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Explain in details. When oncogenes are activated by mutation we most often find that the mutation is a substitution, while when tumor suppressor genes are mutated the common mutation is an insertion/deletion. Why is this? p53 is a tumor suppressor gene yet mutations in p53 found in cancers are more often substitutions not insertion/deletions and these mutations are dominant, loss-of-function, as opposed to recessive. We call this type of mutation “dominant negative” – explain what is meant by that terminology. Explain how the inactivation of p53 is different than for other tumor suppressors.

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Jean Keeling
Jean KeelingLv2
28 Sep 2019
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Related questions

Read the summary and answer questions in bold below:

In this post, we’ll be focusing on Tyler Jacks and his graduate student Francisco J. Sánchez-Rivera’s review, “Applications of the CRISPR-Cas9 system in cancer biology,” circa 2015 in Nature Reviews. So we understand the context of the authors, Jacks is the director of the Koch Institute for Integrative Cancer Research at MIT. His lab has a large mouse experimental component (MIT 2017). This sets the stage for the angle we’ll be reading from. In all, it’s a nice roundup of his and colleagues' cancer applications of CRISPR-Cas9 with great graphics, but leaves a bit desired in crossing the bridge from mouse to human.

Briefly, the CRISPR-Cas9 system stems from the prokaryotic immune system, where the RNA-guided DNA endonuclease Cas9 uses a single guide RNA (sgRNA) containing a CRISPR RNA (crRNA) and trans-activating crRNA (tracrRNA) that binds Cas9 and directs it to the genomic sequence of interest, adjacent to a photospacer adjacent motif (PAM). Cas9 causes a precisely-directed double-stranded break (DSB) in the DNA, that gets repaired via non-homologous end joining (NHEJ) or homology-directed repair (HDR).

With NHEJ, this can disrupt the gene by creating Indels: frameshifts and stop codons. In cancer, individual oncogenes or tumor suppressors can be targeted, or drug response modulators, or synthetic lethality genes. With a multiplexed knockout approach, combinatorial vulnerabilities and epistatic relationships can be assessed.

For gene modification via HDR, target single or double-stranded DNA can be introduced, resulting in precise gene knock-ins, with potential effects of introducing point mutations to mimic cancers, fluorescent reporters/synthetic tags can be created, conditional (Cre-lox/Flp-FRT) constructs can used to turn off/on a mutation, non-coding elements like enhancers/insulators/promoters can turn on proto-oncogenes, and ultimately, HDR can be used for gene correction.

With Cas9 and 2 sgRNAs, there can be genomic rearrangements, leading to deletions, inversions (like EML4-ALK), and translocations (like BCR-ABL).

Dead Cas9 (dCas), which lacks its endonuclease activity via mutation to its HNH and RuvC domains, can be used for reversible, transcriptional repression or activation of coding and non-coding genes, or chromatin modification, via an effector.

Much of the practical applications of CRISPR-Cas9 is in ES cells and mouse models, both germinal and somatic (GEMMs and nGEMMs). With this technology, a plethora of GEMM/nGEMM models of cancer can be created, some with the ability to turn on/off the Cas9 system, and multiplexed sgRNAs can help gain further understanding of multi-hit cancers. Patient derived xenografts (PDX) mice can be assayed with CRISPR-Cas9 to determine different treatment efficacies. Entire libraries of sgRNA can be screened in cancer cell lines for enrichment/depletion with Cas9, and dCas9-activators/repressors can be used for complementarity, both of which providing insights into drug targets, synthetic lethality, and chemotherapy modulators.

The delivery mechanisms for the system are diverse, and include plasmids, lentivirus, adenovirus, nanoparticles, hydrodynamic gene transfer, and protein-based. The authors also cite integrating Cas9 into the GEMMs, so it’s one less thing needed in the delivery vehicle. This of course would not be applicable to human.

Ultimately, human cancer treatment is the goal. Yes, we know the boundaries between ES/mice experimental models and human embryos have already been broken, with an international team targeting the autosomal dominant mutation in MYBPC3, which causes cardiac myopathy (Ledford 2017). But the current compromise position of CRISPR-Cas9 technology toward therapeutics and treatment, beyond basic science understanding, is using primary cells, organoids, PDX, or personalized GEMMs to create genetic and drug screens.

In theory, what would it take to bring CRISPR-Cas9 to the ultimate, targeted gene therapy via either NHEJ or HDR, in human cancer? Are there cancers that are better bets for CRISPR-Cas9 than others, delivery vehicles that are safer or better optimized? Is CRISPR-Cas9 really “on target” enough to introduce into a person, and how do we best assess?

1. A species of flowering plant includes plants with blooms that range from bright golden yellow to very pale yellow; no flowers carrying the yellow pigment allele appear white. The allele for yellow flower color:

a. must be a suppressor of another allele.
b. demonstrates incomplete penetrance.
c. demonstrates variable expressivity.
d. must be a modifier of another allele.
e. demonstrates variable penetrance.

2. Coat color in mice is determined by two alleles acting at a single locus: B is dominant and results in mice with black coats, and b is recessive and results in mice with white coats. In a litter of 12 mice, nine are black (B/–) and three are white (b/b). What is the penetrance of the B coat color allele?

a. zero
b. 25 percent
c. 50 percent
d. 75 percent
e. 100 percent

3. Semisterility in nearly 50 percent of the progeny they produce is often an indication that:

a. the parents are translocation heterozygotes.
b. both parents carry pericentric inversions.
c. both parents carry polytene chromosomes.
d. one of the parents carries a chromosomal deletion that removes a telomere.
e. one of the parents carries a chromosomal deletion that removes a chromosome's centromere.

4. A researcher is studying melanoma cells derived from a patient's skin tumor. He determines that all melanoma cells are 2n + 1, but the chromosome number in all normal skin cells is 2n. The 2n + 1 melanoma cells likely arose from:

a. mitotic nondisjunction.
b. meiotic nondisjunction.
c. mitotic recombination.
d. parthenogenesis.
e. colchicine treatment.

5. Why won't a balancer chromosome in Drosophila produce viable crossover products when paired with a wild-type chromosome?

a. Balancer chromosomes contain multiple inversions.
b. Balancer chromosomes contain multiple deletions.
c. Balancer chromosomes have no centromere.
d. Balancer chromosomes have no telomeres.
e. None of the answers is correct.

6. A doctor notes that a patient's genome contains 100 potentially harmful recessive mutations; however, the patient is heterozygous for all of the loci considered and thus does not demonstrate any abnormal phenotypes. The 100 recessive mutations the doctor discovered represent the patient's:

a. bivalents.
b. monosomy.
c.genetic load.
d. amphidiploidy.
e.nondisjunction.

7.The term describing the relationship between the number of copies of a gene and how much product is made from the gene is:

gene-dosage effect.
gene balance.
dosage compensation.
transcription.
aneuploidy.

8. The gene for upright ears in rabbits has two alleles. The E allele is dominant and results in upright ears, and the recessive e allele results in droopy ears. Of 100 rabbits surveyed, 87 had a genotype for upright ears (E/–). However, only 72 of these 87 rabbits had upright ears; the remaining 15 rabbits had completely droopy ears. This suggests that the allele for upright ears:

a. has incomplete penetrance.
b. has complete penetrance.
c. demonstrates variable expressivity.
d. is lethal.
e. is incompletely dominant.

9. A researcher has selfed an autotetraploid plant with the genotype D/D/d/d, and in the resulting progeny she observes a 35:1 phenotypic ratio. What can she conclude from this observation?

a. The progeny from this cross do not demonstrate a standard Mendelian phenotypic ratio.
b. In the 35:1 phenotypic ratio, the 1 represents the phenotype of the d/d/d/d progeny.
c. During meiosis in the D/D/d/d parent plant, it is likely that only bivalents, no quadrivalents or trivalents, formed.
d. It is likely that in this plant species, gametes associate with one another randomly.
e. All of the answers are correct.

10. A researcher is studying fur color in a new species of bats. He notices that fur color, which is due to the presence of a dominant allele (G), ranges from light gray to very dark gray. In addition, some bats that carry a G allele have no fur pigmentation whatsoever; their coats appear white. This is an example of:

a. only variable expressivity.
b. only incomplete penetrance.
c. both variable expressivity and incomplete penetrance.
d. recessive allele lethality.
e. pleiotropy.

**Please answer ALL 10 QUESTION**

1. A species of flowering plant includes plants with blooms that range from bright golden yellow to very pale yellow; no flowers carrying the yellow pigment allele appear white. The allele for yellow flower color:

a. must be a suppressor of another allele.

b. demonstrates incomplete penetrance.

c. demonstrates variable expressivity.

d. must be a modifier of another allele.

e. demonstrates variable penetrance.

2. Coat color in mice is determined by two alleles acting at a single locus: B is dominant and results in mice with black coats, and b is recessive and results in mice with white coats. In a litter of 12 mice, nine are black (B/–) and three are white (b/b). What is the penetrance of the B coat color allele?

a. zero

b. 25 percent

c. 50 percent

d. 75 percent

e. 100 percent

3. Semisterility in nearly 50 percent of the progeny they produce is often an indication that:

a. the parents are translocation heterozygotes.

b. both parents carry pericentric inversions.

c. both parents carry polytene chromosomes.

d. one of the parents carries a chromosomal deletion that removes a telomere.

e. one of the parents carries a chromosomal deletion that removes a chromosome's centromere.

4. A researcher is studying melanoma cells derived from a patient's skin tumor. He determines that all melanoma cells are 2n + 1, but the chromosome number in all normal skin cells is 2n. The 2n + 1 melanoma cells likely arose from:

a. mitotic nondisjunction.

b. meiotic nondisjunction.

c. mitotic recombination.

d. parthenogenesis.

e. colchicine treatment.

5. Why won't a balancer chromosome in Drosophila produce viable crossover products when paired with a wild-type chromosome?

a. Balancer chromosomes contain multiple inversions.

b. Balancer chromosomes contain multiple deletions.

c. Balancer chromosomes have no centromere.

d. Balancer chromosomes have no telomeres.

e. None of the answers is correct.

6. A doctor notes that a patient's genome contains 100 potentially harmful recessive mutations; however, the patient is heterozygous for all of the loci considered and thus does not demonstrate any abnormal phenotypes. The 100 recessive mutations the doctor discovered represent the patient's:

a. bivalents.

b. monosomy.

c.genetic load.

d. amphidiploidy.

e.nondisjunction.

7.The term describing the relationship between the number of copies of a gene and how much product is made from the gene is:

a. gene-dosage effect. gene balance.

b. dosage compensation.

c. transcription.

d. aneuploidy.

8. The gene for upright ears in rabbits has two alleles. The E allele is dominant and results in upright ears, and the recessive e allele results in droopy ears. Of 100 rabbits surveyed, 87 had a genotype for upright ears (E/–). However, only 72 of these 87 rabbits had upright ears; the remaining 15 rabbits had completely droopy ears. This suggests that the allele for upright ears:

a. has incomplete penetrance.

b. has complete penetrance.

c. demonstrates variable expressivity.

d. is lethal.

e. is incompletely dominant.

9. A researcher has selfed an autotetraploid plant with the genotype D/D/d/d, and in the resulting progeny she observes a 35:1 phenotypic ratio. What can she conclude from this observation?

a. The progeny from this cross do not demonstrate a standard Mendelian phenotypic ratio.

b. In the 35:1 phenotypic ratio, the 1 represents the phenotype of the d/d/d/d progeny.

c. During meiosis in the D/D/d/d parent plant, it is likely that only bivalents, no quadrivalents or trivalents, formed.

d. It is likely that in this plant species, gametes associate with one another randomly.

e. All of the answers are correct.

10. A researcher is studying fur color in a new species of bats. He notices that fur color, which is due to the presence of a dominant allele (G), ranges from light gray to very dark gray. In addition, some bats that carry a G allele have no fur pigmentation whatsoever; their coats appear white. This is an example of:

a. only variable expressivity.

b. only incomplete penetrance.

c. both variable expressivity and incomplete penetrance.

d. recessive allele lethality.

e. pleiotropy.

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