Coupling and repulsion Observed Expected Purple long P L 284 215 Purple round P ll 21 71 Red long ppL 21 71 Red round ppll 55 24 Total 381 381 http www ndsu edu instruct mcclean plsc431 linkage linkage1 htm MCB140 2 2 07 1 Back to Bateson and Punnett Sample Purple long P L Purple round P ll Red long ppL Red round ppll Expected if Observed SMI 284 21 21 55 215 71 71 24 O E 2 4761 0 2500 0 2500 0 961 0 O E 2 div by E 22 1 35 2 35 2 40 0 Chi square value 132 61 Null hypothesis the genes exhibit SMI What is the likelihood that the observed difference is due solely to chance Well below 0 1 The null hypothesis is rejected What is going on What can explain this repulsion and coupling Why are these two genes disobeying Mendel s second law MCB140 2 2 07 2 Macular degeneration is a group of diseases characterized by a breakdown of the macula The macula is the center portion of the retina that makes central vision and visual acuity possible Age related maculopathy ARM also known as age related macular degeneration AMD is the leading cause of irreversible vision loss in the elderly population in the USA and the Western world and a major public health issue Affecting nearly 9 of the population over the age of 65 ARM becomes increasingly prevalent with age such that by age 75 and older nearly 28 of individuals are affected 1 6 As the proportion of the elderly in our population increases the public health impact of ARM will become even more severe Currently there is little that can be done to prevent or slow the progression of ARM 7 http hmg oupjournals org cgi content full 9 9 1329 DDD140TB1 MCB140 2 2 07 3 How to screen for a polymorphism linked to or directly causing AMD First what s the evidence that there is a genetic component to AMD Numerous studies have attempted to establish dietary and environmental risk factors that contribute to ARM however heredity has emerged as the primary determinant of ARM susceptibility for a review see ref 16 First degree relatives of ARM patients are at between two and four times greater risk of developing ARM than the first degree relatives of controls 17 18 Twin studies have consistently shown high levels of concordance of the disease among monozygous sibs and strongly support a genetic etiology 19 22 http hmg oupjournals org cgi content full 9 9 1329 DDD140TB1 MCB140 2 2 07 4 How to screen for a polymorphism linked to or directly causing AMD Second how to find the locus aka candidate region We collected a set of 364 families 2129 individuals containing relative pairs affected with ARM http hmg oupjournals org cgi content full 9 9 1329 DDD14 0TB1 MCB140 2 2 07 5 This effort led to chromosome 1q32 MCB140 2 2 07 6 Now what Two SNPs showed the greatest linkage and they lie in a 260 kb region This stretch contains the complement H gene CFH is a component of the innate immune system which regulates inflammation which in turn is consistently implicated in AMD Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosinehistidine change at amino acid 402 This polymorphism is in a region of CFH that binds heparin and C reactive protein Individuals homozygous for the risk alleles have a 7 4 fold increased likelihood of AMD 95 CI 2 9 to 19 Haines et al Science 308 419 MCB140 2 2 07 7 Daiger Science 308 362 Fig 5 2 MCB140 2 2 07 8 Morgan Science 1911 MCB140 2 2 07 9 Morgan Science 1911 MCB140 2 2 07 10 Batrachoseps attenuatus California Slender Salamander MCB140 2 2 07 11 F A Janssens MCB140 2 2 07 12 Morgan s observation of linkage One of these genes affects eye color pr purple and pr red and the other affects wing length vg vestigial and vg normal The wild type alleles of both genes are dominant Morgan crossed pr pr vg vg flies with pr pr vg vg and then testcrossed the doubly heterozygous F 1 females pr pr vg vg pr pr vg vg MCB140 2 2 07 13 The data 1 1 1 1 MCB140 2 2 07 14 Sample AA ab Ab aB Observed 1339 1195 151 154 Expected if drug is harmless 710 710 710 710 O E 2 395641 235225 312481 309136 O E 2 div by E 557 2 331 3 440 1 435 4 Chi square 1764 1 Null hypothesis genes not linked What is the likelihood that the observed difference is due solely to chance Ummmmm Yeah null hypothesis shmull hypothesis MCB140 2 2 07 15 These two loci do not follow Mendel s second law because they are linked MCB140 2 2 07 16 The data MCB140 2 2 07 17 F A Janssens MCB140 2 2 07 18 MCB140 2 2 07 19 MCB140 2 2 07 20 MCB140 2 2 07 21 MCB140 2 2 07 22 MCB140 2 2 07 23 Recombination Frequency Morgan s data 1339 red normal 1195 vermillion vestigial 151 red vestigial 154 vermillion normal 2839 total progeny 305 recombinant individuals 305 2839 0 107 Recombination frequency is 10 Map distance between the two loci is 10 m u MCB140 2 2 07 24 Recombination frequency a genetic map Sturtevant s data MCB140 2 2 07 25 Unit definition 1 recombinant progeny 1 map unit 1 centimorgan cM 1 Mb note the latter applies to humans MCB140 2 2 07 26 Mapping By Recombination Frequency Morgan s data 1339 red normal 1195 vermillion vestigial 151 red vestigial 154 vermillion normal 2839 total progeny 305 recombinant individuals 305 2839 0 107 Recombination frequency is 10 Map distance between the two loci is 10 m u MCB140 2 2 07 27 The met protooncogene and the CFTR gene are 0 7 Mb apart on chr 7 In 1000 meiotic events how many gametes would you expect to find that have had a recombination event between the two genes MCB140 2 2 07 28 Problem 5 9 If the a and b loci are 20 m u apart in humans and an AB ab woman has a child with an ab ab man what is the probability that this child will be Ab ab MCB140 2 2 07 29 MCB140 2 2 07 30 MCB140 2 2 07 31 If two genes A and B are 80 Mb apart on a human chromosome what percentage recombinant gametes would you expect to be produced in an individual who is AB ab MCB140 2 2 07 32 If genes are more than 50 map units apart they behave as if they were unlinked MCB140 2 2 07 33 The chromosome as a linkage group MCB140 2 2 07 34 Bridges left and Sturtevant in 1920 G Rubin and E Lewis Science 287 2216 MCB140 2 2 07 35 Sturtevant 1961 MCB140 2 2 07 36 The three point testcross From my perspective …
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