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arne › Comments
Dina Schneidman liked this
Nice tool
- arne
3D SIFT descriptors are used for comparison of EM density maps
- Dina Schneidman
Surehy Breter, Samuli Eldfors, Ruchira S. Datta and 4 other people liked this
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: http://www.wired.com/wired...
- 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
personalgenomics.org
- 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
evidence.personalgenomics.org
- 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: http://www.personalgenomes.org/public...
- 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
Is there interest in a Birds of Feather session tomorrow regarding (micro) blogging?
Surehy Breter and Mickey Kosloff liked this
... or simpy a joint luncheon?
- Roland Krause
joint luncheon sounds good.
- Mickey Kosloff
mentioned this before but might have been lost: if ISCB has to do something to support this crucial activity: let us know!
- Burkhard Rost
OK, then let's meet for lunch tomorrow. Please spread the word. It'll be easiest if we meet at 12:50 at the hallway leading to the ballrooms on the 3rd floor. Burkhard: Thanks for the support, we'll get back to you.
- Roland Krause
@Burkhard: most people that sat next to me had no idea about this room or about FF, despite the prominent slide and the links from the ISMB webpage. Perhaps if you show a screenshot before a keynote, awareness will increase?
- Mickey Kosloff
Afraid the horrible wireless connection made (live) blogging nearly impossible for many sessions. Was going to cover the late breaking research session today from 201, but no luck.
- Oliver Hofmann
Must have missed you. Got there a couple of minutes late and didn't see anyone.
- Mickey Kosloff
from iPod
Hmm, let's try to meet at the reception. It'll be a search in 2D space so we should find each other in finite time. I will be in room 302 for the remainder of the afternoon.
- Roland Krause
What about another projector projecting the feed, in talks by some daring presenters?
- Barb Bryant
I won't be able to make the reception. My 3 ideas are: separate (secure) wireless for bloggers. Incentives (e.g. Priority for plos-cb postcard publications). Wider campaign to recruit micro bloggers before ismb.
- Mickey Kosloff
from iPod
1. projection of the feed: don't get the reason. 2. wireless 4 blog: good idea, 3. plos-cb postcard slot: will talk to phil/plos, 4. other incentives: what you want?
- Burkhard Rost
Reason for wireless4blog is most likely due to low speed here
- arne
It's not a bandwidth problem, I had throughputs on the MB/s. More likely, many of our computers have problems in this mixed settings with "smart" handling of receiver power etc. In Vienna, I had a clever tech guy that helped to disentangle these issues with my network card. What we (all) would really need is some sort of true hacker with proper equipment but I have no good idea how to recruit such a person.
- Roland Krause
Can bottleneck be between local server and ISP ?
- Mickey Kosloff
from iPod
arne and Roland Krause liked this
Omic data don't mean what you think
- Roland Krause
Generally little overlap between different experimental screens.
- Roland Krause
Surehy Breter, Guilhem Chalancon, Ruchira S. Datta and 2 other people liked this
p110-p85 complex
- arne
Similar to Lego assembly
- arne
combine different types of data/constraints to solve the docking problem
- Mickey Kosloff
used patchdock for rigid docking
- Mickey Kosloff
Patchdock: http://bioinfo3d.cs.tau.ac.il/PatchDo...
- arne
SAXS: Using a FFT can provide distance between atoms (on average)
- arne
3D-EM: Density map. Superposition to model. fit score
- arne
2D-EM: Similarity
- arne
Fast mapping by NMR spectroscopy
- arne
FIREDOCK (a method for fast flexible refinement) http://bioinfo3d.cs.tau.ac.il/FireDoc...
- arne
Example: Antigen - antibody target..
- arne
Hmm.... my posts never appeared !!
- arne
had strange delay problems during keynote
- Mickey Kosloff
JaraBreter, Roland Krause, Mickey Kosloff and 3 other people liked this
Altshuler is an expert on diabetes type II.
- Dawei lin
It is said that he is also a good dancer.
- Dawei lin
Tap, ballroom, or tango?
- Ted Laderas
Slide dancing
- Dawei lin
motivation is to understand genetic basis of human diseases
- Dawei lin
Genetic basis of human diseases - important disease mechanisms and bio pathways remain unidentified
- Venkata P. Satagopam
gap in knowledge of human disease biology contribute to high failure rates in drug development
- Dawei lin
Why understanding genetic mechanisms ? (1) Important mechanism remain unidentified (ii) Gaps in knowledge causes failure rate in drug development
- arne
It will be a long way to know if the two motivating hypotheses are true
- Dawei lin
one of the most research on T2D. It scaned 100k people for 10 yrs
- Dawei lin
10 years later 50% progressed to have the disease
- Dawei lin
10years of diabetic research - the out come is - 50% of people with good lifestyle improved
- Venkata P. Satagopam
lifestyle has a bigger impact than Metformin
- Dawei lin
Diabetes study with 10-year follow-up of diabetes incidence and weight loss, "T2D". Randomized into treatments: lifestyle, metformin, placebo. Best drug makes relatively little difference in incidence; lifestyle intervention is better than drug but still doesn't help a whole lot.
- Barb Bryant
best prevention was extensive lifestyle changes (50% -> 40% incidence)
- Mickey Kosloff
Diabetes is not only a matter of life style
- arne
success rate in current pharma industry is <5% of molecules entering the clinical trails
- Venkata P. Satagopam
This is bad !!
- arne
mentions well known number of >95% failure rate of new compounds
- Mickey Kosloff
because there are still 40% people got the disease after the lifestyle change, it seems that people do not know the course of the disease
- Dawei lin
a genetic approach - http://www2.massgeneral.org/chrg...
- Venkata P. Satagopam
Genetic mapping started in 1913
- Dawei lin
genetic map came in 1913
- Venkata P. Satagopam
Morgan and Sturtevant 1913
- arne
emphasizes he advocates a genetecist's approach (rather than a genomic approach)
- Mickey Kosloff
And tells you to skip undergraduate work if you have something better to do
- arne
key attributes of genetic mapping - unbiased by prior assumptions about pathways
- Venkata P. Satagopam
saturation mutagenesis reveals pathways
- Venkata P. Satagopam
key attributes of genetic mapping: (1) unbiased by prior assumptions about pathways (2) saturation mutagenesis reveal pathways
- Dawei lin
many mutants -> reveals coherence of pathways
- Ted Laderas
These days we have other methods that are unbiased like expression profiling, but genetic mapping has some unique characteristics relative to these (he’ll explain in a minute).
- Barb Bryant
Drosophola's mutations looked initially random, years they almost all related to pathways.
- Dawei lin
bottleneck is functional determination - biochemical approaches
- Ted Laderas
A lot of current knowledge can track back to genetic mapping
- Dawei lin
Botstein and Fink Science 1988 ....
- Venkata P. Satagopam
A slide based on Galzier et al, Science 2002
- Dawei lin
genetic mapping of human single gene disorders ...over 15 years Botstein paper in 1980, first genetic map in 1985 ....
- Venkata P. Satagopam
It took 10 year to find maker for Huntington disease
- Dawei lin
Once you find a linked region from genetic mapping, it still takes a long time to find the specific gene responsible.
- Barb Bryant
in the 1990's the idea was that common diseases were caused by rare mutations with large effects
- arne
"Chromosome shlepping" - Eic Lander's term for the identification of a very gene in some genomic region.
- Roland Krause
It is robust to find mendelian disease but to not common diseases
- Dawei lin
another approach: population genetics - QTL approach
- Ted Laderas
phenotypic variation is often continuous and may involve variation in many genes
- Dawei lin
Galton invented regression analysis to analyze the measuring of phenotypic data (heights of parents and offspring).
- Roland Krause
The biometric unit --- almost nothing was Mendelian
- arne
Most traits are continuously variable
- Ted Laderas
Francis Galton was a cousin of Darwin. Darwin didn’t explain the source of variation. Galton focused on this; he measured the heights of parents and their offspring, and found a relationship. He invented regression analysis to draw the line. The slope of the line is related to the inheritability of the disease.
- Barb Bryant
It was studied by the cousin of Darwin, Francis Galton (1885)
- Dawei lin
phenotypic variation is often continuous ... some history ... Francis Galton (1885), Ronald Fisher (1918), Hermann Muller (1920)
- Venkata P. Satagopam
This gave rise to the biometric movement – measure every living thing. Traits were related to genetic relatedness; and it wasn’t Mendelian. This led to the biometric-Mendelian debate.
- Barb Bryant
Ronald Fisher, was actually a geneticist, who also invented p-value and Fisher exact test
- Dawei lin
Ronald Fisher (the one with the exact test) was also a geneticist.
- Roland Krause
Solved by assuming that phenotype often is an effect of several Mendelian genes.
- arne
Fisher: individual genes are mendelian, effects of genes additive
- Ted Laderas
Hermann Muller 1920 (Nobel Prize for X-ray induced mutations). PhD thesis not Mendelian trait, but truncate wing. Wasn’t Mendelian. Did genetic mapping.
- Barb Bryant
Hermann Muller decided to use broken wing of fruit fly to study non-Mendelian diseases
- Dawei lin
Muller 1920 paper: 4 chromosomes in fly – 3 contain genes that influence the trait truncate wing. Muller wrote about implications for human traits, like psychological traits. Said that traits were going to be too complicated. Said you could figure out by looking at population, but not looking at Mendelian inheritance in families.
- Barb Bryant
Muller 1920 suggested that it needed to do study on a population.
- Dawei lin
Muller: Truncate wing - 3 genes influence effect of phenotype
- Ted Laderas
Mullers thesis included the notion of surveying complex phenotypes in the population rather than families.
- Roland Krause
Muller: traits are too complex to observe in families, but can observe in population
- Ted Laderas
characterization and catalogue human seq variation is a decade of work .. i.e international HapMap project
- Venkata P. Satagopam
Another decade-long failure: the candidate gene approach. Instead, we need a genome-wide, unbiased approach.
- Barb Bryant
Testing candidate genes was not successful. Only 10-20 successes.
- Dawei lin
779 GWA published for 148 traits
- Mickey Kosloff
out come - 779 published GWA for 148 trails
- Venkata P. Satagopam
For common diseases, GWA was needed
- Ted Laderas
but "correlation does not imply causality"
- Mickey Kosloff
There have been 779 genome-wide association studies (or regions/genes found?) for 148 traits, with p < 5x10^-8
- Barb Bryant
"correlation does not imply causality" ....
- Venkata P. Satagopam
But correlation does not imply causality.
- Barb Bryant
The reasons of "Correlation does not imply causality": irreproducibility, lack of randomization, confounding, arrow of time.
- Dawei lin
If you can't randomize the experiment you can never prove causality as opposed to just being correlated to the underlying cause.
- Barb Bryant
FF lag results in all these duplicate posts
- Mickey Kosloff
a lot of efforts are on finding correlation between rare variation and diseases
- Dawei lin
rare variation is defined as has <5% in population
- Dawei lin
95% of variations is already present in the database
- arne
Identified 50 regions that are associated with T2D
- arne
with in next few years ... the role of rare and less common variants will be characterized in a variety of diseases
- Venkata P. Satagopam
next topic - can we obtains new insights into the basis of disease?
- Venkata P. Satagopam
one example - sickle cell anemia
- Venkata P. Satagopam
Sankaran et al Science 2008
- Venkata P. Satagopam
Lettre et al PNAS 2008
- Venkata P. Satagopam
Uda et al PNAS 2008
- Venkata P. Satagopam
Crohn's disease: 15 years, no idea what was happening. Now many genes and 3 pathways are identified to be relevant.
- Dawei lin
96 loci explain ~25% of cholesterol levels
- Mickey Kosloff
Lipid GWAS found 60 loci that are previous unknown. Some of the positives are drug targets already.
- Dawei lin
Global lipids consortium, forthcoming Nature paper (Nature paper is mentioned about 20 times !!!)
- arne
is there a way to automate validation/function determination?
- Ted Laderas
prediction -- will prediction prove useful --this is depending on the clinical testing and the genetic test
- Venkata P. Satagopam
prediction will be useful when there's a proven intervention
- Mickey Kosloff
BRCA1/2 risk for cancer as an example
- Mickey Kosloff
seq tech will increase the reach of genetic methods
- Venkata P. Satagopam
mendelian fallacy - sub-populations are easily divisible in terms of risk
- Ted Laderas
Prediction will only be useful if there is an intervention that you would not use without the prediction. Otherwise, you should use the intervention anyway.
- Roland Krause
Huntington will not be a representative example - for most diseases/people identified risk will be <<100% even with full genetic information
- Mickey Kosloff
Cautionary tale - PSA prediction results in over-treatment, hasn't been shown that people live longer because of test
- Mickey Kosloff
Very cautious about PSA - no improvements on the mortality but many operations performed.
- Roland Krause
genetics offers a path to discover the underlying biology of human diseases ; the great value will drive from pathophysiology and treatment
- Venkata P. Satagopam
arne, Mickey Kosloff, Saravanamuttu Gnaneshan and 3 other people liked this
An interview with Chris Sander ... http://www.mskcc.org/mskcc...
- Venkata P. Satagopam
Kabsch and Sander paper - over 6000 citations - http://www.ncbi.nlm.nih.gov/pubmed...
- 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. http://www.ncbi.nlm.nih.gov/pmc...
- 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: www.cbio.mskcc.org/cancergenomics
- Barb Bryant
mutationassessor.org
- 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. http://users.ictp.it/~zecchi...
- 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- http://www.nature.com/msb...)
- 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
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
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
Dina Schneidman, Mickey Kosloff, Tomasz Puton and 3 other people liked this
Protein Folding Requires Crowd Control in a Simulated Cell Benjamin R. Jefferys⁎, Lawrence A. Kelley and Michael J. E. Sternberg J. Mol. Biol. (2010) 397, 1329–1338
- arne
Mickey Kosloff, arne and Nir London liked this
Use protein design to understand protein space.
- Mickey Kosloff
Model designs with rigid BB (only side-chains) using rotamer library
- Mickey Kosloff
scoring usually done with pseudo-physical atomic energy + pairwise decomposition
- Mickey Kosloff
use probabilistic approach to bypass the NP hard problem
- Mickey Kosloff
One protein, two structures.
- arne
Original paper: http://www.ncbi.nlm.nih.gov/pubmed...
- Mickey Kosloff
2 examples - g-protein beta subunit and calmodulin
- Mickey Kosloff
arne liked this
LAST, like BLAST but faster. Handles repetetive regions and A+T bias much better than blast Blast etc used fixed seed length (Last uses a adaptive length)
- arne
Second tool: RECOUNT. 1% error per position.... Genomes are repetetive....
- arne
Third tooL SLIDESORT (see poster)
- arne
Change of speaker.....
- arne
Barb Bryant, arne, Mickey Kosloff and Roland Krause liked this
This will probably be a very interesting talk. Just can't wait.
- Tomasz Puton
Not just interesting, but most likely great. Svante is a fantastic speaker
- arne
If you’re interested in human history, the genome is a great source of information. To reconstruct history, we compare sequences of people (and other species) living today. We use models of how DNA changes over time to understand the differences that exist today. This is an indirect way to study history, because we are reconstructing from the present what we think has happened in the past.
- Barb Bryant
specimens are highly contaminated, ....
- Venkata P. Satagopam
original work from 1984 on egyptian mummy - http://www.sciencedirect.com/science...
- Shannon McWeeney
mtDNA - advantage of many copies per cell
- Mickey Kosloff
Replacement (out of africa theory) vs assimilation (i.e. geneflow from modern humans)
- arne
mtDNA is extracted from a specimen from neanderthal
- Venkata P. Satagopam
Started with the original neanderthal specimen
- arne
The variation in human population origins before the split (as measured by mtDNA) of modern and neanderthals
- arne
extract dna from skull, skip PCR and directly sequence
- Mickey Kosloff
only 3.5% actually from neanderthal genome
- Shannon McWeeney
Average length 50 nucleotides
- arne
Vindija Cave, Croatia .... 3 bones
- Venkata P. Satagopam
only about 3.5% of dna came from human
- Mickey Kosloff
3 billion fragments - again most from bacteria
- Shannon McWeeney
most dna is bacterial contaminants
- Mickey Kosloff
avg genome cover is 1.5X
- Venkata P. Satagopam
most DNA extracted is female look at Y chrom % as contaminant
- Ted Laderas
Three females samples (and therefore Y chromosome contamination can be used to calculate noise). Total risk is below 1% risk of contaimination
- arne
at any particular position - 1% chance contamination (broken down by source - 3 measures)
- Shannon McWeeney
consistant nucleotide chemical changes at 5' and 3' ends
- Mickey Kosloff
try to correct by alignments to human and chimpanzee genomes
- Mickey Kosloff
Details on bioinformatics and alignment issues (led by Ed Green) can be found in Science paper - http://www.sciencemag.org/cgi...
- Shannon McWeeney
55% chance of seeing a position covered by at least 1 read
- Ted Laderas
Divergence to human reference genome 12% highest among human is in San 10%
- arne
typical european (French) 8% divergence to human reference compared with 12% in neanderthal
- Shannon McWeeney
78 amino acid substitutions ... a catalog of novel fixed features in the human genome
- Venkata P. Satagopam
But this number will change
- arne
novel fixed features in human genome - 78 aa substitutions (in paper) - now down to 50
- Shannon McWeeney
Three out of six proteins with 2 changes are skin expressed
- arne
next focused on SNPs
- Mickey Kosloff
detection of selective sweeps - look for snps in human, chimps, neanderthals - r egions where neanderthal looks all ancestral.
- Shannon McWeeney
S vs cM plot - visual inspection for widest spread
- Shannon McWeeney
Most extreme case in THADA, http://www.genecards.org/cgi-bin... Transport and diabeted related
- arne
Thada is risk allele for type 2 diabetes - implications for metabolism
- Shannon McWeeney
detection of insertion in intron in Thada (not fixed in humans as initially thought in paper)
- Shannon McWeeney
3-4% in europe has the neanderthal version (and are protected against Diabetes Type II)
- arne
interesting follow-up research here - positive selection yet cost with risk allele
- Shannon McWeeney
RUNX2: Mutations cause CCD (Cleidocranial dysplasia)
- arne
annotation of others associated with autism and other diseases including CCD
- Shannon McWeeney
CCD of interest due to skull morphology phenotype
- Shannon McWeeney
Now comes the most surprising result.
- arne
focusing on - Interbreeding with modern humans?
- Venkata P. Satagopam
Work by Rasmus Nielsen http://ib.berkeley.edu/researc...
- arne
Is Craig Venter a "fully modern human" ?
- arne
analysis of self-identified neanderthals who write to Svante - predominantly men.
- Shannon McWeeney
Comparisons to genomes of humans from different continents suggests interbreeding occured in middle east, before geographic expansion
- Mickey Kosloff
:)
- arne
45% men who are neandertals, 1% women are neandertals....
- Venkata P. Satagopam
future 10-20x coverage of genome
- Mickey Kosloff
Future: (i) Better coverage (10-20x coverage) (ii) Functional analyses of candidate genes Exemplified by FoxP2 http://en.wikipedia.org/wiki...
- arne
next topic - functional analysis of genes - foxp2
- Venkata P. Satagopam
FoxP2 is the same in human and neanderthal.
- arne
hope to identify backmutations in humans -cheaper to find these people because of low cost of sequencing
- Ted Laderas
easier to check phenotypes in mice
- Mickey Kosloff
Human FoxP2 in mouse: The mouse can not speak ! Large scale phenotype study (323 phenotypic traits). -> More cautious in a novel area (stays close to the wall). No difference after 3 minutes. Second phenotype: Altered vocalization !!!
- arne
323 phenotypic traits ... studied ..
- Venkata P. Satagopam
movement more cautious in humanized mice
- Venkata P. Satagopam
next one is altered vocalization
- Venkata P. Satagopam
Enard et al Cell 2009
- Venkata P. Satagopam
mice with human foxp2 grew longer neurons
- Mickey Kosloff
Other hominid forms........
- arne
Denisova individual 1 Myears (400 diffs in mtDNA)
- arne
very good keynote
- Mickey Kosloff
Marina Olhovsky and Tomasz Puton liked this
Wang-Landau sampling instead of using the Stadtler approach
- arne
Extremely well-delivered lecture, informative and engaging
- Marina Olhovsky
Huy Q. Dinh, Ruchira S. Datta, Mickey Kosloff and 2 other people liked this
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
Saravanamuttu Gnaneshan liked this
Any comments (I missed the lecture)
- arne
You can always visit my poster if you want a recap: V01
- Christiaan Klijn
Ruchira S. Datta liked this
Not sure I really got the idea, but the results looked quite good.
- arne
Seems Like Raptor-X is doing OK (but not better than HHPRED) http://www.pdc.kth.se/~bjornw...
- arne
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