MW 11 00 12 15 in Beckman B
MW 11: 00 -12: 15 in Beckman B 302 Profs: Serafim Batzoglou, Gill Bejerano TAs: Cory Mc. Lean, Aaron Wenger http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 1
Lecture 18 Guest Talks Ultraconservation The Projects http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 2
Comparative Genomics what made us human? * human chimp macaque mouse rat cow dog opossum platypus chicken zfish tetra t http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] fugu 3
Genotype http: //cs 273 a. stanford. edu Phenotype [Bejerano Aut 08/09] 44
Comparative Genomics How did some of our relatives go back? human chimp macaque mouse rat * cow dog opossum platypus chicken zfish tetra t http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] fugu 5
Now at the Species Level How did we leave the ocean? human chimp macaque mouse rat * cow dog opossum platypus chicken zfish tetra t http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] fugu 6
Conserved elements in the Human Genome all human-mouse alignments human-mouse ancestral repeats alignment election Difference: 5% of Human Genome 85%id on average [Mouse consortium, Nature 2002] http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 7
Conserved elements in the Human Genome all human-mouse alignments human-mouse ancestral repeats alignment election Difference: 5% of Human Genome Ultraconservation 85%id on average [Mouse consortium, Nature 2002] http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 8
Typical DNA Conservation levels Conserved elements between human and mouse are on average 85% identical. [mouse consortium, 2002] http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] [Bejerano et al. , Science 2004] 9
Ultraconserved Elements fish http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] [Bejerano et al. , Science 2004] 10
No known function requires this much conservation * ? CDS * nc. RNA * * * TFBS seq. http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 11
Discovery can be fun (compared to 4 results day before our Science. Express paper) 31, 800 http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 12
Predictions and Proofs I Based on public domain genome wide data: ultraconserved elements one subset codes protein larger subset does not generate testable hypotheses for function from existing knowledge (2004) [Pennacchio et al. , Nature, 2006] http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 13
Predictions and Proofs II Based on public domain genome wide data: ultraconserved elements one subset codes protein larger subset does not generate testable hypotheses for function from existing knowledge (2004) post transcriptional modification [Pennacchio et al. , Nature, 2006] http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 14
Of the 29 exonic ultraconserved elements in RNA-binding protein genes in human, 15 have human and/or mouse EST evidence suggesting the presence of AS-NMD in those regions. [Ni et al. , Genes & Dev 2007 ]
Model for Homeostatic Auto/Cross-regulation [Ni et al. , Genes & Dev 2007 ]
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. Ultra DAF A A G A humans A chimp Non. Syn DAF [Katzman et al, Science , 2007] http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 17
Genomic Distribution of Ultraconserved Elements • exonic • non • possibly http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 18
UC. 338 comes from an ancient repeat ultraconserved exon novel coelacanth repeat enhancer LF-SINE [Bejerano et al, Nature , 2006] http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 19
Touch an Ultra And You - DIY 4 -8% of documented mouse KO genes display no phenotype (inc. Pbx 2, Nkx 6. 2, Gli 1) http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] [Ahituv et al. , PLo. S Biology, 2007] 20
Hypothesis Can ultraconserved element mutations be under extreme purifying selection but the whole element be expendable? http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 21
What did Mother Nature favor? t DNA element mo use http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 22
Quite Some Time Later The horror … http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 23
Ultras are Fiercely Retained rodents deleted 11/15157 = 0. 072% Ultras are >300 fold more persistent than neutral DNA (25% deleted) http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 24
Enough about us…. http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 25
What we do understand. . Ultraconserved elements exist. They are maintained via strong on-going selection. It is a heterogeneous bunch: Some mediate splicing Some regulate gene expression Some express nc. RNAs (categories are not necessarily mutually exclusive) Knockouts of four regulatory ultras did not lead to severe phenotypes (similar protein cases: Pbx 2, Nkx 6. 2, Gli 1) http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 26
What we don’t understand Their functional density: How did they come to be? What is the selective advantage that lets them persist? http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 27
Broad Guess It’s about 3 -D structure. Observation: r. DNA (18 S, 28 S) have ultraconserved stretches, multiple constraints in a complex 3 -D structure, the Ribosome. • nc. RNA ultras: structure confers function • Splicing related ultras: the Splicosome • Cis-reg ultras: TSS 3 -D proximity, chromatin and/or packed TFBS (Transcription factories? ) TSS http: //cs 273 a. stanford. edu [Bejerano Aut 08/09] 28
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