E the calculation in part d depends on the specific

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E. The calculation in part D depends on the specific assumptions. If the target size were 10 kb (instead of 100 kb), the calculation in part D would decrease to 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 were more 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 of preference for actively transcribed genes. An entirely different approach to this question takes such preferences into account. If 2 out 600 tumors had a retroviral integration at Lmo2, and 2 out of 600 had a retroviral integration at Il2rg , then the chance of having both is (2/600) ¥ (2/600) = 0.000011, or about 1 in 100,000 tumors. The chance of not finding a dual integration in 600 tumors would be P N = (0.999989) 600 = 0.993. Thus, there would be a 7/1000 chance of finding a dual integration. This differs by a factor of 100 from the result calculated in part D. Yet, both suggest that dual integration should be a relatively rare event. References: Dave UP, Jenkins NA & Copeland NG (2004) Gene therapy inser- tional mutagenesis insights. Science 303, 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 HANDLING 20–43 A. Fibroblasts and tumor cells from the same patient have different patterns of hybridization because the tumor cells have lost portions of the Rb gene. Loss of this gene is a very rare somatic event that affects less than one in a million cells. Only in the retina does its loss cause uncontrolled growth and tumor formation. No doubt the same proportion of fibroblasts also lose the Rb gene, but its loss from fibroblasts has no known biological consequence, so its absence cannot be readily detected. B. The fibroblasts from the patient with unilateral retinoblastoma appear to be identical to those from normal cells, suggesting that the patient with unilat- eral retinoblastoma inherited two good Rb genes. Fibroblasts from the patient with bilateral retinoblastoma are not normal. Three of the four restriction fragments are present at half the normal intensity, suggesting that one of the Rb genes contains a deletion that encompasses those three restriction fragments. Note that the three affected fragments are adjacent on the map of the Rb gene (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 present at half the normal intensity. This pattern indicates that each copy of the Rb gene has undergone deletion: one deletion encompasses the 9.8-kb and the 6.2-kb fragments; the other encompasses these two fragments and the 5.3-kb fragment. The patient with bilateral retinoblastoma is missing three fragments
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