifies visualization and analysis of chromosomes. Staining protocol involves hybridizing stained probes to specific chromosomes

Question 26

How many chromosomes does a SKY labeling probe target?

Answer 26

1 - each probe is labeled with a color that is complementary to various regions of a single target chromosome

Question 27

How many probes are used in SKY labeling?

Answer 27

24 probes with 24 different colors

Question 28

What is FISH?

Answer 28

(fluorescence in situ hybridization): technique used to detect and visualize specific sequences within cells or tissues

Question 29

How many probes/colors are used in FISH?

Answer 29

1, 1

Question 30

What is deletion in a chromosome structure?

Answer 30

the loss of 1+ nucleosomes from a segment of DNA

Question 31

What is duplication in a chromosome structure?

Answer 31

the duplication of 1+ nucleosomes from a segment of DNA

Question 32

Duplication may arise from _____?

Answer 32

unequal crossing overs during meiosis

Question 33

What can duplication lead to?

Answer 33

Gene redundancy (rRNA duplicated genes) & CNVs (copy # variations: 5-10% of the genome are 50 bp to 3Mb duplicated sequences)

Question 34

What is inversion in a chromosome structure?

Answer 34

when a segment breaks off and reattaches within the same chromosome, but in reverse orientation

Question 35

What is Nonreciprocal translocation in a chromosome structure?

Answer 35

2 nonhomologous chromosomes → a segment of one is removed and added to the other

Question 36

What is reciprocal translocation in a chromosome structure?

Answer 36

2 nonhomologous chromosomes → a segment of each chromosome is removed and added to the other (trade pieces)

Question 37

What is under-replicated DNA (UR-DNA) and its effect during mitosis?

Answer 37

UR-DNA occurs when DNA doesn’t finish replicating before cell division, creating ultra-fine bridges (UFBs) between sister chromatids. These bridges can break and form micronuclei in the next cell cycle.

Question 38

What happens when one-ended double-strand breaks are unrepaired?

Answer 38

Unrepaired one-ended double-strand breaks can lead to chromosome breaks during mitosis, forming acentric fragments (without a centromere), which are known sources of micronuclei.

Question 39

What are acentric fragments, and why are they important?

Answer 39

Acentric fragments are chromosome pieces without centromeres, formed from unrepaired DNA breaks, and they can lead to the formation of micronuclei (MN).

Question 40

What happens when fully duplicated chromosomes experience kinetochore-microtubule attachment problems during anaphase?

Answer 40

They may lag at the metaphase plate during anaphase and form chromosome micronuclei in the next cell cycle

Question 41

What are some mechanisms that can lead to polyploidization?

Answer 41

Polyploidization can occur through cytokinesis failure, mitotic slippage, or endocycling.

Question 42

What is Colchicine?

Answer 42

naturally occurring plant secondary metabolite known for its potent antimitotic properties

Question 43

Explain how colchicine is antimitotic

Answer 43

colchicine binds to tubulin preventing the polymerization of microtubules → disrupts the formation of mitotic spindle (essential for cell division). Colchicine halts the cell division at the early anaphase stage: the chromosomes are duplicated without mitosis and cell wall formation → results in polyploidy of the plant cells

Question 44

How does liver polyploidization change with age?

Answer 44

Hepatocyte ploidy increases with age, with a rapid rise around the time of weaning

Question 45

Why does polyploidization slow after maturation?

Answer 45

It slows because hepatocyte proliferation rates decrease after maturation

Question 46

How does insulin influence liver polyploidization?

Answer 46

Insulin promotes cytokinesis failure, which partially controls polyploidization.

Question 47

What is another mechanism of hepatocyte polyploidization in later stages?

Answer 47

Hepatocytes can undergo polyploidization through endoreduplication in later stages.

Question 48

How does polyploidy benefit the liver?

Answer 48

Polyploid hepatocytes help protect the liver from mutation-induced tumorigenesis.

Question 49

What is the current understanding of polyploidy in the human liver?

Answer 49

The functions of polyploidy in the human liver remain controversial.

Question 50

How can chromosomal instability (CIN) lead to carcinogenesis?

Answer 50

CIN can cause normal tissue to become tumorigenic, leading to tumor cells with low levels of instability. This can further transform cells, enabling carcinogenesis.

Question 51

What happens to tumor cells as cancer progresses with increasing CIN?

Answer 51

Tumor cells become more genetically unstable, which can promote drug resistance and metastasis as CIN levels rise.

Question 52

What occurs when CIN reaches very high levels in tumor cells?

Answer 52

Cells may reach a point where they are no longer viable, though surviving cells remain unstable and promote tumor growth and spread.

Question 53

What is the relationship between CIN and cancer prognosis?

Answer 53

CIN correlates with poor patient prognosis, as increased genetic diversity in tumor cells drives cancer progression

Question 54

What is a common characteristic of human solid malignant tumors?

Answer 54

They are often marked by chromosomal instability, which involves the gain or loss of whole or parts of chromosomes

Question 55

What are potential consequences of genomic instability?

Answer 55

Genomic instability can lead to cancer, telomere dysfunction, and aneuploidy (abnormal chromosome numbers)

Question 56

How does the immune system prepare for unknown antigens?

Answer 56

The immune system has evolved to respond to any possible antigen, with 3–9 million different antibodies in human blood.

Question 57

What system do lymphocytes use to create diverse antibodies?

Answer 57

Lymphocytes use gene translocation (gene-shuffling) to combine different V (variable), D (diversity), and J (joining) genes along a chromosome.

Question 58

How does each B-lymphocyte contribute to antibody diversity?

Answer 58

A B-lymphocyte expresses V(D)J genes from only one parent, adding to the diversity of antibodies.

Question 59

What are the segments involved in antibody diversity for the human heavy chain?

Answer 59

38-46 V (variable) segments, 23 D (diversity) segments, and 6 J (joining) segments.

Question 60

What is combinatorial diversity in antibody formation?

Answer 60

Combinatorial diversity arises when each B cell randomly selects one V, D, and J segment to form the variable region of the antibody

Question 61

What is junctional diversity, and how does it contribute to antibody diversity?

Answer 61

Junctional diversity is introduced when nucleotides are added or deleted during the joining of V, D, and J segments, further increasing antibody variability

Question 62

What is somatic hypermutation?

Answer 62

After antigen exposure, immune cells undergo somatic hypermutation in their variable regions, introducing mutations that help produce higher affinity antibodies.