Assignment 6
Contents
Assignment 6 - Patterns, Regulons and Systems
Please note: This assignment is currently inactive. Unannounced changes may be made at any time.
- A theory can be proved by an experiment; but no path leads from experiment to the birth of a theory.
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- (Variously attributed to Albert Einstein and Manfred Eigen)
Systems biology is about systems ... but what is a system, anyway? Definitions abound, the recurring theme is that of connected "components" forming a complex "whole". Complexity describes the phenomenon that properties of components can depend on the "context" of a component; the context is the entire system. That fact that it can be meaningful to treat such a set of components in isolation, dissociated from their other environment, tells us that not all components of biology are connected to the same degree. Some have many, strong, constant interactions (often these are what we refer to "systems"), others have few, weak, sporadic interactions and thus can often be dissociated in analysis. Given the fact that complex biological components can be perturbed by any number of generic environmental influences as well as specific modulating interactions, it is non-trivial to observe that we can in many cases isolate some components or sets of components and study them in a meaningful way. A useful mental image is that of clustering in datasets: even if we can clearly define a cluster as a number of elements that are strongly connected to each other, that usually still means some of these elements also have some connections with elements from other clusters. Moreover, our concepts of systems is often hierarchical, discussing biological phenomena in terms of entities or components, subsystems, systems, supersystems ..., as well it often focusses on particular dimensions of connectedness, such as physical contact, in the study of complexes, material transformations, in the study of metabolic systems, or information flow, in the study of signalling systems and their higher-order assemblies in control and development.
At the end of the day, a biological system is a conceptual construct, a model we use to make sense of nature; nature however, ever pragmatical, knows nothing of systems.
In this sense systems biology could be dismissed as an artificial academic exercise, semantics, even molecular Mysticism, if you will (and some experimentalists do take this position), IF systems biology were not curiously successful in its predictions. For example, we all know that metabolism is a network, crosslinked at every opportunity; still, the concept of pathways appears to correlate with real, observable properties of substrate flow in living cellls. Nature appears to prefer constructing components that interact locally, complexes, modeules and systems, in a way that encapsulates their complex behaviour, rather than leaving them free to interact randomly with any other number of components in a large, disordered bag.
The mental construct of a "system" thus provides a theory of the functional organisation of biological components.
In this assignment we will briefly explore two of the tools that are currently in common use to map molecular observations to integrated systems concepts and consider how complete that mapping currently is.
Preparation, submission and due date
Read carefully. Be sure you have understood all parts of the assignment and understand what you are expected to do! Sadly, we see too many assignments in which students have overlooked directive verbs such as explain, enumerate, list, name, compare, contrast, describe, summarize, outline, apply, justify, establish, defend, account for, sketch, clarify, state, illustrate or discuss. If any of these verbs don't catch your attention, you need to get more coffee before you start. Prepare a Microsoft Word document with a title page that contains:
- your full name
- your Student ID
- your e-mail address
- the organism name you have been assigned (see below)
Follow the steps outlined below. You are encouraged to write your answers in short answer form or point form, like you would document an analysis in a laboratory notebook. However, you must
- document what you have done,
- note what Web sites and tools you have used,
- paste important data sequences, alignments, information etc.
If you do not document the process of your work, we will deduct marks. Try to be concise, not wordy! Use your judgement: are you giving us enough information so we could exactly reproduce what you have done? If not, we will deduct marks. Avoid RTF and unnecessary formating. Do not paste screendumps. Keep the size of your submission below 1.5 MB.
Write your answers into separate paragraphs and give each its title. Save your document with a filename of:
A3_family name.given name.doc
(for example my first assignment would be named: A3_steipe.boris.doc - and don't switch the order of your given name and familyname please!)
Finally e-mail the document to boris.steipe@utoronto.ca before the due date.
Your document must not contain macros. Please turn off and/or remove all macros from your Word document; we will disable macros, since they pose a security risk.
With the number of students in the course, we have to economize on processing the assignments. Thus we will not accept assignments that are not prepared as described above. If you have technical difficulties, contact me.
The due date for the assignment is Thursday, December 7. at 24:00 (last day of class). In case you need more time since the assignment was posted late, an extension is automatically granted to Tuesday, December 19. at 10:00 in the morning.
Grading
Don't wait until the last day to find out there are problems! Assignments that are received past the due date will have one mark deducted at the first minute of every twelve hour period past the due date. Assignments received more than 5 days past the due date will not be assessed.
Marks are noted below in the section headings for of the tasks. A total of 10 marks will be awarded, if your assignment answers all of the questions. A total of 2 bonus marks (up to a maximum of 10 overall) can be awarded for particularily interesting findings, or insightful comments. A total of 2 marks can be subtracted for lack of form or for glaring errors. The marks you receive will
- count directly towards your final marks at the end of term, for BCH441 (undergraduates), or
- be divided by two for BCH1441 (graduates).
(1) Pathways
Pathways are perhaps the earliest biochemical representation of cellular systems. They are a particularly active area of bioinformatics research, because many have a sense that it should be possible to construct patway descriptions essentially automatically from databases of known properties of components. For instance if Enzyme A produces metabolite 1 and Enzyme B consumes metabolite 1, even a computer can figure out that A and B could be on the same pathway. However, what if metabolite one is ATP? Or H2O? Careful, manual curation of pathway data is going to be with us for a long time.
(1.1)KEGG (5 marks)
The Kyoto Encyclopedia of Genes and Genomes is one of the oldest and best curated databases of metabolic and functional pathways. Access the KEGG Web site.
record three letter code
Navigate to the KEGG2 page and find the link to BLAST search against genes in the database. Upload the APSES domain sequence for your organism, and click on the "Compute" button to execute the search. In the list of hits, click on the link yeast Mbp1 (if there are more than one, use the one associated with Mbp1's systematic name).
Click on the Help button on top of the record to find information about what the returned results contain.
Access the Pathway associated with this gene. The position of Mbp1 is emphasized with a red box.
Study the cell cycle control system: note that mbp1 binds to swi6 and swi 6 can also bind to swi4.
Briefly (!) compare this pathway with the cell-cycle diagram contained in Figure 4 of Richard Young's conceptual analysis of the yeast cell cycle, based on transcriptional regulatory networks (see resources, below; for the purpose of this assignment, let's consider this expert curated schematic to correspond to the standard of truth for the current thinking on this particular system.):
(i) Are the same genes involved?
(ii) Are the same connections shown?
(iii) Is the same concept of time/progression being represented?
Does your organism have a swi4 orthologue?
click on swi4.
click on ortholgues.
Find the three-letter code in that table. What do you conclude?
Falllback file: three letter codes, Swi 4 orthologues.
- Task
Instruction
- Task.
(2) Interactions
(2.1) BioGRID (5 marks)
We will thus briefly explore BioGRID, to retrieve interactions for Mbp1, the yeast gene for which we have been studying orthologues in other organisms.
Access the the BioGRID.
Search for interactions of the Mbp1 gene.
Briefly (!) comment on the two interactors that are retrieved:
(i) What experiment type(s) do they come from?
(ii) Do they appear in the KEGG map?
(iii) Do they appear in Figure 4 of the Young group's publication?
- Task
Instruction
- Task.
(3) Summary of Resources
- Links
- Sequences
[End of assignment]
If you have any questions at all, don't hesitate to mail me at boris.steipe@utoronto.ca or post your question to the Course Mailing List
