http://cs273a.stanford.edu [Bejerano Fall09/10]

Halfway Feedback (yours) Lecture 11 HW1 Feedback (ours) Upcoming Project Non-Coding RNAs Halfway Feedback (yours) http://cs273a.stanford.edu [Bejerano Fall09/10]

Upcoming Project Project will be in groups of 3-4. We will be assigning you into groups. Overlap with CS229 (Machine Learning): How many people take both classes? Are interested in combining projects? http://cs273a.stanford.edu [Bejerano Fall09/10]

Structural RNAs http://cs273a.stanford.edu [Bejerano Fall09/10]

Central Dogma of Biology:

RNA is an Active Player:

What is ncRNA? Non-coding RNA (ncRNA) is an RNA that functions without being translated to a protein. Known roles for ncRNAs: RNA catalyzes excision/ligation in introns. RNA catalyzes the maturation of tRNA. RNA catalyzes peptide bond formation. RNA is a required subunit in telomerase. RNA plays roles in immunity and development (RNAi). RNA plays a role in dosage compensation. RNA plays a role in carbon storage. RNA is a major subunit in the SRP, which is important in protein trafficking. RNA guides RNA modification. In the beginning it is thought there was an RNA World, where RNA was both the information carrier and active molecule.

RNA Folds into (Secondary and) 3D Structures AAUUGCGGGAAAGGGGUCAA CAGCCGUUCAGUACCAAGUC UCAGGGGAAACUUUGAGAUG GCCUUGCAAAGGGUAUGGUA AUAAGCUGACGGACAUGGUC CUAACCACGCAGCCAAGUCC UAAGUCAACAGAUCUUCUGU UGAUAUGGAUGCAGUUCA We would like to predict them from sequence. Waring & Davies. (1984) Gene 28: 277. Cate, et al. (Cech & Doudna). (1996) Science 273:1678.

Nearest Neighbor Model for RNA Secondary Structure Free Energy at 37 OC: Mathews, Disney, Childs, Schroeder, Zuker, & Turner. 2004. PNAS 101: 7287. http://cs273a.stanford.edu [Bejerano Fall09/10]

RNA structure: Basics Key: RNA is single-stranded. Think of a string over 4 letters, AC,G, and U. The complementary bases form pairs. Base-pairing defines a secondary structure. The base-pairing is usually non-crossing. Bafna

Energy Landscape of Real & Inferred Structures http://cs273a.stanford.edu [Bejerano Fall09/10]

Unfortunately… Random DNA (with high GC content) often folds into low-energy structures. What other signals determine non-coding genes?

Evolution to the Rescue http://cs273a.stanford.edu [Bejerano Fall09/10]

http://cs273a.stanford.edu [Bejerano Fall09/10]

RNA sequence analysis - SCFGs MP A – U G – C A G MP MP ML ML ML G G A A G A U C C < < < . . . > > >

http://cs273a.stanford.edu [Bejerano Fall09/10]

http://cs273a.stanford.edu [Bejerano Fall09/10]

MicroRNA http://cs273a.stanford.edu [Bejerano Fall09/10]

Genomic context known miRNAs in human intergenic intronic polycistronic monocistronic

Example: tRNA Bafna

http://cs273a.stanford.edu [Bejerano Fall09/10]

RNA structure: pseudoknots Sometimes, unpaired bases in loops form ‘crossing pairs’. These are pseudoknots. Bafna

http://cs273a.stanford.edu [Bejerano Fall09/10]

http://cs273a.stanford.edu [Bejerano Fall09/10]

Human Specific Rapid Evolution maximally changed r m h r m c h 100%id near 100%id http://cs273a.stanford.edu [Bejerano Fall09/10]

Human accelerated http://cs273a.stanford.edu [Bejerano Fall09/10]

Other Non Coding Transcripts http://cs273a.stanford.edu [Bejerano Fall09/10]

http://cs273a.stanford.edu [Bejerano Fall09/10]

mRNA http://cs273a.stanford.edu [Bejerano Fall09/10]

EST http://cs273a.stanford.edu [Bejerano Fall09/10]

X chromosome inactivation in mammals Dosage compensation X X X Y

Xist – X inactive-specific transcript Avner and Heard, Nat. Rev. Genetics 2001 2(1):59-67

Microarrays, Next Gen(eration) Sequencing etc. http://cs273a.stanford.edu [Bejerano Fall09/10]

End Results http://cs273a.stanford.edu [Bejerano Fall09/10]

http://cs273a.stanford.edu [Bejerano Fall09/10]

http://cs273a.stanford.edu [Bejerano Fall09/10]

Transcripts, transcripts everywhere Human Genome Transcribed (Tx) Leaky tx? Functional? Tx from both strands http://cs273a.stanford.edu [Bejerano Fall09/10]

Halfway Feedback http://cs273a.stanford.edu [Bejerano Fall09/10]