International Summer School

   From Genome to Life:

    Structural, Functional and Evolutionary approaches

 


BRENNER Steven

University of California, 461 Koshland Hall, #3102, Berkeley, CA 94720-3102

title: Challenges in genome annotation

Functional description of the complete repertoire of proteins encoded by a genome lies at the core of genomic biology. In general, one accepts genome sequence, gene predictions, and gene annotation as reliable sources from which biological inferences may be drawn and further experiments devised. However, computational functional characterization is fraught with challenges and the ultimate result is often of questionable reliability.

In this session, I will review the typical steps in genome annotation, indicating which steps are reliable and which remain a challenge. We will make a case study of the annotation of M. genitalium, where multiple groups’ annotations provide us with the ability to gain some measure of the accuracy of genome annotation. A second case study will explore a set of proteins which are both transmembrane and transcription factors, as an example of the incredible challenge of making meaningful functional predictions. The session will conclude with discussion of approaches that may make functional annotation more reliable and valuable.

References (available at http://compbio.berkeley.edu/people/brenner/pubs/):

  • Brenner SE. 1999. Errors in genome annotation. Trends in Genetics 15:132-133.
  • Zupicich J, Brenner SE, Skarnes WC. 2001. Computational prediction of membrane-tethered transcriptions factors. Genome Biology 2:research0050.1-0050.6.
  • Brenner SE, Chothia C, Hubbard TJP. 1998. Assessing sequence comparison methods with reliable structurally-identified distant evolutionary relationships. Proceedings of the National Academy of Sciences of the United States of America 95:6073-6078.
  • Brenner SE, Hubbard T, Murzin A, Chothia C. 1995. Gene duplications in the H. influenzae genome. Nature 378:140.


 BRENNER Steven

University of California, 461 Koshland Hall, #3102, Berkeley, CA 94720-3102

title: Structural genomics of proteins and RNA

Structural genomics aims to provide a good experimental structure or computational model of every tractable protein in a complete genome. Underlying this goal is the immense value of protein structure, especially in permitting recognition of distant evolutionary relationships for proteins whose sequence analysis has failed to find any significant homolog. A considerable fraction of the genes in all sequenced genomes have no known function, and structure determination provides a direct means of revealing homology that may be used to infer their putative molecular function. The solved structures will be similarly useful for elucidating the biochemical or biophysical role of proteins that have been previously ascribed only phenotypic functions. More generally, knowledge of an increasingly complete repertoire of protein structures will aid structure prediction methods, improve understanding of protein structure, and ultimately lend insight into molecular interactions and pathways.

In this session, I will begin by outlining the basic principles underlying structural genomics. Methods to be discussed include target selection and structure analysis. I will review the classifications used to analyze solved protein and RNA structures. I will review progress from structural genomics to date and provide an outline of expectations for structural genomics.

References (available at http://compbio.berkeley.edu/people/brenner/pubs/):

  • Brenner SE. 2001. A tour of structural genomics. Nature Reviews Genetics 2:801-9.
  • Brenner SE. 2000. Target selection for structural genomics. Nature Structural Biology, Structural Genomics supplement. 7:967-969.
  • Brenner SE, Levitt M. 2000. Expectations from structural genomics. Protein Science. 9:197-200.
  • Murzin AG, Brenner SE, Hubbard T, Chothia C. 1995. SCOP: a structural classification of proteins database for the investigation of sequences and structures. Journal of Molecular Biology 247:536-540.
  • Klosterman PS, Holbrook SR, Brenner SE. 2002. SCOR: a structural classification of RNA database. Nucleic Acids Research 30:392-394.





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                  References
                  
  • Molecular structure, classification & evolution
  • Murzin AG, Brenner SE, Hubbard T, Chothia C. 1995. Scop: a structural classification of proteins database for the investigation of sequences and structures. Journal of Molecular Biology 247:536-540.
  • Brenner SE, Chothia C, Hubbard TJP. 1997. Population statistics of protein structures. Current Opinion in Structural Biology 7:369-376.
  • Brenner SE, Chothia C, Hubbard TJP, Murzin AG. 1996. Understanding protein structure: Using SCOP for fold interpretation. Chap. 37 in: Doolittle RF, ed. Computer Methods for Macromolecular Sequence Analysis. Methods in Enzymology. Vol. 266. Orlando, FL: Academic Press. 635-643.
  • Klosterman PS, Holbrook SR, Brenner SE. 2002. SCOR: a structural classification of RNA database. Nucleic Acids Research. in press.
  • Reliable pairwise sequence comparison
  • Chandonia JM, Walker NS, Lo Conte L, Koehl P, Levitt M, Brenner SE. 2002. ASTRAL compendium enhancements. Nucleic Acids Research. in press.
  • Brenner SE, Chothia C, Hubbard TJP. 1998. Assessing sequence comparison methods with reliable structurally-identi?ed distant evolutionary relationships. Proceedings of the National Academy of Sciences of the United States of America 95:6073-6078.
  • Genome annotation challenges
  • Brenner SE. 1999. Errors in genome annotation. Trends in Genetics 15:132-133.
  • Brenner SE, Hubbard T, Murzin A, Chothia C. 1995. Gene duplications in the H.influenzae genome. Nature 378:140.
  • Zupicich J, Brenner SE, Skarnes WC. 2001. Computational prediction of membrane-tethered transcriptions factors. Genome Biology 2:research0050.1-0050.6.
  • Structural genomics
  • Brenner SE. 2001. A Tour of Structural Genomics. Nature Reviews Genetics 2:801-9.
  • Brenner SE. 2000. Target selection for structural genomics. Nature Structural Biology, Structural Genomics supplement. 7:967-969.
  • Brenner SE, Levitt M. 2000. Expectations from structural genomics. Protein Science 9:197-200.
  • Brenner SE, Barken D, Levitt M. 1999. The PRESAGE database for structural genomics. Nucleic Acids Research. 27:251-253.