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Genomic ORFans: Past, Present and Future Naomi Siew and Daniel Fischer Ben-Gurion University Be’er-Sheva, Israel
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1995: The Genomic Revolution Dozens of genomes were fully sequenced Dozens more are underway ORF – Open Reading Frame start codon ……… stop codon
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Descent With Modification (Divergent Evolution)..KSMEDQRRIMIRPID....QSMEQIRRIMLRPTD....KSLDDIRRIPIRPID..
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ORF S. sofataricus E. coli M. tuberculosis S. cerevisiae T. volcanium M. genitalium C. elegans H. influenzae E. coli M. pneumoniae B. subtilis B. halodurans B. subtilis
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Orphan ORFs = ORFans (Fischer and Eisenberg, Bioinformatics,15(9),1999) Singleton ORFan : An ORF that has no sequence similarity to any other sequence in the databases. Little can be inferred about ORFans using bioinformatic tools.
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20-30% of ORFs in each new genome are singleton ORFans.
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ORFans May Be… New, previously unseen proteins, (with new function, new structure) unique to one organism (species-specific). Distant relatives of known families (similar function, similar 3D structure) whose sequence diverged beyond recognition by sequence comparison tools.
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The Puzzle of ORFans If new ORFs, where did they come from? How did they evolve? If distant relatives, why aren’t there similar sequences? Where are the intermediates?
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Census and Dynamics of ORFans Built a database of fully sequenced genomes. Added genomes one by one in chronological order of publication. For each ORF, ran BLAST: if there is a match non-ORFan if there is no match ORFan Previous ORFans can become non-ORFans.
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The number of ORFans is growing, while their percentage is declining.
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Each new genome contains ORFs that match previous ORFans, but also new ORFans
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Addition of a closely related organism causes a large drop in the percentage of ORFans of the relative
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Future Trends: the number of ORFans may start dropping, and their percentage may keep declining ? ?
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Length Distribution
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Length Bias Bias among short sequences for ORFans. (almost half of short sequences are ORFans) Bias among ORFans for short sequences. (half of ORFans are short)
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Separate dynamics analyses of short and long ORFans show different behaviors Percentage of short ORFans is declining more slowly. Possible explanations: not expressed; frame shifts; wrong stop codons; technical limitations. Percentage of long ORFans is declining faster. Possible explanations: more conserved; ORFan modules.
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ORFan Modules MGTGDKFCKDKIECAPL KFSRDKIECAFLHGRFCGRFCGDGSP GEISFLIGGRYL ORFan Module: A segment of a sequence that has no matches with other sequences.
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Interim Conclusions Evolution has left us with two types of sequences: homologs and ORFans. The number of singleton ORFans has been growing. Their percentage is diminishing.
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Interim Conclusions II There is a bias towards short sequences among singleton ORFans, and vice versa. Most longer singleton ORFans may disappear with time. New genomes of closely related organisms will have fewer singleton ORFans.
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A Broader ORFan Perspective Orthologous ORFan: An ORF with matches in a family of closely related genomes only and none outside this family. B. subtilis B. halodurans ORF
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Currently orthologous ORFans are counted as non-ORFans. Family-specific? Most probably expressed proteins.
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Paralogous ORFan: An ORF with matches in the same genome only and none outside the genome.
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Currently paralogous ORFans are counted as non-ORFans. Species-specific? Most probably expressed proteins.
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Future and On-Going Work Study the other types of ORFans (orthologous, paralogous, modules). Try to assign distantly related ORFans to known families: * in silico: using more sensitive bioinformatic tools such as fold recognition. * In the lab: determining the 3D structure of selected ORFans. However, even if all ORFans were assigned to known families, the puzzle of their evolution will still remain.
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Ongoing in silico/experimental ORFan studies in BGU Mini-structural genomics project to study selected paralogous ORFans in the archeon Halobacterium NRC-15. Bioinformatics (our group) Archea biology (Dr. Gerry Eichler) Crystallography (Prof. Boaz Sha’anan)
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Acknowledgements Prof. Joel Bernstein Department of Chemistry, BGU
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