As discussed in the lectures, independent mutations in 4 different gene types ar
ID: 70627 • Letter: A
Question
As discussed in the lectures, independent mutations in 4 different gene types are required for the cell to become cancerous. Assume that a hypothetical intestinal stem cell divides every 4 days. The general DNA replication error is 10-8 per nucleotide per replication, average gene length is 8000 nucleotides, and the person average lifespan is 70 years. If we assume that mutations in both alleles of 4 specific genes are required for the cell to become cancerous, what is an average random chance for that intestinal stem cell to acquire these specific mutations during its lifetime? After calculating this number, think how it compares to the lifetime chances of a person getting cancer, and why these numbers do not seem to match (remember that human body has 1013 cells).
Explanation / Answer
Ans: Human crypt stem cell studies are limited because of the inability to use the powerful fate mapping experimental techniques of model systems. humans are long-lived and therefore it is possible to measure the “success” of fidelity mechanism by directly measuring mutations in colons isolated from different aged individuals . Measurable mutations should accumulate over decades of aging, even with relatively low mutation or stem cell division rates. Human stem cell fidelity mechanisms can be inferred from the numbers and types of somatic mutations accumulated over a lifetime.A practical problem with measuring somatic mutations is that because different mutations occur in different cells, the frequency of any specific mutation in a population of human cells is likely to be too low (<5%) to measure with most techniques.Loeb have suggested that mutator mutations, i.e. mutations which increase the rate of genetic change, maybe required for cancer cells to be formed within a human lifetime.because the rate of mutation per nucleotide locus is estimated to be as low as 109 per cell generation in somatic cells , and may be as low as 1011 in the immortal stem cells which likely give rise to tumors.The number of stem cell generations in a human lifetime is unknown and varies among tissues, but estimates range from on the order of for the majority of reproductive stem cells which are usually not in cycle to on the order of for colonic stem cells. The total probability of any stem cell in the body reaching this state would be approximately the probability for any one stem cell lineage multiplied by the number of stem cells.according to this argument, a mutator mutation would be required to explain the appearance of malignant cells.it has been estimated that 30% of human tumors examined to date express DNA polymerase- variant proteins One of these variants K289M, which that was identified in human adenocarcinoma of the colon, confers a 16-fold increase in mutation frequency in copying repetitive sequences in DNA.It has also been assumed that DNA polymerase slippage and a lack of mismatch repair contribute to the occurrence of MIN(microsatellite instability ) i.e. instability in the length of repetitive DNA sequences termed microsatellites.
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