Milestones due today. Anything to report?

1. Milestones due today. Anything to report? http://cs273a.stanford.edu [Bejerano Fall09/10]

2. Lecture 17 Ultraconservation evolutionary data Finish early – come hear the talk with us? http://cs273a.stanford.edu [Bejerano Fall09/10]

3. Sequence Conservation implies Function • (but which function/s?...) Comparative Genomics of Distantly related species: functional region! ...CTTTGCGA-TGAGTAGCATCTACTATTT... human mammalian ancestor ...ACGTGGGACTGACTA-CATCGACTACGA... mouse http://cs273a.stanford.edu [Bejerano Fall09/10]

4. Human Genome full of Conserved Non-Coding Elements Human Genome: 3*109 letters 1.5% known function compare to other species >50% junk >5% human genome functional 3x more functional DNA than known! ~106 substrings do not code for protein What do they do then? http://cs273a.stanford.edu [Bejerano Fall09/10]

5. Conserved elements in the Human Genome all human-mouse alignments human-mouse ancestral repeats alignment human-mouse ancestral repeats alignment election Difference: 5% of Human Genome 85%id on average [Mouse consortium, Nature 2002] http://cs273a.stanford.edu [Bejerano Fall09/10]

6. Conserved elements in the Human Genome all human-mouse alignments human-mouse ancestral repeats alignment human-mouse ancestral repeats alignment Simple but Unexpected (the lure of Bioinormtaics) election Difference: 5% of Human Genome Ultraconservation 85%id on average [Mouse consortium, Nature 2002] http://cs273a.stanford.edu [Bejerano Fall09/10]

7. Typical DNA Conservation levels (dot = base identical to human) Conserved elements between human and mouse are on average 85% identical. [mouse consortium, 2002] http://cs273a.stanford.edu [Bejerano Fall09/10]

8. Ultraconserved Elements fish 481 elements perfectly conserved (100%id) over 200bp or more between human, mouse and rat. http://cs273a.stanford.edu [Bejerano Fall09/10] [Bejerano et al., Science 2004]

9. * * * * * Ultraconserved Elements: Why? Hundreds of long substrings identical between amniotes they must have rejected many different changes. But... all functions we understand in our genome are encoded using redundant codes. CDS ncRNA TFBS seq. http://cs273a.stanford.edu [Bejerano Fall09/10]

10. Ultras are Functional Back in 2004 we hypothesized: 481 ultraconserved elements “nonexonic” subset – transcriptional regulators exonic subset – post transcriptional regulation [Pennacchio et al., Nature, 2006] [Ni et al., Genes Dev.; Lareau et al., Nature, 2007] http://cs273a.stanford.edu [Bejerano Fall09/10]

11. Genomic Distribution of Ultraconserved Elements • exonic • non • possibly Origins? http://cs273a.stanford.edu [Bejerano Fall09/10]

12. UC.338 comes from an ancient repeat ultraconserved exon novel coelacanth repeat enhancer LF-SINE [Bejerano et al, Nature ,2006] http://cs273a.stanford.edu [Bejerano Fall09/10]

13. Ultras are Under Strong Human Selection Mutational cold spots? NO. Rare (new) mutations are introduced to the population. Fierce purifying selection? YES. Very few of these get anywhere near fixation. A A G A A humans chimp NonSyn DAF Ultra DAF [Katzman et al, Science ,2007] http://cs273a.stanford.edu [Bejerano Fall09/10]

14. No Apparent Phenotype Touch an Ultra And You - DIY [Ahituv et al., PLoS Biology, 2007] http://cs273a.stanford.edu [Bejerano Fall09/10]

15. What can’t we measure in the lab? Ne is population size, s selective dis/advantage. Both of which are VERY wrong in the lab. http://cs273a.stanford.edu [Bejerano Fall09/10]

16. So it can happen – but does it FIX? DNA element t mouse http://cs273a.stanford.edu [Bejerano Fall09/10]

17. Count Fraction Lost, Binned by %id bin by %id count_all t human macaque dog mouse rat count_hole 100bp sliding window dog rat mouse human macaque http://cs273a.stanford.edu [Bejerano Fall09/10]

18. Quite Some Time Later http://cs273a.stanford.edu [Bejerano Fall09/10]

19. Pragmatic Genomics define goal run sensible approach while (results full of artefacts*) { characterize artefact write handler into code rerun } bio cs bio cs * eg: sequencing errors, assembly errors contaminating sequence, ambiguous situations, etc. http://cs273a.stanford.edu [Bejerano Fall09/10]

20. Ultras are Fiercely Retained through Evolution No Apparent Phenotype 100%id primates-dog: 1,691,090bp rodents deleted: 1,447bp (0.086%) Ultras are >300 fold more persistent than neutral DNA But Doomed ... the genomic deletion is (25% deleted) http://cs273a.stanford.edu [Bejerano Fall09/10]

21. How special are the Ultras? election Ultraconservation http://cs273a.stanford.edu [Bejerano Fall09/10]

22. Adding More Species Aha!! http://cs273a.stanford.edu [Bejerano Fall09/10]

23. Adding More Species More and more species Few species Hmmm…. http://cs273a.stanford.edu [Bejerano Fall09/10]

24. Most Non-Coding Elements likely work in cis… “IRX1 is a member of the Iroquois homeobox gene family. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.” gene deserts regulatory jungles 9Mb http://cs273a.stanford.edu [Bejerano Fall09/10]

25. … and Ultras are the tip of a functional iceberg gene deserts regulatory jungles 9Mb This dense regulatory jungle contain a single ultra http://cs273a.stanford.edu [Bejerano Fall09/10]