2008problemset6key

2008problemset6key - ProblemSet#6 BICD100W08(L.Smith)

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Problem Set #6 BICD 100 W’ 08 (L. Smith) 1.) A 2001 article in Nature reported the identification of a gene responsible for a familial (heritable) form of thrombotic thrombocytopenic pupura (TTP). This is a life-threatening illness in which blood clots composed mainly of platelets can damage multiple organs, causing major complications or death due most often to renal failure or neurological damage. Clotting of platelets in TTP patients is associated with a failure to proteolyze (enzymatically break down) Von Willebrand Factor (VWF), a blood clotting protein that acts as a platelet adhesive. Familial TTP is inherited as a recessive trait that is fully penetrant. Blood plasma from affected individuals has very low levels of VWF proteolytic activity. Testing of plasma shows which unaffected individuals are carriers, because VWF proteolytic activity in carriers’ plasma is intermediate between that in affected individuals’ and non-carriers’ plasma. The following pedigree illustrates the pattern of inheritance for this disease in one family; affected individuals are shown as filled symbols, and cross-hatching indicates carriers (as determined by blood tests). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 0 2 1 22 Linkage analysis with 382 DNA markers distributed throughout the genome showed that the ttp mutation maps to a region on chromosome 9 called 9q34. Fine-scale mapping was then carried out with multiple microsatellite markers in this region to pinpoint the map location as precisely as possible. A gel illustrating PCR products amplified from the DNA of each individual in the pedigree is shown below for three of these markers: D9S1863, D9S164, and D9S1818. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 0 2 1 2 2 D9S1863 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 0 2 1 2 2 D9S164 1
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 2 0 2 1 2 2 D9S1818 a. Which of the SSLP markers is most closely linked to the ttp mutation? D9S164 (no recombinants) b. Based on the information for this one family, estimate the map distance from each SSLP marker to the ttp mutation. There are 21 possible recombinant chromosomes (1 in 5,6,7,8,9,10,11,12,14,15,20, 21,22; 2 in 16,17,18,19). Of these, 2 are recombinant for D9S1863, 1 for D9S1818. D9S1863: 2/21 -> 9.5 cM D9S164: 0/21 -> less than 4.8 cM D9S1818: 1/21 -> 4.8 cM c. At what linkage value (how many cM) would you expect the LOD score for marker D9S1818 to reach a maximum (factoring in only data from this pedigree)? Answer: 4.8 cM d. The map below shows the location of each of the SSLP markers and the distances between them. Indicate the location of the ttp mutation on this map as precisely as the data allows, clearly indicating the distance from ttp to flanking markers on the left and right.
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2008problemset6key - ProblemSet#6 BICD100W08(L.Smith)

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