Chromosomal Instability Flashcards
Module 5: Gene/Genome alterations and repairs
What is Chromosomal Instability (CIN)?
describes the rate (cell-to-cell) of gain or loss of whole chromosomes or fractions of chromosomes
What is Genomic instability?
includes CIN & other forms of presently known genomic instabilities, like microsatellite instability (MIN)
What are CIN syndromes?
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.
What are causes of CIN syndromes?
defects in proteins or enzymes essential for DNA repair & chromosomal maintenance → leads to higher risk of different pathologies including certain cancers
How are CIN syndromes diagnosed?
requires genetic testing & evaluation of chromosomal breakage
What is Ataxia-telangiectasia (Louis-Bar syndrome)?
CIN syndrome: lack of coordination and dilated blood vessels; caused by mutations in the ATM gene (crucial for NA repair & cell cycle control)
What is Bloom syndrome?
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.
What is Fanconi anemia?
CIN syndrome: due to mutation in FANCA gene, leading to genomic instability and an increased risk of cancer
What is Nijmegen breakage syndrome?
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
What is a Microsatellite?
short, repetitive sequences of DNA found throughout the genome
What do microsatellites consist of?
short repeating units of 1-9 base pairs & can be highly variable in length among individuals
How does microsatellite variation make them useful for genetic studies?
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
What is the evolutionary origin of microsatellites?
duplication errors during mitosis –> microsatellites have a higher mutation rate compared to other DNA regions
How likely are human microsatellites of viral origin?
Unlikely
What are the putative roles of microsatellites?
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
Describe the variation in the human genome
> 99.5% of the human genome does not vary. Within the variant areas are the special polymorphic sequences used in forensic applications
Where are Polymorphic DNA sequences used for forensic typing are derived from?
chromosome regions that do not control any known traits & have no known functions (i.e. STRs)
What is trisomy?
genetic disorder in which a person has 3 chromosomes instead of the usual 2
What is the most well-known trisomy?
Down-syndrome (trisomy 21)
What are the effects of trisomy?
can range from few/no symptoms - severe birth defects that make life & pregnancy unsustainable
What does Canadian prenatal screening focus on the most?
Trisomy 21, 18, 13 represent 0.2% pregnancies (most frequent chromosomal anomalies)
What is Chorionic villus sampling?
tiny projections of placental tissue matching the fetus’ genetic material
What is Karyotyping through Chorionic villus sampling?
process used to analyze the chromosomes of a fetus to detect genetic abnormalities
What is Karyotyping?
(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
What does SKY (special karyotyping)-labeled human chromosomes do?
Offers enhanced and simplifies visualization and analysis of chromosomes. Staining protocol involves hybridizing stained probes to specific chromosomes
How many chromosomes does a SKY labeling probe target?
1 - each probe is labeled with a color that is complementary to various regions of a single target chromosome
How many probes are used in SKY labeling?
24 probes with 24 different colors
What is FISH?
(fluorescence in situ hybridization): technique used to detect and visualize specific sequences within cells or tissues
How many probes/colors are used in FISH?
1, 1
What is deletion in a chromosome structure?
the loss of 1+ nucleosomes from a segment of DNA
What is duplication in a chromosome structure?
the duplication of 1+ nucleosomes from a segment of DNA
Duplication may arise from _____?
unequal crossing overs during meiosis
What can duplication lead to?
Gene redundancy (rRNA duplicated genes) & CNVs (copy # variations: 5-10% of the genome are 50 bp to 3Mb duplicated sequences)
What is inversion in a chromosome structure?
when a segment breaks off and reattaches within the same chromosome, but in reverse orientation
What is Nonreciprocal translocation in a chromosome structure?
2 nonhomologous chromosomes → a segment of one is removed and added to the other
What is reciprocal translocation in a chromosome structure?
2 nonhomologous chromosomes → a segment of each chromosome is removed and added to the other (trade pieces)
What is under-replicated DNA (UR-DNA) and its effect during mitosis?
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.
What happens when one-ended double-strand breaks are unrepaired?
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.
What are acentric fragments, and why are they important?
Acentric fragments are chromosome pieces without centromeres, formed from unrepaired DNA breaks, and they can lead to the formation of micronuclei (MN).
What happens when fully duplicated chromosomes experience kinetochore-microtubule attachment problems during anaphase?
They may lag at the metaphase plate during anaphase and form chromosome micronuclei in the next cell cycle
What are some mechanisms that can lead to polyploidization?
Polyploidization can occur through cytokinesis failure, mitotic slippage, or endocycling.
What is Colchicine?
naturally occurring plant secondary metabolite known for its potent antimitotic properties
Explain how colchicine is antimitotic
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
How does liver polyploidization change with age?
Hepatocyte ploidy increases with age, with a rapid rise around the time of weaning
Why does polyploidization slow after maturation?
It slows because hepatocyte proliferation rates decrease after maturation
How does insulin influence liver polyploidization?
Insulin promotes cytokinesis failure, which partially controls polyploidization.
What is another mechanism of hepatocyte polyploidization in later stages?
Hepatocytes can undergo polyploidization through endoreduplication in later stages.
How does polyploidy benefit the liver?
Polyploid hepatocytes help protect the liver from mutation-induced tumorigenesis.
What is the current understanding of polyploidy in the human liver?
The functions of polyploidy in the human liver remain controversial.
How can chromosomal instability (CIN) lead to carcinogenesis?
CIN can cause normal tissue to become tumorigenic, leading to tumor cells with low levels of instability. This can further transform cells, enabling carcinogenesis.
What happens to tumor cells as cancer progresses with increasing CIN?
Tumor cells become more genetically unstable, which can promote drug resistance and metastasis as CIN levels rise.
What occurs when CIN reaches very high levels in tumor cells?
Cells may reach a point where they are no longer viable, though surviving cells remain unstable and promote tumor growth and spread.
What is the relationship between CIN and cancer prognosis?
CIN correlates with poor patient prognosis, as increased genetic diversity in tumor cells drives cancer progression
What is a common characteristic of human solid malignant tumors?
They are often marked by chromosomal instability, which involves the gain or loss of whole or parts of chromosomes
What are potential consequences of genomic instability?
Genomic instability can lead to cancer, telomere dysfunction, and aneuploidy (abnormal chromosome numbers)
How does the immune system prepare for unknown antigens?
The immune system has evolved to respond to any possible antigen, with 3–9 million different antibodies in human blood.
What system do lymphocytes use to create diverse antibodies?
Lymphocytes use gene translocation (gene-shuffling) to combine different V (variable), D (diversity), and J (joining) genes along a chromosome.
How does each B-lymphocyte contribute to antibody diversity?
A B-lymphocyte expresses V(D)J genes from only one parent, adding to the diversity of antibodies.
What are the segments involved in antibody diversity for the human heavy chain?
38-46 V (variable) segments, 23 D (diversity) segments, and 6 J (joining) segments.
What is combinatorial diversity in antibody formation?
Combinatorial diversity arises when each B cell randomly selects one V, D, and J segment to form the variable region of the antibody
What is junctional diversity, and how does it contribute to antibody diversity?
Junctional diversity is introduced when nucleotides are added or deleted during the joining of V, D, and J segments, further increasing antibody variability
What is somatic hypermutation?
After antigen exposure, immune cells undergo somatic hypermutation in their variable regions, introducing mutations that help produce higher affinity antibodies.
