21 21 55 381 Purple round P ll Red long ppL Red round ppll Total 381 24 71 71 215 Expected http hmg oupjournals org cgi content full 9 9 1329 DDD140TB1 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 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 http www ndsu edu instruct mcclean plsc431 linkage linkage1 htm 284 Purple long P L Observed Coupling and repulsion MCB140 2 2 07 3 MCB140 2 2 07 1 Expected if SMI 215 71 71 24 Observed 284 21 21 55 4761 0 2500 0 2500 0 961 0 O E 2 22 1 35 2 35 2 40 0 O E 2 div by E Chi square value 132 61 http hmg oupjournals org cgi content full 9 9 1329 DDD140TB1 MCB140 2 2 07 4 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 How to screen for a polymorphism linked to or directly causing AMD MCB140 2 2 07 2 What is going on What can explain this repulsion and coupling Why are these two genes disobeying Mendel s second law 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 Purple long P L Purple round P ll Red long ppL Red round ppll Sample Back to Bateson and Punnett 1 Haines et al Science 308 419 MCB140 2 2 07 7 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 Now what MCB140 2 2 07 5 http hmg oupjournals org cgi content full 9 9 1329 DDD14 0TB1 Second how to find the locus aka candidate region We collected a set of 364 families 2129 individuals containing relative pairs affected with ARM How to screen for a polymorphism linked to or directly causing AMD Fig 5 2 Daiger Science 308 362 MCB140 2 2 07 8 MCB140 2 2 07 6 This effort led to chromosome 1q32 2 California Slender Salamander Batrachoseps attenuatus Morgan Science 1911 MCB140 2 2 07 11 MCB140 2 2 07 9 F A Janssens Morgan Science 1911 MCB140 2 2 07 12 MCB140 2 2 07 10 3 1339 1195 151 154 Observed Expected if drug is harmless 710 710 710 710 395641 235225 312481 309136 O E 2 557 2 331 3 440 1 435 4 O E 2 div by E 1764 1 Chi square MCB140 2 2 07 15 Null hypothesis genes not linked What is the likelihood that the observed difference is due solely to chance Ummmmm Yeah null hypothesis shmull hypothesis AA ab Ab aB Sample MCB140 2 2 07 13 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 F1 females pr pr vg vg pr pr vg vg Morgan s observation of linkage MCB140 2 2 07 14 MCB140 2 2 07 16 These two loci do not follow Mendel s second law because they are linked 1 1 1 1 The data 4 The data MCB140 2 2 07 18 MCB140 2 2 07 20 MCB140 2 2 07 17 MCB140 2 2 07 19 F A Janssens 5 MCB140 2 2 07 23 MCB140 2 2 07 21 Recombination frequency is 10 305 2839 0 107 305 recombinant individuals 2839 total progeny 154 vermillion normal 151 red vestigial 1195 vermillion vestigial 1339 red normal Recombination Frequency Morgan s data MCB140 2 2 07 24 MCB140 2 2 07 22 6 Map distance between the two loci is 10 m u Recombination frequency is 10 305 2839 0 107 305 recombinant individuals 2839 total progeny 154 vermillion normal 151 red vestigial 1195 vermillion vestigial 1339 red normal Mapping By Recombination Frequency Morgan s data MCB140 2 2 07 27 MCB140 2 2 07 25 Recombination frequency a genetic map Sturtevant s data MCB140 2 2 07 26 MCB140 2 2 07 28 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 1 recombinant progeny 1 map unit 1 centimorgan cM 1 Mb note the latter applies to humans Unit definition 7 MCB140 2 2 07 31 MCB140 2 2 07 29 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 Problem 5 9 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 MCB140 2 2 07 30 8 G Rubin and E Lewis Science 287 2216 Bridges left and Sturtevant in 1920 MCB140 2 2 07 35 MCB140 2 2 07 33 If genes are more than 50 map units apart they behave as if they were unlinked Sturtevant 1961 The chromosome as a linkage group MCB140 2 2 07 36 MCB140 2 2 07 34 9 MCB140 2 2 07 37 MCB140 2 2 07 …
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