Problem set questions from Final Exam Human Genetics Nondisjunction and Cancer Mapping in humans using SSRs and LOD scores 1 You set out to genetically map the locus for color blindness with respect to SSR markers Color blindness shows X linked recessive inheritance and therefore is usually found in males However the mutant allele frequency is sufficiently high that colorblind females do occur Alleles normal cb associated with color blindness Here is a family in which some individuals are affected SSR95 SSR96 A B a b c a Diagram the two possible phase relationships between the SSR95 and SSR96 alleles in the mother b Calculate the LOD score for linkage at 0 2 between SSR95 and SSR96 in this family c Diagram the two possible phase relationships between the SSR95 alleles and the alleles at the color blindness locus in the mother d Calculate a LOD score for linkage at 0 2 between SSR95 and the color blindness locus in this family 2 You are conducting genetic linkage studies to search for a locus whose chromosomal location has not been firmly established associated with an autosomal recessive disease You are focused on two SSR markers that may be linked to each other and to the disease Here are two families in which some individuals are affected Family 1 SSR42 SSR43 Family 2 SSR42 SSR43 Calculate LOD scores for linkage at 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 these findings 3 Childhood deafness is often hereditary Consider two pedigrees in which some individuals were deaf from birth due to a rare form of hereditary deafness Assume complete penetrance and no new mutations Family 1 1 B Family 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 from Family 2 individual 2 A attend the same school for deaf children and they ultimately marry and have two children Both children have normal hearing Provide a likely genetic explanation for their children having normal hearing c You find an SSR that shows linkage to the locus for hereditary deafness in Family One and calculate the corresponding LOD score Is it reasonable to use the same SSR to calculate a LOD score for Family Two and then add together the LOD scores calculated from two families Why or why not 4 Your colleague a human geneticist is conducting genetic linkage studies on the locus associated with an autosomal dominant disease Your colleague is presently focused on two SSR markers that may be linked to each other and to the disease Here are two families in which some individuals are affected Family 1 SSR 1 SSR 2 Family 2 SSR 1 SSR 2 Calculate LOD scores for linkage at 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 human families 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 the SSRs themselves and indeed this is how detailed genetic maps of the human genome were constructed in the 1990 s Shown here are results of genotyping the members of a family for two SSRs on chromosome 12 SSR 1 SSR 2 a Calculate a LOD score for linkage at 0 1 between SSR1 and SSR2 in this family b Identify a value of at which this family will yield a higher LOD score for linkage between SSR1 and SSR2 than was calculated in part a Calculate the LOD score for linkage between SSR1 and SSR2 at that new value c Estimate roughly the genetic distance between SSR1 and SSR2 in cM Assume that additional family studies confirm that SSR1 and SSR2 are located on the same chromosome and are genetically linked 6 You are studying a mutation that causes an autosomal recessive phenotype of blindness in humans Through genetic linkage analysis you map the mutation to a 0 6Mb region of chromosome 12 a Using electronic tools you identify three predicted genes within this region which are 2 kb 15 kb and 100 kb in length You know that one mRNA produced from this region is 1900 bp long Based only on the information that you have been given can you 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 mutation mapping to this region You also obtain DNA samples from 10 individuals with normal vision How would you determine which one of the three predicted genes is responsible for the blindness that maps to this region Calculating Phenotypic concordance using twin studies 1 Congenital pyloric stenosis an obstruction to the stomach s outlet to the small intestine has a population incidence of 0 5 in newborn boys and of 0 1 in newborn girls When a disease is more common in newborn boys than in newborn girls two possibilities come to mind 1 X linked recessive inheritance 2 autosomally inherited disease susceptibility modified by sex hormones e g increased by high levels of testosterone a Which of these 2 possibilities are consistent with the observed population incidence in newborn males and that in females Explain your answer b Can you be confident based on this data alone that there is a genetic component to 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 you now confident that this is a genetic component and if so how many genes are involved Is there an environmental component Assume the disease phenotype is recessive d 5 5 of the sons and 2 4 of the daughters of males with congenital pyloric stenosis are affected By contrast 19 4 of the sons and 7 3 of the daughters of females with congenital pyloric stenosis are affected Why might the offspring of affected females be at higher risk than the offspring of affected males 2 What phenotypic concordance rates approximate answers will suffice might you expect in MZ twins DZ twins and first cousins for
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