Two lociTwo loci, incomplete dominance (new and improved)2-locus interactionNO progeny as extreme as diploid hybridSlide 5Tested in hybrid diploidsOne mutant gene…Slide 8Two mutant genes…Slide 10Slide 11Three mutant genesSlide 13Slide 14Slide 15Three mutant genes in same “locus”Slide 17Slide 18Slide 19Slide 20Linked mutations of opposite effectSlide 22Slide 23“Multiple linked loci”Model organism to humanWhy pigmentation?Golden mutationSlide 28Slide 29Slide 30PowerPoint PresentationSlide 32Slide 33Library screenSlide 35Slide 36Fine-mappingSlide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Gene is strongly conservedSlide 47Slide 48Slide 49Human can rescue fish!Slide 51What is this gene?Slide 53Slide 54Slide 55Slide 56Importance in humans?No truncation in humans, but…Slide 59Slide 60Slide 61Slide 62Population geneticsSlide 64Slide 65Slide 66Correlates with human differencesSlide 68Slide 69Slide 70Slide 71Slide 72The contrast with albinismSlide 74“Normal” skin color variation is genetically complexSlide 76Slide 77Two lociAA/AA x BB/BBAB/AB(F1)A AA Along chromshort chromlocus 1locus 2Parent AB BB Blong chromshort chromlocus 1locus 2Parent BLocus1/Locus 2AB/AB x AB/AB(F2)16 possibilitiesQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Two loci, incomplete dominance(new and improved)2-locus interactionQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Effect of J at locus 2Effect of variation at locus 2 depends on genotype at locus 1: non-additiveFor example: locus 2 is polymorphism in a transcription factor gene that affects protein binding affinity, locus 1 is in a binding siteNO progeny as extreme as diploid hybridQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Lab parent Pathogenic parentNO progeny as extreme as diploid hybridDiploid hybridTested in hybrid diploidsQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Different in sequenceLabPathogenicLabPathogenicOne mutant gene…QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From pathogenic strainOne mutant gene…QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From pathogenic strainFrom lab strainQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Two mutant genes…QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From lab strainQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From pathogenic strainTwo mutant genes…QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From pathogenic strainQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From lab strainTwo mutant genes…QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From pathogenic strainFrom lab strainAgain, diploid with this gene from the pathogenic strain grows BETTER at high T.Three mutant genesQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.From lab strainDiploid with this gene from the pathogenic strain grows WORSE at high T!From pathogenic strainQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Three mutant genesFrom pathogenic strainFrom pathogenic strainFrom pathogenic strainQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Three mutant genesFrom pathogenic strainFrom pathogenic strainFrom pathogenic strainQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Three mutant genesFrom pathogenic strainFrom pathogenic strainFrom pathogenic strainAlleles from the same strain at different genes/loci can have different effects.Three mutant genes in same “locus”QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Three mutant genes in same “locus”QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Three mutant genesSo why did 0/900 haploid progeny have a phenotype as extreme as the diploid hybrid?Lab parent Pathogenic parentNO progeny as extreme as diploid hybridDiploid hybridLab parent Pathogenic parentNO progeny as extreme as diploid hybridDiploid hybridQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Linked mutations of opposite effectPathLinked mutations of opposite effectPathLabLinked mutations of opposite effectPathLabVery unlikely“Multiple linked loci”Model organism to humanQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Why pigmentation?• Camouflage• Sexual selection• Protection from UV• Controlling light scatter• (Sunlight for vitamin D)• Accident—something else selected for nearbyGolden mutationQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Golden mutationQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Melanosomes, melanin-producing organellesGolden mutation1981: original mutant arose spontaneously in the lab.Showed mendelian segregation (1 locus), and is recessive.Golden mutation1981: original mutant arose spontaneously in the lab.Showed mendelian segregation (1 locus), and is recessive. Dramatic, single-locus differences not common in the wild. Why not?Linkage analysis with sparse markers mapped golden to markers on chromosome 18, but high-resolution position of markers unknown.Linkage analysis with sparse markers mapped golden to markers on chromosome 18, but high-resolution position of markers unknown.Genome sequence not completed…Linkage analysis with sparse markers mapped golden to markers on chromosome 18, but high-resolution position of markers unknown.Genome sequence not completed…Hybrid cell lines not available…Library screenNative WT chromosomesShear, ligateLibrary screenNative WT chromosomes Genomic libraryShear, ligateLibrary screenNative WT chromosomes Genomic libraryShear, ligateHybridize to marker oligoDNA
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