What is genomics? Genes, promoters, regulatory elements, alignments, trees, …

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What is genomics? Genes, promoters, regulatory elements, alignments, trees, …

What is the “Genome”? Protein 3 billion units (nucleotides) Sizes:

GGGCTGGGCGAGTATCTCTTCGAAAGGCTCACTCTCAAGCACGACTAAGAGCCTTCTGAGC What is genomics?...

GGGCTGGGCGAGTATCTCTTCGAAAGGCTCACTCTCAAGCACGACTAAGAGCCTTCTGAGC What is genomics? GLGEYLFERLTLKHD*.....

What is genomics? TTCCTTAGACTCTTAGAAAGTACCTCAAAAACGAAATGCG AACAC

What is genomics? TTCCTTAGACTCTTAGAAAGTACCTCAAAAACGAAATGCG AACAC

What is genomics? TTCCTTAGACTCTTAGAAAGTACCTCAAAAACGAAATGCG AACAC ATGGAGT microRNA

What is comparative genomics? TTCCCTAG CAAGTACCTCA TTCCCTAG CAAGTACCTCA TTCCCTAG CAAGTACCTCA TTCCTTAGACTCTTAGCAAGTACCTCA TTCCTTAGACTCTTAGAAAGTACCTCAAAAACGAAATGCG AACACGACTCT---- TTTTAGCAAGTACCTCAAAATATTTAATTAAA-AC ACTCTT- ---TTTTAGCAAGTACCTCAAGAATTACAATTAAATAT TTCCTTAGACTCTTAGAAAGTACCTCAAAAACGAAATGCGAACAC Grun et al. microRNA target predictions across seven Drosophila species and comparison to mammalian targets, PloS Computational Biology, June 2005 Lall et al. A genome wide map of conserved microRNA targets in C. Elegans, submitted to Cell, ATGGAGT let-7

The Drosophila Genome Project 1911 Genetic Mapping in Drosophila Sturtevant and Morgan 2000 Drosophila melanogaster genome sequenced Celera and LBNL publish Drosophila genome in Science 2003 Proposal for Drosophila as a model system for comparative genomics Clark, Gibson, Kaufman, McAllister, Myers, O’Grady 2005 Twelve Drosophila genomes sequenced Consortium involving Agencourt, Broad Institute, Baylor College Medicine, Washington University St. Louis and the Venter Institute.

Female Male Karyotype A project to compare and contrast Drosophila

BP England, U Heberlein, R Tjian. Purified Drosophila transcription factor, Adh distal factor-1 (Adf-1), binds to sites in several Drosophila promoters and activates transcription, J Biol Chem 1990.

S. Chatterji and L. Pachter, GeneMapper: Reference based annotation with GeneMapper,2005.

Alignment of an exon DroAna_ _ GTCGCTCAACCAGCATTTGCAAAAGTCGCAGAACTTGCGCTCATTGGATTTCCAGTACTC DroEre_ _ GTCGCTCAGCCAGCATTTGCAGAAGTCGCAGAACTTCCGCTCGTTTGACTTCCAGTACTC DroMel_4_ GTCGCTCAGCCAGCATTTGCAGAAGTCGCAGAACTTGCGCTCGTTTGATTTCCAGTACTC DroMoj_ _ GTCGCTTAACCAGCATTTACAGAAATCGCAATACTTGCGTTCATTGGATTTCCAGTACTC DroPse_1_ GTCGCTCAGCCAGCACTTGCAGAAGTCGCAGTACTTGCGCTCGTTTGATTTCCAGAATTC DroSim_ _ GTCGCTCAGCCAGCA-TTGCAGAAGTCGCAGAACTTGCGCTCGTTTGATTTCCAGTACTC DroVir_ _ GTCGCTCAACCAGCATTTGCAGAAGTCGCAATACTTGCGTTCATTCGACTTCCAGTACTC DroYak_1_ GTCGCTCAGCCAGCATTTGCAGAAGTCGCAGAACTTCCGCTCGTTTGACTTCCAGTACTC ****** * ****** ** ** ** ***** **** ** ** ** ** ****** * **

Is the Adf1 binding site conserved? mel TGTGCGTCAGCGTCGGCCGCAACAGCG pse TGT GACTGCG *** ** *** mel TGTG----CGTCAGC--G----TCGGCC---GC-AACAG-CG pse TGTGACTGCG-CTGCCTGGTCCTCGGCCACAGCCAAC-GTCG **** ** * ** * ****** ** *** * ** mel TGTGCGTCAGC------GTCGGCCGCAACAGCG pse TGTGACTGCGCTGCCTGGTCCTCGGCCACAGC- **** * ** *** * ** *****

Characterizing promoters: The APO(a) gene Plasminogen (PLG) APO(a) (LPA) Part of the apolipoprotein gene family Regulation not well understood High plasma levels of the protein important risk factor for cardiovascular disease

Human Baboon Chimp Apo(a) : Limited Distribution Among Mammals Hedgehog Plasminogen (PLG) APO(a) (LPA) Lemur (prosimian) Mouse New-World Monkeys

A G G C C A G C T A G G C C A G C A A G A G C A G C A A G A C C A G C A ACGTACGT ACGT A A A A A G G G C G neutral constrained compute two numbers: fast lik & slow lik

Phylogenetic shadowing of the apo(a) promoter conserved non-conserved TATA HNF-1  EXON sequence position (bp)

Gel-shift assay to assess DNA-protein interactions nuclear extract non-conserved elements conserved elements DNA-protein complex unbound DNA

nuclear extract non-conserved elements conserved elements DNA-protein complex unbound DNA Gel-shift assay to assess DNA-protein interactions

nuclear extract non-conserved elements conserved elements DNA-protein complex unbound DNA

Gel-shift analysis of conserved elements in the apo(a) promoter Non-conserved elements Conserved elements

ENCODE pilot phase 1% of the genome. 44 regions target selection. commitee has selected sequence targets –manual targets – a lot of information –radom targets – stratified by non exonic conservation with mouse by gene density