E.The calculation in part D depends on the specific assumptions. If the targetsize were 10 kb (instead of 100 kb), the calculation in part D would decreaseto 1 chance in 100,000. If there were, on average, fewer than 2 retroviral inte-grations per tumor, the calculation in part D would decrease; if there weremore than 2 integrations per tumor, the calculation would increase. The assumption of randomness of retroviral integration is the most diffi-cult to evaluate in terms of this calculation. Retroviruses are decidedly non-random in their integration, with most varieties showing some degree ofpreference for actively transcribed genes. An entirely different approach tothis question takes such preferences into account. If 2 out 600 tumors had aretroviral integration at Lmo2,and 2 out of 600 had a retroviral integration atIl2rg, then the chance of having both is (2/600) ¥(2/600) = 0.000011, orabout 1 in 100,000 tumors. The chance of not finding a dual integration in600 tumors would be PN= (0.999989)600= 0.993. Thus, there would be a7/1000 chance of finding a dual integration. This differs by a factor of 100from the result calculated in part D. Yet, both suggest that dual integrationshould be a relatively rare event.References:Dave UP, Jenkins NA & Copeland NG (2004) Gene therapy inser-tional mutagenesis insights. Science303, 333.Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIn-tyre E, Radford I, Villeval J-L, Fraser CC, Cavazzana-Calvo M & Fischer A(2003) A serious adverse event after successful gene therapy for severe com-bined immunodeficiency syndrome. N. Engl. J. Med.348, 255–256.DATA HANDLING20–43A.Fibroblasts and tumor cells from the same patient have different patterns ofhybridization because the tumor cells have lost portions of the Rbgene. Lossof this gene is a very rare somatic event that affects less than one in a millioncells. Only in the retina does its loss cause uncontrolled growth and tumorformation. No doubt the same proportion of fibroblasts also lose the Rbgene, but its loss from fibroblasts has no known biological consequence, soits absence cannot be readily detected.B.The fibroblasts from the patient with unilateral retinoblastoma appear to beidentical to those from normal cells, suggesting that the patient with unilat-eral retinoblastoma inherited two good Rbgenes. Fibroblasts from thepatient with bilateral retinoblastoma are not normal. Three of the fourrestriction fragments are present at half the normal intensity, suggestingthat one of the Rbgenes contains a deletion that encompasses those threerestriction fragments. Note that the three affected fragments are adjacent onthe map of the Rbgene (see Figure 20–8B).The tumor cells from both patients are abnormal. The patient with uni-lateral retinoblastoma is missing two fragments entirely and a third is presentat half the normal intensity. This pattern indicates that each copy of the Rbgene has undergone deletion: one deletion encompasses the 9.8-kb and the6.2-kb fragments; the other encompasses these two fragments and the 5.3-kbfragment. The patient with bilateral retinoblastoma is missing three fragments
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