1 7.03 PROBLEM SET 7 BASED ON LECTURES 30-36 THIS PROBLEM SET WILL NOT BE GRADED 1) Cancer is a term used to describe a number of diseases characterized by unregulated cell growth. Cancers typically are associated with genetic changes, which can range from point mutations to large-scale chromosome abnormalities. The net effect of such mutations generally is the release of cells from their normal growth constraints. The results from a sarcoma study involving ten individuals recently were reported. Wild-type and tumor cells were analyzed to determine the genotype of a gene involved in cell cycle regulation. In all cases, wild-type cells were heterozygous, carrying a wild-type allele and a previously uncharacterized allele. In contrast, all tumor cells were homozygous with two copies of the uncharacterized allele. a) Based on the above information, is it more likely that this gene is an ongocene or tumor suppressor gene? Explain. Given this information, it seems more likely to be a tumor suppressor gene. The unknown allele may contain a loss of function mutation. If this were the case, then the cancer cells would lack a functional allele resulting in unregulated growth. The unknown allele identified in this study was sequenced. A mutation was detected in the promoter region of one study participant. In the other nine study participants, sequencing disclosed a mutation in the coding region of this allele. b) Describe how these mutations could result in a cancer phenotype. The promoter region mutation may prevent transcription, so the absence of gene product could lead to unregulated cell growth. In contrast, the coding region mutation may abolish the wild-type activity of the encoded polypeptide, preventing it from executing its role in cell cycle regulation. c) Offer an explanation for the different frequencies observed between the two types of mutations detected in this study. Nine of the individuals in the study are from the same family. One allele is more common in the population than the other. The coding region may contain a hotspot for mutation. If the coding region were considerably longer than the promoter region, then the probability of a coding region mutation event would be comparatively greater.2 The results from a carcinoma study recently were reported. Of the ten individuals examined, nine were homozygous recessive for a gene involved in the detection of altered DNA. d) Is this gene more likely to be an oncogene or tumor suppressor gene? Explain. It is more likely a tumor suppressor gene. If this were the case, then the homozygous recessive individuals would be without any functional gene product. The absence of functional gene product could lead to tumor formation. e) Propose a hypothesis to account for how the homozygous recessive condition could lead to carcinoma development. The absence of gene product prevents the cell from detecting DNA damage due to mutation. This defect leads to the accumulation of deleterious mutations, potentially ranging from point mutations to chromosome abnormalities. These mutations eventually will lead to cell-cycle de-regulation.3 2) You have been interested in a rare genetic disorder for some time. After conducting an exhaustive search, you identified three families with this disorder in the US. Preliminary findings suggest that the gene causing this disorder may be linked to a specific SSR. This SSR locus has four alleles, each with a different number of repeats. To begin your analysis, you constructed a pedigree for each of the three families. The pedigrees are listed below (affected individuals are darkened and the SSR genotype is listed below each individual). FAMILY #1 FAMILY #2 FAMILY #3 a) What is the most likely mode of inheritance for this disorder? Based on its appearance in both generations, it would seem to be autosomal dominant. We will use information in the pedigree to calculate a LOD score for each family. b) Which of these families can be used to calculate a LOD score to test for linkage between the SSR marker and the gene of interest? Explain. Families one and two can be used. The relevant parents in each of these families are heterozygous for the SSR and exhibit the disorder. 2, 3 2, 3 1, 2 1, 2 1, 2 1, 2 2, 4 2, 4 1, 2 2, 4 1, 3 1, 4 1, 4 2, 2 1, 3 2, 2 1, 2 3, 4 2, 3 1, 2 2, 3 1, 24 c) Calculate the LOD score at theta (θ) values of (.05, .1, .2, .3, and .4). Which θ value shows the highest odds of linkage for each family? Calculating the LOD scores for the US families requires accounting for both possible phases in the relevant parent, as the phase is unknown. US FAMILIES THETA FAMILY1 FAMILY2 0.05 0.8139 -1.4424 0.1 0.7201 -0.8873 0.2 0.5171 -0.3876 0.3 0.2978 -0.1514 0.4 0.0939 -0.0354 Among the theta values tested, a theta value of 0.05 showed the highest odds of linkage for family #1. Keep in mind, though, that this low LOD score does not suggest linkage. For family #2, a theta value of 0.4 showed the highest odds of linkage. Again, this low LOD score does not suggest linkage between the disorder-causing gene and the SSR.5 Three families with this disorder also were identified in Argentina. In contrast to the US families, genetic information is available for three generations in these families. The pedigree for each family is listed below. FAMILY #1 FAMILY #2 FAMILY #3 d) Which of these families can be used to calculate a LOD score? Which is the relevant parent in each pedigree? All three families can be used to calculate LOD scores. In family 1, the mother in the second generation is the relevant parent. As her phase is unknown, both possible phases must be accounted for in the LOD score calculation. For family 2, the mother in the first generation is relevant to establish the phase of the father in the second generation, who is the relevant parent. For family 3, the mother in 1, 3 2, 3 1, 2 2, 4 1, 2 1, 4 1, 4 3, 4 1, 3 1, 2 2, 4 3, 4 1, 4 2, 3 1, 4 2, 3 1, 3 1, 2 3, 3 2, 3 3, 3 2, 3 1, 3 1, 2 2, 3 1, 3 1, 1 3, 4 1, 26 the first generation is relevant to establish the phase of the father in the second generation, who is the relevant parent. e) Calculate the LOD score at theta (θ) values of (.05, .1, .2, .3, and .4). Which θ value shows the highest odds of linkage for
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