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

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

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

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

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

6. http://cs273a.stanford.edu [Bejerano Spr06/07] 6 Repeats / obile Elements ("selfish DNA") Human Genome: 3*10 9 letters 1.5% known function >50% junk

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

23. 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:

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

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

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

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

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

29. 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)

30. 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.

31. 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

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