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TTh  11:00-12:15 in Clark S361 Profs: Serafim Batzoglou, Gill Bejerano

TTh  11:00-12:15 in Clark S361 Profs: Serafim Batzoglou, Gill Bejerano TAs: George Asimenos, Cory McLean. Lecture 14. Co-option: Case study to Survey Course Project. Genomic Distribution of Ultraconserved Elements. exonic non possibly. Origins?. Looks Like A Novel Coelacanth Repeat.

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TTh  11:00-12:15 in Clark S361 Profs: Serafim Batzoglou, Gill Bejerano

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  1. TTh  11:00-12:15 in Clark S361 Profs: Serafim Batzoglou, Gill Bejerano TAs: George Asimenos, Cory McLean http://cs273a.stanford.edu [Bejerano Spr06/07]

  2. Lecture 14 • Co-option: Case study to Survey • Course Project http://cs273a.stanford.edu [Bejerano Spr06/07]

  3. Genomic Distribution of Ultraconserved Elements • exonic • non • possibly Origins? http://cs273a.stanford.edu [Bejerano Spr06/07]

  4. Looks Like A Novel Coelacanth Repeat http://cs273a.stanford.edu [Bejerano Spr06/07]

  5. Uniquely Abundant in Coelacanth Upto 80%id between Coelacanth instances and some human instances, inc uc.338. ? x 100 diverged copies in a Gigabase 60 highly similar copies in a Megabase http://cs273a.stanford.edu [Bejerano Spr06/07]

  6. Repeats / obile Elements ("selfish DNA") Human Genome: 3*109 letters 1.5% known function >50% junk http://cs273a.stanford.edu [Bejerano Spr06/07]

  7. The LF SINE (for Lobefin Fish / “Living Fossil”) not similar to any known repeat out back Reconstruction target site duplications http://cs273a.stanford.edu [Bejerano Spr06/07]

  8. >360My Old and Going Strong Upto 80%id between Coelacanth SINE and some human instances, inc uc.338. D ? B x http://cs273a.stanford.edu [Bejerano Spr06/07]

  9. Cis-reg & Ultra elements from obile Elements Co-option event, probably due to favorable genomic context All other copies are destined to decay over time at a neutral rate [Yass is a small town in New South Wales, Australia.] http://cs273a.stanford.edu [Bejerano Spr06/07] [Bejerano et al., Nature 2006]

  10. Exapted Into Which Cellular Roles? No evidence for Transcription (Tx) as small RNAs, no orientation preference in introns, not in antisense Tx. ? Human instances cluster together, found <1Mb from 35 TFs (P<3*10-6). x http://cs273a.stanford.edu [Bejerano Spr06/07]

  11. Instance 500kb Downstream of ISL1 1Mb ISL1 is a neuro-developmental gene, also expressed in testis. Three previously known enhancers are conserved across vertebrates. http://cs273a.stanford.edu [Bejerano Spr06/07]

  12. Repeat made Regulatory Region in situ Conserved Element Minimal Promoter Reporter Gene transgenic http://cs273a.stanford.edu [Bejerano Spr06/07]

  13. Co-option into Different Roles protein coding repeat generegulating http://cs273a.stanford.edu [Bejerano Spr06/07]

  14. Age old Hypothesis: Repeat to Rewire! [Davidson & Erwin, 2006] [Britten & Davidson, 1971] http://cs273a.stanford.edu [Bejerano Spr06/07]

  15. Elsewhere… Screened repeat copies found in all annotated human promoters for many TF binding site matrices Found many enrichments: … … [Thornburg et al., Gene, 2006] http://cs273a.stanford.edu [Bejerano Spr06/07]

  16. ? x The Co-Optionome quantify co-option transposition event functionalelements ? LF-SINE, DeuSINE, MER121, … [Lowe, Bejerano & Haussler, PNAS, 2007] http://cs273a.stanford.edu [Bejerano Spr06/07]

  17. Computationally Driven Biology Simplified hypothesis generalize survey case study set BIO CS analyze experiment candidates http://cs273a.stanford.edu [Bejerano Spr06/07]

  18. ? x How to Generalize? http://cs273a.stanford.edu [Bejerano Spr06/07]

  19. In Search of the Co Optionome [%age of H.G] repetitive conserved 5% 50% 1.5% 20% >100Mya highly conserved non-coding (think functional, regulatory) >100Mya mobile element instances 10,000 elements! 1Mb, 0.04% H.G 50-489bp, avg 100bp http://cs273a.stanford.edu [Bejerano Spr06/07]

  20. Specimen ZFPM2: Zinc Finger TF, Regulator of GATA TFs. Alus http://cs273a.stanford.edu [Bejerano Spr06/07]

  21. Co-options are from all Repeat Classes 1Mb http://cs273a.stanford.edu [Bejerano Spr06/07]

  22. Co-options correlate with gene deserts genome wide http://cs273a.stanford.edu [Bejerano Spr06/07]

  23. Co-options show clear functional preferences • GO term enrichment for nearest gene to co-opted element: • 10-75 Development (and system devel, nervous sys devel, etc) • 10-72 Transcription Regulator Activity (and related terms) • 10-23 Cell Recognition (neuron recog, tyros kinas sign, cell adhesion, etc) Densest co-option “clouds” in the human genome: http://cs273a.stanford.edu [Bejerano Spr06/07]

  24. Britten & Davidson redux [Britten & Davidson, 1971] http://cs273a.stanford.edu [Bejerano Spr06/07]

  25. Example: The reelin pathway involved in neuronal development and function. En-1 binding sites. Similar phenomenon for Oct-1 (Pou2f1), SRY, v-Myb and YY1. http://cs273a.stanford.edu [Bejerano Spr06/07]

  26. Particular Repeat Portions More Prone To Co-option all instances exapted instances only http://cs273a.stanford.edu [Bejerano Spr06/07]

  27. Compare to exonization all instances exapted instances only required for repeat life cycle in exonization: 3’ 5’ polyA 3’ 5’ polyT http://cs273a.stanford.edu [Bejerano Spr06/07]

  28. Compare to exonization all instances exapted instances only required for repeat life cycle in exonization: 3’ found in most alt-splice exons 5’ polyA 3’ 5’ polyT http://cs273a.stanford.edu [Bejerano Spr06/07]

  29. A Significant Minority of Putative Cis-Reg At least 7.5% of conserved non coding born after opposum split originate in exaptation (0.3% of all repeat instances born in this time period) http://cs273a.stanford.edu [Bejerano Spr06/07]

  30. Inconclusive Evidence • “Clouds” of exaptation around genes sometimes have many instances of same type, sometimes one of each, sometimes some random mix in between. • The most frequently co-opted portions of a repeat are no more enriched for GO terms or annotated pathways than the set of all co-options of that mobile element. • Sequence-similar (sub) families of co-options are not more enriched for GO terms or pathways either. http://cs273a.stanford.edu [Bejerano Spr06/07]

  31. Summary • Co-option of interspersed repeats into regulatory roles • appears to be a force of nature to be reckoned with. • Some open questions: • What functions do repeats co-opt into? • How are they pre-disposed to take these on? • Prove Brittten & Davidson: Have they really contributed • significantly/triggered the formation of any gene circuitry? • (enticing to think about clade specific traits: placenta, brain, …) • Some Implications: • microarray experiments, eg, ChIP-chip • functional dissections of loci • computational analysis & modeling of cis-reg network http://cs273a.stanford.edu [Bejerano Spr06/07]

  32. discuss projects http://cs273a.stanford.edu [Bejerano Spr06/07]

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