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necessary & sufficient

Rachel Drysdale (Genetics) rd120 at gen.cam.ac.uk
Wed Feb 18 08:00:51 PST 2004


Hi,

while I understand that there are good reasons for not
over-complicating the GO evidence codes by subdividing them further, I
do think that David has a strong point regarding the splitting of IMP
into 'inferred from over-expression phenotype' and 'inferred from loss
of function phenotype'.

Were IEP to be split into 'IEP by in situ hyb' vs 'IEP by antibody
staining' etc IEP would still convey the meaning that the GO term was
conferred on the gene in question on the basis of its expression pattern.
Either way the gene is being expressed.  This is a good reason NOT to
complicate the IEP evidence code unecessarily.

However, over-expression phenotypes and loss of function phenotypes
provide qualitatively different types of evidence, and there is value
in recording the distinction at the point of curation.  Speaking as a
curator, the extra curational load to be incurred by making this
distinction would most likely be more than offset in the value to the
user, who depending on the question that they are asking might choose
to ask for GO statements based on one kind of phenotypic evidence but not
the other.  (Please speak up if you disagree). This is true
irrespective of Stan's (erstwhile?) ambitions in trying to model
necessary & sufficient based on GO/evidence codes.


Rachel.







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> From: David Sutherland <djs93 at gen.cam.ac.uk>
> To: Rebecca Foulger <ref26 at gen.cam.ac.uk>
> cc: SLetovsky at aol.com, gofriends at genome.stanford.edu
> Subject: Re: necessary & sufficient
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> 
> Hi all,
> 
> The reason my attempted definitions were so genetic is that, at least as I
> understand them, necessary and sufficient are fundamentally genetic
> concepts.  I find it particularly difficult to see what a non-genetic
> concept of whether a gene is necessary for some process might consist of.
> (I chose to work in flies, after a PhD in Xenopus development, precisely
> because I was dissatisfied with the impossibility of finding
> whether a gene is necessary for a process by overexpressing it.)
> 
> Clearly, genetics is just one source of useful evidence for assigning GO
> terms (I certainly didn't intend to imply otherwise).  Where I think that
> the terms necessary or sufficient could potentially be useful is in
> subdividing the "inferred from mutant phenotype" evidence code. Providing
> that it is possible to come up with useable (sufficiently unambiguous)
> rules for curators to apply these terms, they would provide an additional
> tool (along with existing evidence codes) allowing users of GO data to
> assess confidence.  My own personal bias is that necessary alone inspires
> more confidence than sufficient alone, and both together trump either
> seperately, but users with a different bias needn't follow this. 
> 
> Perhaps a less terminologically loaded way of getting the same info
> across would be to split IMP into 'inferred from over-expression
> phenotype' and 'inferred from loss of function phenotype'.  Looked at like
> this, maybe the use of GO-terms at the allele level as part of a phenotype
> ontology system solve this anyway (?)
> 
> David
> 
> 
> On Wed, 18 Feb 2004, Rebecca Foulger wrote:
> 
> > 
> > Hi Stan,
> > 
> > Just to clarify on your last point:
> > 
> > 
> > > it is surprising that [snip]
> > > purely phenotypic criteria are used to associate a gene with a biological 
> > > processes.
> > 
> > > I always thought part of the goal of GO was to move away from describing
> > > things in terms of mutant phenos to associating genes with normal biological
> > > processes
> > 
> > 
> > Curators just use a mutant phenotype to infer the 'normal' biological
> > process a gene product is involved in. This is only one of the types of
> > evidence that a curator may use though. Genetic interactions, direct
> > assays, sequence/structural homology, expression patterns etc can all
> > lead a curator to assign a GO term to a gene product. And curator
> > judgement is used to interpret the phenotype/interaction results
> > against the genetic background and other experimental variables in
> > these cases (like an un-written version of the conditions you propose).
> > 
> > 
> > Becky
> > 
> > 
> > > Envelope-to: ref26 at gen.cam.ac.uk
> > > Delivery-date: Tue, 17 Feb 2004 22:14:45 +0000
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using -f
> > > From: SLetovsky at aol.com
> > > Date: Tue, 17 Feb 2004 15:22:38 EST
> > > Subject: Re: necessary & sufficient
> > > To: jblake at informatics.jax.org, djs93 at gen.cam.ac.uk
> > > CC: gofriends at genome.stanford.edu
> > > MIME-Version: 1.0
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> > > 
> > > In a message dated 2/16/2004 4:42:24 PM Eastern Standard Time, 
> > > jblake at informatics.jax.org writes:
> > > Hi Stan,
> > > 
> > > I think David illustrates well that biological knowledge is the 
> > > accumulation of experimental information that allows a 'judgement' ;  there 
> > > is not a 'necessary and sufficient' component of a GO term association that 
> > > would be easy to define, I think. The evidence codes provide a method of 
> > > 'summary statement' of the evidence used in standardized way that allows 
> > > users a 'confidence' assessment in a way. The citation provides the 
> > > researcher access to the information about the experimental procedures 
> > > used, etc.
> > > Judy,
> > > 
> > > What I was after was a general recipe for testing predicted GO assignments. 
> > > So the
> > > evidence for known GO assignments doesn't really help. David's criteria are 
> > > more
> > > on target, but they are quite complex, and fundamentally genetic. They 
> > > suggest (to me)
> > > the following N&S conditions:
> > > 
> > >     gene G gets biological process term T iff
> > >     there exists a homo/heterozygous loss/gain-of-function mutant for G, 
> > >                       a genetic background
> > >                and an environment 
> > >     that together show a perturbed T which is not attributable to some other 
> > > process U 
> > >     which is causally upstream from T but not "part-of" T,
> > >     and which is not evident in the same genetic background and environment 
> > > with 
> > >     the wild-type G.
> > > 
> > > (I am trying to make the definition handle lethals and pathway redundancy 
> > > correctly. Both cause problems -- lethals because they affect everything, yet we 
> > > don't say they are involved in all processes, and redundant pathway steps 
> > > because they may not have a pheno in wild type, yet we still may say they are 
> > > involved in some processes. So the "which is not attributable to" is for lethals, 
> > > and the "in some genetic background" is for redundants.)
> > > 
> > > To use this definition for experimental design would seem to require:
> > > 
> > >     1. ability to generate KO / OEX constructs for any gene of interest
> > >     2. screens/phenotypes for any process T, sensitive to "direct effects" on 
> > > T only
> > >     3. a potentially unlimited set of background genotypes (to detect 
> > > interactions) and 
> > >       environmental conditions
> > > 
> > > 1&2 is not inconceivable given high-throughput screens that have been 
> > > developed.
> > > 3 is much more problematic. Part of the beauty of the "module networks" paper
> > > was that (2) was always microarrays, and (3) was specified by the
> > > automatically generated hypotheses. 
> > > 
> > > David's criteria make sense, but I am somewhat surprised at how "genetic" 
> > > they are --
> > > not that it is surprising that David would propose genetic criteria, but 
> > > rather that
> > > purely phenotypic criteria are used to associate a gene with a biological 
> > > processes.
> > > I always thought part of the goal of GO was to move away from describing
> > > things in terms of mutant phenos to associating genes with normal biological
> > > processes, but maybe that's just a terminological shift. Does this mean that 
> > > there is (in a given species) always a clear mapping between phenos and BPs?
> > > 
> > > Cheers, -Stan
> > 
> > 
> > --
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> 
> 
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