Problem set questions from Final Exam – Human Genetics, Nondisjunction, and CancerMapping in humans using SSRs and LOD scores1. You set out to genetically map the locus for color blindness with respect to SSRmarkers. Color blindness shows X-linked recessive inheritance and therefore is usuallyfound in males. However, the mutant allele frequency is sufficiently high that colorblindfemales do occur.Alleles: + (normal) cb (associated with color blindness)Here is a family in which some individuals are affected:ASSR95 BaSSR96 bc(a) Diagram the two possible phase relationships between the SSR95 and SSR96alleles in the mother.(b) Calculate the LOD score for linkage at θ = 0.2 between SSR95 and SSR96 in thisfamily.(c) Diagram the two possible phase relationships between the SSR95 alleles and thealleles at the color blindness locus in the mother.(d) Calculate a LOD score for linkage at θ = 0.2 between SSR95 and the colorblindness locus in this family.2. You are conducting genetic linkage studies to search for a locus (whosechromosomal location has not been firmly established) associated with an autosomalrecessive disease. You are focused on two SSR markers that may be linked to eachother and to the disease. Here are two families in which some individuals are affected:Family 1 SSR42 SSR43Family 2 SSR42 SSR43 Calculate LOD scores for linkage at θ = 0.02 between:(a) The disease and SSR42 in Family 1.(b) The disease and SSR43 in Family 1.(c) The disease and SSR42 in Family 2.(d) The disease and SSR43 in Family 2.(e) SSR42 and SSR43 in Family 1.(f) SSR42 and SSR43 in Family 2.Is it appropriate to add together the LOD scores calculated in:(g) Parts (a) and (b) of this question? Why or why not?(h) Parts (b) and (d) of this question? Why or why not?(i) Parts (e) and (f) of this question? Why or why not?(j) What conclusion (with respect to genetic linkage) can you publish based on thesefindings?3. Childhood deafness is often hereditary. Consider two pedigrees in which someindividuals were deaf from birth due to a rare form of hereditary deafness. Assumecomplete penetrance and no new mutations.Family #1: 1-BFamily #2: 2-A(a) What is the likely mode of inheritance of this deafness from birth?(b) The affected male from Family #1 (individual 1-B) and the affected female fromFamily #2 (individual 2-A) attend the same school for deaf children, and they ultimatelymarry and have two children. Both children have normal hearing. Provide a likelygenetic explanation for their children having normal hearing.(c) You find an SSR that shows linkage to the locus for hereditary deafness in FamilyOne, and calculate the corresponding LOD score. Is it reasonable to use the sameSSR to calculate a LOD score for Family Two, and then add together the LOD scorescalculated from two families? Why or why not?4. Your colleague, a human geneticist, is conducting genetic linkage studies on thelocus associated with an autosomal dominant disease. Your colleague is presentlyfocused on two SSR markers that may be linked to each other and to the disease. Hereare two families in which some individuals are affected:Family 1 SSR 1 SSR 2Family 2 SSR 1 SSR 2 Calculate LOD scores for linkage at θ = 0 between:(a) The disease and SSR1 in Family 1.(b) SSR1 and SSR2 in Family 1.(c) The disease and SSR1 in Family 2.(d) SSR1 and SSR2 in Family 2.5. As we have discussed in class, SSR-based genetic linkage studies in humanfamilies can be used to chromosomally localize the loci associated with heritable traits,including diseases. Such studies can also be used to build genetic maps among theSSRs themselves, and indeed this is how detailed genetic maps of the human genomewere constructed in the 1990's. Shown here are results of genotyping the members of afamily for two SSRs on chromosome 12. SSR 1 SSR 2(a) Calculate a LOD score for linkage at θ = 0.1 between SSR1 and SSR2 in this family.(b) Identify a value of θ at which this family will yield a higher LOD score for linkagebetween SSR1 and SSR2 than was calculated in part (a). Calculate the LOD score forlinkage between SSR1 and SSR2 at that new θ value.(c) Estimate (roughly) the genetic distance between SSR1 and SSR2 in cM. (Assumethat additional family studies confirm that SSR1 and SSR2 are located on the samechromosome and are genetically linked.)6. You are studying a mutation that causes an autosomal recessive phenotype ofblindness in humans. Through genetic linkage analysis, you map the mutation to a 0.6-Mb region of chromosome 12.(a) Using electronic tools, you identify three predicted genes within this region, whichare 2 kb, 15 kb, and 100 kb in length. You know that one mRNA produced from thisregion is ~1900 bp long. Based only on the information that you have been given, canyou tell which of the three predicted genes is likely (or unlikely) to be the source of the~1900-bp mRNA? Briefly explain your answer.(b) You obtain DNA samples from 10 patients who are blind because of the mutationmapping to this region. You also obtain DNA samples from 10 individuals with normalvision. How would you determine which one of the three predicted genes is responsiblefor the blindness that maps to this region?Calculating Phenotypic concordance using twin studies1. Congenital pyloric stenosis (an obstruction to the stomach’s outlet to the smallintestine) has a population incidence of 0.5% in newborn boys and of 0.1% in newborngirls. When a disease is more common in newborn boys than in newborn girls, twopossibilities come to mind: 1) X-linked recessive inheritance, 2) autosomally inheriteddisease susceptibility modified by sex hormones (e.g. increased by high levels oftestosterone).(a) Which of these 2 possibilities are consistent with the observed population incidencein newborn males and that in females? Explain your answer.(b) Can you be confident, based on this data alone, that there is a genetic componentto the risk of congenital pyloric stenosis? Explain your answer.(c) The concordance rate in MZ twins is 22% while that in DZ twins is 1.5%. Are younow confident that this is a genetic component, and, if so, how many genes areinvolved? Is there an environmental component? (Assume the disease phenotype isrecessive.)(d) 5.5% of the sons and 2.4% of the daughters of males with congenital pyloricstenosis are
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