Office hours Wednesday 3 4pm 304A Stanley Hall Review session 5pm Thursday Dec 11 GPB100 Coding sequence array Fig 1 13 RNA seq AAAAA AAAAA AAAAA Solexa sequencing counts seq 26982 25885 17851 15715 14963 610 607 602 602 601 600 599 TCGTTCACTTGTATTGG TCTCTACTGGTGGTGGT GACAAACTGTCGCTGTC TCTCTACCGGTGGTGGT TCGTTCACTTGTAATGG TTGAAGCTACCACCAAC TGTCCTTATCTATGTGT CGTACTTTTTTAATTGT ATCATTGTTCCAGAAAT TTATCAGAGGTGCTGGT CAAAGACCTCATTTAAT AGGAGGGTATATATGCT maps genome pos U0 U0 R0 U0 U0 sbaySum fsa chr03 fsa 3002121 138912 R F sbaySum fsa chr04 fsa 11182634 1489376 F R sbaySum fsa chr11 fsa 8491512 145622 R F chr14 fsa sbaySum fsa chr14 fsa 694435 4671591 575509 R R R R0 U0 U1 R0 U0 U0 U0 orient Expression effects of cancer QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Diagnosis via transcriptional profile patient samples transcripts QuickTime and a TIFF Uncompressed decompressor Diagnosis via transcriptional profile QuickTime and a TIFF Uncompressed decompressor are needed to see this picture QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Linkage mapping of mRNA levels Black 6 mouse x DBA mouse 111 F2 progeny Microarray each F2 liver Genotype each F2 Looking for linkage coinheritance between marker and mRNA level Marker is linked to polymorphism in expression regulation cascade G kinase TF TF G G TF ORF Locally acting polymorphisms 25 of varying mRNAs are caused by locally acting polymorphism QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Polymorphism responsible for mRNA difference is at the locus of the gene itself Nonlocal polymorphisms QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Nonlocal polymorphisms One polymorphism in a key regulator can affect a regulon 100 s of related mRNAs Clinical applications Black 6 mouse x DBA mouse 111 F2 progeny Microarray each F2 liver Genotype each F2 Measure fat pad each F2 QuickTime and a TIFF decompressor QuickTime and a QuickTime and a are Uncompressed needed to see this picture TIFF Uncompressed decompressor TIFF Uncompressed decompressor are needed to see this picture are needed to see this picture Clinical applications QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Clinical applications Colored curves fat mass at different body QuickTime and a TIFF Uncompressed decompressor locations are needed to see this picture Clinical applications Finding polymorphism responsible for difference in macroscopic phenotype is hard Clinical applications Finding polymorphism responsible for difference in macroscopic phenotype is hard If mRNAs change too can learn mechanism from known function of encoded proteins Clinical applications Clinical applications Clinical applications QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Clinical applications Counts allele 1 allele 2 cases 1 5 Counts allele 1 allele 2 controls QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Clinical applications Clinical applications Marker predicts quantitative expression level association Can we map expression traits first disease afterward Linkage of human transcripts QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Linkage of human transcripts QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Association of human transcripts QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Association of human transcripts linkage families assoc unrelated QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Association in multiple populations European Americans in Utah QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Han Chinese and Japanese Association in multiple populations QuickTime and a TIFF Uncompressed decompressor are needed to see this picture A new brand of genetic variation Translation Fig 8 25 Translation Fig 8 25 PSI yeast read through STOPs PSI yeast read through STOPs PSI yeast read through STOPs 40 150 bp Weird genetics of read through Haploid PSI Haploid psi Diploid PSI Weird genetics of read through Haploid PSI Haploid psi Diploid PSI sporulate Haploid PSI Haploid PSI Haploid PSI Haploid PSI Weird genetics of read through Haploid PSI Haploid psi Diploid PSI But why wouldn t it get diluted over many divisions sporulate Haploid PSI Haploid PSI Haploid PSI Haploid PSI Cytoplasmic aggregates of Sup35 Cytoplasmic aggregates of Sup35 How would this explain the results Hard to make aggregate easy to join QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Protein inheritance Protein inheritance Original from PSI nucleates in all progeny PSI begets more PSI Not due to dominant genetics in the usual way Nucleating prions in mad cow disease Is PSI the yeast analog of mad cow or Alzheimer s If bad would be lost QuickTime and a TIFF Uncompressed decompressor are needed to see this picture If bad would be lost Pichia methanolica vs S cerevisiae QuickTime and a TIFF Uncompressed decompressor are needed to see this picture a ompressor picture PSI phenotypes a ompressor picture Genetically distinct S cerevisiae strains PSI phenotypes Genetically distinct S cerevisiae strains PSI phenotypes a ompressor picture QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Genetically distinct S cerevisiae strains PSI phenotypes QuickTime and a TIFF Uncompressed decompressor are needed to see this picture a ompressor picture 50 C Genetically distinct S cerevisiae strains PSI phenotypes QuickTime and a TIFF Uncompressed decompressor are needed to see this picture a ompressor picture 50 C PSI phenotypes Why would aggregates result in so many novel abilities and traits PSI phenotypes Why would aggregates result in so many novel abilities and traits Apparently does not happen in Alzheimer s The clincher QuickTime and a TIFF Uncompressed decompressor are needed to see this picture The clincher partial LOF QuickTime and a TIFF Uncompressed decompressor are needed to see this picture The clincher partial LOF QuickTime and a TIFF Uncompressed decompressor are needed to see this picture What do you conclude A Sup35 does not cause resistance to paraquat B Prions do not cause resistance to paraquat C Aggregation is not necessary to cause resistance to paraquat D Aggregation is not sufficient to cause resistance to paraquat
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