[Annotation] phenotype or GO-still struggling
Judith Blake
jblake at informatics.jax.org
Fri Jul 11 07:11:58 PDT 2008
Hi,
I sent a response with ppt and it's waiting to be moderated
J
Harold Drabkin wrote:
>
> On the other hand, we have to be careful about applying what we think
> we know to ignore what a mutant phenotypes is telling you, because
> things can be complicated. .I just finished looking at one of the
> ribosomal proteins, Rpl10. There is very little mouse data, but from
> skimming some other references (human), it appears to be originally
> identified in a screen for tumor suppressors. It is unclear why. It
> appears to be a protein that associates with the large subunit after
> the subunit is exported from the nucleus. However, there is some
> reference to it's release from the 60S ribosomal subunit as a
> mechanism of transcript-specific translational control. This might
> have been reflected in the search for tumor suppressors. Yet another
> paper describes it is a zinc-binding transcription regulatory
> protein: which can bind to c-Jun i ( this binding is dependent upon
> zinc ions and phosphorylation by protein kinase C ). Haven't looked at
> those papers in detail; But there is something interesting going on
> (no one has done a KO in mouse that I can find which might tell us a
> bit more), and I'm not at all sure one should rule out that it
> participates in other processes other than the one obvious from it's
> name. Just grist for the mill.
>
> h
>
>
> Valerie Wood wrote:
>> I agree completely with Karen/SGD and this has been the procedure I
>> have always followed.
>> In the absence of any other information, a mutant phenotype is
>> frequently used to infer a specific process. Once more information
>> is available it often becomes clear that this is a downstream
>> (indirect affect).
>> For example defects in ribosome biogenesis and translation and
>> general translation will often have plieotrophic affects which are
>> indirect, as it will affect nearly every process downstream (for
>> example there are associated downstream effects in chromosome
>> segregation, cell division, and in multicellular organisms, multiple
>> developmental processes). This does not mean that a biologist would
>> expect to see the annotations to these processes once the upstream
>> process is known. If we did follow this logic, then we would find
>> that all genes involved in translation, ribosome biogenesis and
>> general replication would eventually become annotated to most other
>> processes.
>>
>> Another classic example from yeast is vacuolar targeting. Many
>> mutants result in defects which result in proteins usually localized
>> to the vacuole becoming mislocalised and were initially interpreted
>> as a defect in protein targeting. It has since become clear that many
>> of these defects are very far upstream of the vacuolar targeting
>> pathway, and this is just a downstream consequence of things being
>> mis folded, mis transcribed etc. Subsequently these annotations have
>> gradually been removed as better information has become available.
>>
>> On the other hand, mutations in a gene may have phenotypic effects
>> which you DO want to capture as processes (for example the effects of
>> phenylalanine hydroxylase on skin pigmentation etc). However you
>> would not necessarily want to curate the effect of a gene involved in
>> all translation initation in a developmental process from a high
>> throughput screen (once better information was avaiable). In Doug's
>> example I would also follow Karen's suggestion and make the
>> annotation if this is possibly specific transcription for the pathway
>> (i.e specific to a subset of genes), but if the defect is definately
>> general transcription I would not make the annotation.
>>
>> Not caputuring EVERY phenotype using biological process should not be
>> considered underannotation. The purpose of GO process annotations is
>> to capture processes not phenotypes. Sometimes phenotypes are direct
>> indicators of the process a gene is involved in sometimes they are not.
>> A major consequence of making these ubiquitous annotations is that
>> can distort genome wide analysis (not improve it), and this is
>> often the case when annotations come from high throughput screens
>> and early experiments. Over the past couple of years cerevisiae and
>> pombe have done a lot of 'tidying' of these legacy annotations, and
>> the genome-wide GO data is much improved and useful as a result.
>>
>> This is also why annotations to orthologs made using ISS should only
>> be made by a curator on a gene by gene basis and not by an automated
>> process. A curator is able to assess all of the available information
>> to make an ISS annotation (from different organisms) and distinguish
>> between current annotations and legacy annotations.
>>
>> One way to distinguish these is whether the targets are generic (i.e
>> every gene ) or specific (a subset of genes). If the genes targets
>> are a subset of genes then the annotations is probably valid.
>>
>> Val
>>
>> Karen Christie <kchris at genome.stanford.edu> wrote:
>>> I don't think the GOC has ever had a policy, or even a
>>> recommendation, that process annotations should be made from all
>>> mutant phenotypes, nor do I think that it should.
>>>
>>> For example, SGD is currently working on annotating phenotypes for
>>> Cell Division Cycle (CDC) mutants, i.e. mutations which cause a cell
>>> cycle arrest phenotype. Here are some of the ones I worked on
>>> yesterday:
>>>
>>> CDC60 leucyl tRNA synthetase
>>> PRT1 Subunit of eIF3
>>> ALA1 alanyl-tRNA synthetase
>>> CDC65 mitochondrial tRNA-Glu
>>> SPT16 Subunit FACT transcription elongation complex
>>>
>>> I don't think that anyone in the yeast community would expect or
>>> want to see any of these genes annotated to a GO process related to
>>> the cell cycle. There are lots of examples of where a mutant
>>> phenotype is due to some downstream effect and not due to the
>>> primary defect.
>>>
>>> So, at SGD, we try to focus on the primary process. Obviously, we
>>> don't always know, but once we do, we like to avoid making GO
>>> annotations for processes that are known to be downstream, rather
>>> than direct, results of the mutation.
>>>
>>> For Doug's specific example, if comparative data suggested that the
>>> gene was a specific regulatory transcription factor, I'd probably be
>>> inclined to go ahead and make specific process annotations. However,
>>> if comparative data suggested that it was related to a Pol II
>>> general transcription factor, I might not want to make a GO process
>>> annotation to such a specific process.
>>>
>>> At all of the Annotation Camps, we've always said that one should be
>>> careful when making annotations from mutant phenotypes. At both of
>>> the public ones, the question has come up of how much to annotate
>>> from mutant phenotypes. The answer we've given has been that if one
>>> only has a mutant phenotype to annotated from, then make the best
>>> annotations you can. However, be aware that as you learn more, you
>>> may find that some of the mutant phenotypes are indirect results
>>> rather than something the gene product is directly involved in, and
>>> that in these cases you may choose to remove process annotations
>>> based on these phenotypes.
>>>
>>> I think this is still good advice, that curator judgement should
>>> play a role in deciding whether a GO process annotation is merited
>>> from any particular mutant phenotype.
>>>
>>> -Karen
>>>
>>>
>>> On Sun, 6 Jul 2008, Judith Blake wrote:
>>>
>>>
>>>> I can understand the duplication of effort, but since the GO and
>>>> phenotype annotations aren't co-mingled in GOdb, the SGD genes
>>>> would I think appear under-annotated if the effect of the gene on
>>>> phenotype is not curated in BP. For comparative genomics studies
>>>> using GO, this would be missing, yet available in the literature,
>>>> information.
>>>>
>>>> for mouse, the phenotype data is effectively 'disfunction' data, so
>>>> the phenotype annotation reflects a different view from the GO
>>>> annotation.
>>>>
>>>> Judy
>>>>
>>>> Julie Park wrote:
>>>>
>>>>> Hi Doug,
>>>>>
>>>>> SGD's practice on this is that if it is known that what is being
>>>>> observed is a secondary/downstream effect, then we only capture it
>>>>> via phenotypes and not as a GO process. However, if the gene
>>>>> product in question is not well characterized or there is a
>>>>> conflict in the literature about whether it is a direct or
>>>>> indirect involvement then we would give it a GO annotation.
>>>>>
>>>>> We've made a decision to use GO to try and capture the primary
>>>>> role of a gene product as much as possible and to reduce the
>>>>> duplication of effort required to capture data both in GO and as
>>>>> phenotypes.
>>>>>
>>>>> Just our take on things.
>>>>>
>>>>> Regards,
>>>>> -Julie
>>>>>
>>>>>
>>>>> On Jul 3, 2008, at 3:16 PM, Doug howe wrote:
>>>>>
>>>>>
>>>>>> Hi David,
>>>>>> It still seems like there is a line that has to be drawn somewhere.
>>>>>> We've talked in the past about the scope of a process...when does it
>>>>>> start and when does it end? A gene that has as it's primary role
>>>>>> regulation of transcription (perhaps binds DNA etc. etc.) may have a
>>>>>> secondary effect upon eye morphogenesis. However, the process of
>>>>>> eye
>>>>>> morphogenesis does not start with the binding of such a gene to a
>>>>>> regulatory sequence...it is a downstream consequence....and
>>>>>> perhaps it
>>>>>> is the gene who's expression is being regulated that is really
>>>>>> involved
>>>>>> in the downstream process. It seems like there is a significant
>>>>>> amount
>>>>>> of redundant curation work to do if we always annotate both GO and
>>>>>> phenotype using the same GO process terms. I'm not strongly
>>>>>> opposed to
>>>>>> such annotations, I just want to revisit the discussion and see if
>>>>>> anyone has other views on the issue.
>>>>>> -Doug
>>>>>>
>>>>>> David Hill wrote:
>>>>>>
>>>>>>> Doug,
>>>>>>>
>>>>>>> I do this all the time. I just finished systematically doing all
>>>>>>> the homeobox genes in mouse. Many of them are annotated to
>>>>>>> things like pattern specification. I think in the future, it
>>>>>>> will be very nice to know these are playing roles in regulating
>>>>>>> transcription but that regulation is fundamental in other
>>>>>>> processes as well.
>>>>>>>
>>>>>>> David
>>>>>>>
>>>>>>> Doug howe wrote:
>>>>>>>
>>>>>>>> I'm still struggling with the issue of whether to make a GO
>>>>>>>> annotation (processes in particular) or only phenotype
>>>>>>>> annotation. The zebrafish literature is replete with mutant
>>>>>>>> papers that often describe phenotypes involving eyes, otic
>>>>>>>> vesicles, or pharyngeal arches, organ development etc. Often,
>>>>>>>> the IEA annotations for a gene seems to indicate that the gene
>>>>>>>> is binding DNA, and may be some sort of transcriptional
>>>>>>>> regulator. Should such a gene be annotated with GO terms like
>>>>>>>> 'otic vesicle development', or 'eye morphogenesis', or should
>>>>>>>> that be left for phenotype annotations?
>>>>>>>>
>>>>>>>>
>>>>>> --
>>>>>> Doug Howe, Ph.D.
>>>>>> ZFIN Scientific Curator
>>>>>> Zebrafish Nomenclature Coordinator
>>>>>>
>>>>>>
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