From csbi-events at mit.edu Tue Oct 11 11:30:56 2005 From: csbi-events at mit.edu (csbi-events@mit.edu) Date: Tue, 11 Oct 2005 11:30:56 -0400 Subject: [CSBi-events] CSBi Seminar Series - Save the Date! Message-ID: CSBi Community, You may want to take note of the upcoming seminar on Friday, October 21. Thank you. Dr. Philip Green Howard Hughes Medical Institute and Genome Sciences Department, University of Washington Signal and Noise in Genome Sequences Friday, October 21, 2005 Maclaurin Building (4-270) 3:00 - 4:00 p.m. Light refreshments served. Abstract Interpreting genome sequences requires distinguishing 'signal' (encoded functional elements) from 'noise' (non-functional, neutrally evolving sequence). The characteristics of neutrally evolving sequence reflect underlying mutation and substitution processes, which are poorly understood but of independent interest due to their critical role in evolution. Studies of mammalian DNA by several investigators have revealed a number of substitution rate trends: transitions occur more frequently than transversions; in general G:C mutates to A:T at a higher rate than does A:T to G:C; rates depend significantly on the flanking nucleotide context, with methylated C's in CpG dinucleotides being notable hotspots; rates per year tend to be higher in lineages with short generation times, and higher in males than in females, suggesting that most mutations occur in conjunction with DNA replication (work of Li and colleagues); and recombination appears to play an important role in the neutral substitution process, likely reflecting the effects of biased gene conversion (recent work of Duret and colleagues). Using orthologous mammalian sequences from NISC (www.nisc.nih.gov/), we have been working to better understand and model the characteristics of naturally occurring mutations, and to use this knowledge to more efficiently identify sequences under selection. We have found (Nat Genet 33, 514-517 (2003)) a mutational asymmetry associated with transcribed regions that likely reflects an interaction between DNA polymerase errors and transcription-coupled repair; this mutational asymmetry has acted over long evolutionary periods to produce a compositional asymmetry within most genes. More recently, Dick Hwang in my group has developed a powerful Bayesian Markov chain Monte Carlo approach to modeling sequence evolution that allows systematic exploration of context-dependent rates and mutational asymmetry by position within an evolutionary tree and within a sequence. We have applied this to investigate variation in substitutional patterns in mammalian evolution, finding in particular that CpG mutations show a reduced generation time effect relative to other mutation types (Hwang and Green, PNAS 101, 13994-14001 (2004)). I will discuss recent extensions to this work allowing us to detect selected features and explore variation in selection strength in coding and non-coding sequences across the mammalian phylogeny. Host: Dr. Christopher B. Burge Biology and Biological Engineering Contact: Brenda Pepe, Biology, 452-3885 http://csbi.mit.edu/ Sponsored by CSBi Annual CSBi Seminar Series in Computational and Systems Biology Directions can be found at the following url: http://whereis.mit.edu/map-jpg -- From csbi-events at mit.edu Tue Oct 18 14:37:09 2005 From: csbi-events at mit.edu (csbi-events@mit.edu) Date: Tue, 18 Oct 2005 14:37:09 -0400 Subject: [CSBi-events] seminar notice Message-ID: Brigham and Women's Hospital Division of Genetics Seminars in Molecular Medicine presents: ALEXANDER HARTEMINK, Ph.D. ASSISTANT PROFESSOR DEPARTMENT OF COMPUTER SCIENCE DUKE UNIVERSITY "BAYESIAN MACHINE LEARNING IN COMPUTATIONAL SYSTEMS BIOLOGY" FRIDAY, OCTOBER 21ST, 2005 3:00 - 4:00 PM BWH GENETICS DIVISION SEMINAR ROOM 4TH FLOOR, ROOM 457 HMS NEW RESEARCH BUILDING 77 AVENUE LOUIS PASTEUR Corporate Sponsorship provided by Millennium Pharmaceuticals Inc. Refreshments at 2:45 PM HOSTED BY DR. MARTHA BULYK -- From csbi-events at mit.edu Wed Oct 19 14:37:49 2005 From: csbi-events at mit.edu (csbi-events@mit.edu) Date: Wed, 19 Oct 2005 14:37:49 -0400 Subject: [CSBi-events] REMINDER - CSBi Seminar Series-Dr. Philip Green Message-ID: Dear CSBi Community, You may want to take note of the following CSBi Seminar Series event on Friday, October 21. Thank you! Dr. Philip Green Howard Hughes Medical Institute and Genome Sciences Department, University of Washington Signal and Noise in Genome Sequences Friday, October 21, 2005 Maclaurin Building (4-270) 3:00 - 4:00 p.m. Light refreshments served. Abstract Interpreting genome sequences requires distinguishing 'signal' (encoded functional elements) from 'noise' (non-functional, neutrally evolving sequence). The characteristics of neutrally evolving sequence reflect underlying mutation and substitution processes, which are poorly understood but of independent interest due to their critical role in evolution. Studies of mammalian DNA by several investigators have revealed a number of substitution rate trends: transitions occur more frequently than transversions; in general G:C mutates to A:T at a higher rate than does A:T to G:C; rates depend significantly on the flanking nucleotide context, with methylated C's in CpG dinucleotides being notable hotspots; rates per year tend to be higher in lineages with short generation times, and higher in males than in females, suggesting that most mutations occur in conjunction with DNA replication (work of Li and colleagues); and recombination appears to play an important role in the neutral substitution process, likely reflecting the effects of biased gene conversion (recent work of Duret and colleagues). Using orthologous mammalian sequences from NISC (www.nisc.nih.gov/), we have been working to better understand and model the characteristics of naturally occurring mutations, and to use this knowledge to more efficiently identify sequences under selection. We have found (Nat Genet 33, 514-517 (2003)) a mutational asymmetry associated with transcribed regions that likely reflects an interaction between DNA polymerase errors and transcription-coupled repair; this mutational asymmetry has acted over long evolutionary periods to produce a compositional asymmetry within most genes. More recently, Dick Hwang in my group has developed a powerful Bayesian Markov chain Monte Carlo approach to modeling sequence evolution that allows systematic exploration of context-dependent rates and mutational asymmetry by position within an evolutionary tree and within a sequence. We have applied this to investigate variation in substitutional patterns in mammalian evolution, finding in particular that CpG mutations show a reduced generation time effect relative to other mutation types (Hwang and Green, PNAS 101, 13994-14001 (2004)). I will discuss recent extensions to this work allowing us to detect selected features and explore variation in selection strength in coding and non-coding sequences across the mammalian phylogeny. Host: Dr. Christopher B. Burge Biology and Biological Engineering Contact: Brenda Pepe, Biology, 452-3885 http://csbi.mit.edu/ Sponsored by CSBi Annual CSBi Seminar Series in Computational and Systems Biology Open to the entire MIT Community -- From csbi-events at mit.edu Wed Oct 26 10:03:09 2005 From: csbi-events at mit.edu (csbi-events@mit.edu) Date: Wed, 26 Oct 2005 10:03:09 -0400 Subject: [CSBi-events] CSBi Speaker Series - Dr. Carla Mattos - 11/4/05 Message-ID: Dear CSBi Community, You may want to note the upcoming CSBi Speaker Series seminar, on Friday, November 4, and join us if your schedule permits. Thanks! ------------------------------------------------------------------------------------------------------------ Dr. Carla Mattos North Carolina State University Department of Molecular and Structural Biochemistry Deciphering Binding Sites on Ras GTPases Friday, November 4, 2005 Maclaurin Building (4-270) 3:00 - 4:00 p.m. Light refreshments served. Abstract Details of the surface of the RasGTPase bound to the GTP analogue GppNHp are studied using two main approaches. The first is through a new crystal form of the protein that presents the switch regions in a very different conformation than observed in the previously published crystal forms. In our new structure the conformation of Switch I superimposes well with the structure observed in the Raps/Raf complex, while the canonical form shows Switch I in the conformation found in the Ras/RasGAP interaction. Both of these forms can be correlated with structures observed in solution by 31P NMR spectroscopy and can be identified by having Tyr 32 in a closed or open conformation respectively. Our structure reveals that Switch II, which adopts multiple conformations in solution, is found in a conformation not previously seen in Ras, but which is similar to the non-catalytic conformation of Ran-GTP stabilized by importin-beta. The structure of the Q61L oncogenic mutant in the new crystal form reveals a network of hydrophobic interactions where Leu61 is stacked against Tyr32 on one side and Tyr64 on the other. These interactions appear to stabilize a non-catalytic form of Ras-GppNHp and may be an important factor in the oncogenic phenotype of the Q61L mutant. The second approach used to study the surface of Ras-GppNHp is called the Multiple Solvent Crystal Structures (MSCS) method. Crystals are crosslinked with gluteraldehyde and transferred to several distinct organic solvent solutions, resulting in a series of crystal structures that can be superimposed for analysis. Using this method we identify two putative sites of protein-protein interaction in Ras away from the Switch regions. The locations of these sites coincide with the clustering of conserved residues in the close family member Ral-GppNHp. Host: Dr. Bruce Tidor Department of Electrical Engineering and Computer Science and Biological Engineering Contact: Brenda Pepe, Biology, 452-3885 http://csbi.mit.edu/ Sponsored by CSBi Annual CSBi Seminar Series in Computational and Systems Biology The entire MIT Community is welcome at this event! --