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Keynote: George Church - BI/O: Reading and Writing Genomes
George Church has developed an amazing amount of technology. - Barb Bryant
I am always wondering that if he gets any sleep at all. - Dawei lin
Which is the introducer? - Dawei lin
michal linial, if I'm not wrong (which I was, need new glasses) - arne
The My First DNA sequencer reference: - Shannon McWeeney
First challenge on computational interpretation and integration: personal genomes =stem cell epigenome + mC environments + traits. - Dawei lin
Olga Troyanskaya - Barb Bryant
Cost of drugs goes up linearly; cost of sequencing is dropping exponentially - Barb Bryant
40,000 fold price drop for 4 years - Dawei lin
CGI price for genome is $1500/year? - Dawei lin
In 2005 we abandoned a monopolistic capillary electrophoresis; instead we have a couple and now 21 different technologies for sequencing. Resulted in a jump in rate of change of sequencing capacity - Barb Bryant
He thinks that many of the sequencing companies will find a niche :) - arne
Cost of personal genome: 2007: $57M; 2009 $1500, for 40-fold coverage. - Barb Bryant
Close to the $1000 genome - arne
(+ $100,000 interpretation cost?) (he doesn't really think that) - Barb Bryant
Drmanac et al Science Jan 2010 - Dawei lin
Sidetrack: One friend said when he started his PhD it took 6 month to sequence a bacteria and 6-60 month to analyse it. Not it takes 6 minuted to sequence it and still 6-60 month to analyze it. - arne
limitation is several hundreds nm in scale on chip (positive charge molecules on hydrophobic background - Dawei lin
7% human genome is missing so far because of technical challenges - Dawei lin
trio genomics information (father, mother, child) is increasing important in genomics research - Dawei lin
From open acess Sequences to Bio-Fab - arne
One of the 21 sequencing technologies is open-access. Reads and writes DNA with light. - Barb Bryant
2nd-gen synthesis ($500 per 15 Mbp) - arne
Second-generation synthesis - four different kinds of technologies. - Barb Bryant
Next Gen synthesis: off chips $500 15Mbp - Dawei lin
Tian et al 2004 Nature - arne
The work started around 2003 - Dawei lin - arne
person genome 3M allele -> immunology + microbome -> trait - Dawei lin
Issues of personal identification from genomic data. Informed consent as one solution. - Barb Bryant
Have 16,000 volunteers for Personal Genome Project so far; 100,000 target. - Barb Bryant
Claims that ~1800 genes are highly predictive and medically actionable. - Barb Bryant
They are rare but collective common at 10% level - Dawei lin
Example of the Madsen family with two diseases. Found causative allelles - 4 total (2 from each parent). - Barb Bryant - Dawei lin
Each time we find a scary allele in a person, it could be a sequencing error; it could be a problem with the literature. - Barb Bryant
found a dozen cases in the literature got allele sequence wrong - Dawei lin
The oldest volunteer for PGP is 96.7 years old - Dawei lin
Q: Are these genomes available ? - arne
Circulating tumor, pathogen, fetal, and immune cells. - Barb Bryant
Microbe vs Immunome - arne
If you want to look for a microorganism in a body, you can either look directly for the microbe, or look for the body's reaction. - Barb Bryant
immune test is to focus on response to exposure. - Dawei lin
Sequencing after vaccination - response is maximum after 7 days - arne
Generating human tissue from pluripotent stem cells - Barb Bryant
The Economist 20-May-2010 cover - Dawei lin
Genome engineering - Barb Bryant
E.g., change the genetic code -- for resistance to pathogens, new amino acids, and something else. - Barb Bryant
You have to do this safely. - Barb Bryant
For $400M, Dupont made 27 changes to the 4.6 Mbp E. coli, to make a chemical. - Barb Bryant
Another application: bio-petroleum from microbes. - Barb Bryant
Identify enzymes that synthesize alkane. Many cyanobacteria made trace amounts; others made none. Did genome sequence "subtraction" to find which genes were in the former. Isolated & tested these genes. Overproduced them; it worked. Green chemistry. - Barb Bryant
Multiplex Automated Genome Engineering (MAGE)... - Barb Bryant
Church's own genome is available: - Christiaan Klijn
So: subtract my genome from Church's, then overproduce those genes --> TOTAL BRILLIANCE! - Barb Bryant
Example of freeing up a codon by changing those codons to a different one./ - Barb Bryant
Is this not just the analysis. Not the sequence ? (or did I miss a link) - arne
See the 'Datasets' header -> you can get 500k Affy data as well as exome - Christiaan Klijn
Metabolic engineering example. Historically, you'd get obsessed with one step in the pathway and overproduce one enzyme. But then you'd get product inhibition, or the product might be toxic. - Barb Bryant
Would be nice with a map to the reference genome as well, but guess that can be done - arne
DNA Nanostructures: (DNA origami). Proposes a combination of DNA and proteins. - arne
DNA nanostructures help solve structures of membrane proteins. - Barb Bryant
First practical application: Made a long rod that was stiffer than other DNA. Used in NMR for membrane proteins (Cooooll idea but, it has been tried with proteins before) - arne
caDNAno is a software tool that is free available - Dawei lin
Time for questions. - arne
Keynote: Chris Sander - Systems Biology of Cancer Cells
An interview with Chris Sander ... - Venkata P. Satagopam
Kabsch and Sander paper - over 6000 citations - - Shannon McWeeney
Note the subliminal message in the announcement slide - Iddo Friedberg from Android
Prediction by transparency - no computation necessary story - Shannon McWeeney
Awards should be shared: People working with Chris includes: Burkhard Rost, Alfonso Valencia, Liisa Holm and many more - arne
Announcement of unpublished and new work. A good trend at this ISMB. - Roland Krause
Cancer genome atlas: TCGA - arne
Mapping of molecular alterations (cpy number variation) to 200 glioblastoma samples. - Roland Krause
Difference between patients is huge - arne
extract network, find relevant modules. - Roland Krause
illustration of netbox algorithm - Shannon McWeeney
When grouping mutations into pathways up to 85% of GBM have a muation in the most important pathways, while individual genes are down to a few % - arne
Each oncogene may have relatively low frequency across patients; but when you group genes across pathways, a pathway may explain a large fraction of patients with a given type of cancer. - Barb Bryant
"Network pharmacology" - Barb Bryant
can see a change in pathway activation between primary tumor and mets - Mickey Kosloff
Dominant alterations changes between cancer types and states. - Roland Krause
GBM: copy number is rare (and noisier) Ovarian: more regular and higher - arne
profiles of copy numbre variations differ between types of cancers - Mickey Kosloff
Metastatic tumor samples have more copy number changes than primary tumors. Not surprising. But maybe primary samples with more copy number changes than others are more likely to metastasize? Generally, better outcome with fewer somatic copy number changes. - Barb Bryant
BRCA1 and BRCA2 mutations convey germline inherited cancer risk - Barb Bryant
These genes act in the homologous repair pathway. Half of all patients have mutations in some homologous repair pathway gene. - Barb Bryant
and more generally, homologous repair genes are altered in > 50% of ovarian cancer - Mickey Kosloff
Tumor suppressor genes can be inactivated in various ways: germline mutation, somatic mutation, epigenetic silencing, etc. - Barb Bryant
There are drugs under development that might work particularly well in patients with defects in this particular pathway. - Barb Bryant
Cancer genomics portal: - Barb Bryant - Barb Bryant
Topic shift: now, perturbation cell biology. "and belief propagation". (eh?) - Barb Bryant
Perturbation Cell Biology - arne
In recent past, says Chris, you make a few perturbations: overexpress or knock down a gene; inhibit with a compound, etc. - Barb Bryant
use network inference algorithms - Mickey Kosloff
goal = predictive models for therapy - Mickey Kosloff
with only 200 datapoints -> derive validated (known) pathways - Mickey Kosloff
Prediction of networks does not scale to larger networks - arne
Large data generation with the number of pertubation > than proteins. - Roland Krause
Still prohibitively large number of networks even for small number of nodes. - Roland Krause
Use statistical physics methods to tackle combinatorial explosion of possible networks. - Barb Bryant
Inference using belief propagation known from statistical physics. - Roland Krause
Ah, here is where "belief" comes in. Network inference using belief propagation. Reference Riccardo Zecchina et al. - Barb Bryant
Instead of going through all the models that are possible, you derive statistical properties across a set of good models for each of the Wij weights in the model. - Barb Bryant
This is sort of like partition functions in statistical physics - Barb Bryant
evolving work on Wij (transition from Nelander et al 2008- - Shannon McWeeney
Cavity approach - optimize locally on global background iteratively cover all local cavities - Shannon McWeeney
Mm, this is rather opaque to me. - Barb Bryant
"Let me give you some intuition about how this all works." Yes, I'd like that. - Barb Bryant
Nice results on toy experiment - constraints from 10 experiments with 5 interactions (the nodes W in factor graph). - Shannon McWeeney
Almost looks too good - arne from iPhone
after step 1 - generation of probability distributions then step 2- decimation - Shannon McWeeney
So you have a probability distribution for each Wij, which represents the interaction between element i and element j. I'm not really getting how you "update" these probability distributions in the iterative steps. I do understand that at the end you take the most "certain" (narrowest) distribution and fix its value (some Wij) at the most probable value, then update all the other Wij's given this fixation. And so on. To get your final model in a sort of greedy fashion. - Barb Bryant
And by the way, the underlying model is a simple differential equation sort of thing: change of one variable xi is a sigmoidal function of weighted (Wij) sum of all variables xj, less a decay term. - Barb Bryant
thanks for the summary bb - Michael Jones
Mike! - Barb Bryant
Mentions bunches of other stuff in passing. Like bioPAX: paper in press. - Barb Bryant
bioPAX is community project on pathways, ontology, and exchange format. - Barb Bryant
"no science without people; science for the people; ask good questions" - Shannon McWeeney - arne from iPhone
Ask good questions !!!!! - arne from iPhone
Question: Interacting network tend to be modular, with strongly-interacting subnetworks that interact weakly with each other. ... - Barb Bryant
Chris: Is the modular approach really useful in confronting the data? [Is that what he said?] - Barb Bryant
Question: can you get at causal relationships? - Barb Bryant
Chris: yes - if the network model allows you to predict correctly the result of a particular perturbation applied to a particular node, then you can simulate using that model. - Barb Bryant
Question: with a big network, how many experiments will you need to model? - Barb Bryant
Chris: Good question. Could use an entropy measure. Help us figure this out. Help us design the experiments. It's important because of the costs of experiment. This is going to be broadly applicable in cell biology. - Barb Bryant
bb - he said one should see if approach is useful by confronting with real data - Shannon McWeeney from BuddyFeed
Ah, thx - Barb Bryant
Chris gets at the difference between a model that tells a story and a model that is truly predictive. - Barb Bryant
Question: yes, but, what are the semantics of the graph? What kinds of interaction? Answer: The semantics are in the mathematics of your model. - Barb Bryant
Question: mean field approach is interesting. Compared to Monte Carlo approach, you are assuming some decoupling. Loss of posterior coupling between weights - is that an issue? - Barb Bryant
Chris: If you look at a coupled system overall, the extent to which the algorithms work depends on correlations within the system. Long-range (in terms of network distance) correlations are problematic. There are some clever approaches to handle some of this. Mentions non-ergotic space; deal with parts of space separately or iteratively. - Barb Bryant
Keynote: Susan Lindquist - Protein Folding and Environmental Stress REDRAW the Relationship between Genotype and Phenotype
Inherited Environmentally acquired traits - lamarck wasn't so insane - Ted Laderas
Protein folding - environment is very important ... showed videos - Venkata P. Satagopam
experiments in heat shock tolerance -initial small shock allowed for survival -hsp proteins are made in massive amounts - role in protein folding - Ted Laderas
Hsp90 a special chaperone. - John Greene from fftogo
in excess in cell - acts as homeostasis buffer - Ted Laderas
Hsp90 a special chaperone. - John Greene from fftogo
hsp70 helps early stage folding and works with a number of proteins, but not hsp90. - Dawei lin
HSP 90 a special chaperone ... because very abundant, it induced by two folds, it has extra folding capability .... acts as a buffer - Venkata P. Satagopam
Signal transduction networks & HSP90 ... Hanahan and Weinberg, cell 2000 - Venkata P. Satagopam
showed signal transduction network involved by hsp90. It seems pretty spread. - Dawei lin
hsp90's function is found by an accident. - Dawei lin
Hsp90 mutations in fruit flies leads to death of flies - Venkata P. Satagopam
some mutated fruit flies survived revealed that hidden genetic variant. Hsp90 does not destabilize development. - Dawei lin
raise fly at high temperature can reduce the amount hsp90 level, easier than did it in a genetic way - Dawei lin
Hsp90 a special chaperone. - John Greene from fftogo
acts as a capacitor for some variation .... it also acts as a potentiator for other variation - Venkata P. Satagopam
both fly and arabidopsis experiments show that hsp90 acts a buffer for variations. - Dawei lin
hsp90 can complex with inactive hormone receptors and oncogenic kinases - Dawei lin
hsp90 helps mutated kinase, which lost the ability to inhibit itself. - Dawei lin
same thing happened in human diseases. - Dawei lin
so hsp90 inhibitor can be used for a drug. - Dawei lin
there are a few fungi drugs available clinically - Dawei lin
remove level hsp90 buffer level completely removed the drug resistance evolution - Dawei lin
Raise temperature again eliminated the drug resistant development. Should the patient be put in fever stage. - Dawei lin
talked about some unpublished data - Dawei lin
Where is the bioinformatics ? - arne
when added hsp90 inhibitor, some traits disappeared but some showed up - Dawei lin
ame, people who analyzed the data, :-) - Dawei lin
it should be a huge work to make genotype to phenotype map - Dawei lin
the polymorphism in NFS1 that required for tRNA modifications caused the phenotype charge - Dawei lin
polymorphisms in 3' UTR of HNI1 is also affected by hsp90, but not directly instead through the proteins binding to that region. - Dawei lin
has Hsp90 left an imprint on genomes that exist today? - Dawei lin
hsp90 affects polymorphisms throughout the genome even non-coding, in combinatorial way - Dawei lin
it is benefit to human is the big reason to continue the research. - Dawei lin
yeast prions - genetic element based on protein conformation - Saravanamuttu Gnaneshan
prion also switches on with environmental stress - Saravanamuttu Gnaneshan
prion has similar behavior of hsp90. It generates new phenotypes. - Dawei lin
Keynote: Steven Brenner - Ultraconserved nonsense: gene regulation by splicing & RNA surveillance
ISMB2010 just kicked off - Venkata P. Satagopam
Prof Søren Brunak introducing Steven Brenner, ISCB overton prize winner - Venkata P. Satagopam
Brenner contributed to many fields in bioinformations, starting in structureal biology ober RNA to metagenomics. - Roland Krause
A short biography, summarizing Soren Brunaks kind introduction - Roland Krause
The morphology of steves paper: - Shannon McWeeney
Intro: The ultraconservative (as seen from Berkely) and nonsense (as found in Through the Looking Glass - Roland Krause
The jabberwocky poem does have meanings and is elegantly crafted. - Roland Krause
Generally, nonsens in biology is bad. - Roland Krause
Nonsense is generally bad, even in a codon - Venkata P. Satagopam
Truncated proteins might interfere with physiological function (dominant negative). The cell removes such transcripts through nonsense-mediated decay (NMD). - Roland Krause
Good example for NMD: Sox10 - Roland Krause
Mutations early in the gene leads to less severe phenotypes than later ones - Roland Krause
NMD is an mRNA surveillance system - Venkata P. Satagopam
NMD important to development of the immunesystem and cleans up other transcriptional errors. - Roland Krause
We do not know how NMD works outside the mammals. - Roland Krause
The mechanism involves the splicing machinery. If a stop is found wwithin 50nt upstream of the exon junction complex, it is removed.. - Roland Krause
50 nucleotide rule - translated normally or degraded by NMD - Venkata P. Satagopam
brilliant nytimes article title - surviving on low number of genes - Shannon McWeeney
splicing can introduce PTC - premature termination codon - Venkata P. Satagopam
AS as mechanism to introduce PTCs - can lead to unproductive splicing - Shannon McWeeney
these isoforms often have PTC - Venkata P. Satagopam
Humans have fewer genes but better genes, due to AS. - John Greene from fftogo
Are PTC splice forms funcitonal? - Venkata P. Satagopam
Many PTC mRNAs are noise - Venkata P. Satagopam
analgous mechanism to shrinter: - Shannon McWeeney
Humans have fewer genes but better genes, due to AS. - John Greene from fftogo
Alt splicing can yield isoforms differentially subjected to NMD - Venkata P. Satagopam
SR protein - 11 in human which are serine and arginine rich - Venkata P. Satagopam
SR proteins have premature stop codons. - Roland Krause
SR genes has mRNAs with premature termination codons - Venkata P. Satagopam
AS of PTC isoforms is mechanism for autoregulation of proteins - Ted Laderas
NMD has a large effect on isoform abundance - Venkata P. Satagopam
NMD has impact on isoform abundance - example of NMD clearing the major isoform - Shannon McWeeney
minor isoforms are only shared 25% of time - modrek and lee 2003 - Shannon McWeeney
Not just anecdotal stories, splice patterns are conserved in mouse, implying functional significance. - Roland Krause
(Unpulbished work) - Roland Krause
All the SR proteins are talking to each other - Venkata P. Satagopam
SR proteins 'compensate' for each other via coupling via AS and NMD - Ted Laderas
SR genes have ultraconversed elements .. Bejerano et al 2004 Science 304: 1321 - Venkata P. Satagopam
Most ultraconserved regions are in intergenic regions, the regions in SR within genes. - Roland Krause
question of why conserved - not protein coding, no obvious significant RNA secondary structure - Shannon McWeeney
No proteins are produced from these genes. - Roland Krause
The reason why SR sequences are highly conserved - most of the seq are not protein coding, - Venkata P. Satagopam
no repetitive elements - Venkata P. Satagopam
why conserved part 2 - no overrepresentation of binding / regulatory elements - Shannon McWeeney
No simple explanations e.g. from miRNA binding etc. - Roland Krause
no similarity elsewhere in genome except retropseudogenes - Venkata P. Satagopam
analysis on origin of unproductive splicing - Shannon McWeeney
No sequence similarity between the conserved elements. Seems to have been introduced mutliple times. - Roland Krause
mouse and human SRp55 conserved but changing - Venkata P. Satagopam
working on chordate SR proteins - Venkata P. Satagopam
here intron and exon structure is more informative - Venkata P. Satagopam
at this point - he has requested no further blogging - unpublished work - Shannon McWeeney
no blog slides may be over - Burkhard Rost
# Looks like interesting work. - Roland Krause
wonderful talk - Shannon McWeeney
Tells a (hard to blog) story about the successful treatment of collaborator with novel treatment based on genotyping. - Roland Krause
Wow - what a conclusion! Fantatic talk... - John Greene from fftogo
# Certainly great work. The talk was nice too, and he only bitched at other reseachers in person once, another step up. - Roland Krause
"Ultraconversed elements in SR genes ONLY show similarity to retropseudogenes" - what does this mean? Any takers? - Saravanamuttu Gnaneshan
HL07: Roy Navon - Novel statistics reveal cancer universal miRNA activity
HL05: Christiaan Klijn - Finding co-occurrence of copy number changes in tumors.
Any comments (I missed the lecture) - arne
You can always visit my poster if you want a recap: V01 - Christiaan Klijn
SIG: HiTSeq: High Throughput Sequencing
Current BAM file format forces significant loss of informarion. Probabilistic model proposed for NextGen BAM format by David Haussler. - John Greene from fftogo
best keynote (dh) i've attended in years... - andrzej
break point graphs very interesting. might try to explore further - Saravanamuttu Gnaneshan
Michael Kuhn
Hackathon at ISMB 2009
Reinhard Schneider approached me if I was interested in organizing a hackathon at next year's ISMB. I couldn't say for sure that I'd come next year, but I told him that there was community interest for some sort of Open Science hackathon. I think this would be an interesting thing to put together. We should discuss this at Tuesday's BOF meeting, but I just wanted to put this here to get you thinking about it. - Michael Kuhn
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