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Berkeley MCELLBI 140 - Lecture Notes

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1MCB140 2-2-07 1381 381 Total 24 55 Red, round (ppll) 71 21 Red, long (ppL_) 71 21 Purple, round (P_ll) 215 284 Purple, long (P_L_) Expected Observed http://www.ndsu.edu/instruct/mcclean/plsc431/linkage/linkage1.htm“Coupling” and “repulsion”MCB140 2-2-07 2Back to Bateson and PunnettSample ObservedExpected (if SMI)(O-E)^2(O-E)^2 div by EChi square valuePurple, long (P_L_ ) 284 2154761.0 22.1 132.61Purple, round (P_ll ) 21 712500.0 35.2Red, long (ppL_ ) 21 712500.0 35.2Red, round (ppll ) 55 24961.0 40.0Null 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 3Macular 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#DDD140TB1MCB140 2-2-07 4How 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#DDD140TB12MCB140 2-2-07 5How 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#DDD140TB1MCB140 2-2-07 6This effort led to chromosome 1q32MCB140 2-2-07 7Now 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 tyrosine-histidine 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 8Fig. 5.2Daiger Science 308: 362.3MCB140 2-2-07 9Morgan Science 1911MCB140 2-2-07 10Morgan Science 1911MCB140 2-2-07 11Batrachoseps attenuatusCalifornia Slender SalamanderMCB140 2-2-07 12F.A. Janssens4MCB140 2-2-07 13Morgan’s observation of linkageOne 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 F1females: pr+/pr · vg+/vg × pr/pr · vg/vg .MCB140 2-2-07 14The data1:1:1:1?! ☺MCB140 2-2-07 15Sample ObservedExpected (if drug is harmless)(O-E)^2(O-E)^2 div by EChi squareAA 1339 710 395641 557.2 1764.1ab 1195 710 235225 331.3Ab 151 710 312481 440.1aB 154 710 309136 435.4Null 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 16These two loci do not follow Mendel’s second law because they are linked5MCB140 2-2-07 17The data?MCB140 2-2-07 18F.A. JanssensMCB140 2-2-07 19 MCB140 2-2-07 206MCB140 2-2-07 21 MCB140 2-2-07 22MCB140 2-2-07 23 MCB140 2-2-07 24Recombination 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%.7MCB140 2-2-07 25Recombination frequency a genetic map (Sturtevant’s data)MCB140 2-2-07 26Unit definition1% recombinant progeny = 1 map unit = 1 centimorgan (cM) ~ 1 Mb(note: the latter applies to humans)MCB140 2-2-07 27Mapping 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 28The 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?8MCB140 2-2-07 29If 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 5.9MCB140 2-2-07 30MCB140 2-2-07 31 MCB140 2-2-07 32If 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?9MCB140 2-2-07 33If genes are more than 50 map units apart, they behave as if they were unlinked.MCB140 2-2-07 34The chromosome as a “linkage group”MCB140 2-2-07 35Bridges (left) and Sturtevant in 1920.G. Rubin and E. Lewis Science 287: 2216.MCB140 2-2-07 36Sturtevant 196110MCB140 2-2-07 37The three-point testcrossFrom my perspective, the single most majestic epistemological accomplishment of “classical” geneticsMCB140 2-2-07 38MCB140 2-2-07 39ReadingTwo chapters from


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Berkeley MCELLBI 140 - Lecture Notes

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