PLEASE:evolution vs function...Re: [go] ISA/ISO

[Judith Blake]

Hi All,

Here are some thoughts.

1.  Functional groupings, such as are identified by shared GO 
annotations, should NOT be termed orthologs in my opinion.  These are 
functional equivalents.  In my mind, orthology relates to evolutionary 
lineage, descent from common ancester.  It is VERY important, in the 
context of comparative genomics, to be able to distinquish those things 
that share function from those things that shared evolutionary 
lineages.  These are not the same thing, although the genes in these 
sets overlap.

2.  I recognize that we use shared function/sequence as a default 
'predictor' for our functional annotations.  Fine.  That is useful for 
hypothesis generation.  However, that is JUST why we have such a 
distinction between experimental and predictive evidence codes.

3.  This is also why we want to distinquish the use of generic 'sequence 
similarity' from the use of 'orthologs' in the annotation sets. It is 
why Kara's work is important, so that the orthology sets of annotations 
can be /clearly/ distinquish from those cases where annotations are 
based on some undefined level of similarity that someone uses primarily 
to get /any/ annotation.  It is also why I personally would prefer these 
generic sequence similarity annotations be tagged as IEA.

4.  This is also why we don't include genes in the GO trees...because we 
want the GO to focus on shared MF/BP/CC rather than on the determination 
of evolution.  THEN we can use this experimental evidence to guide 
investigations in comparative genomics.

I have strong feelings on this subject...can you tell?

best,
Judy


Kara Dolinski wrote:
> Hi,
>
> These are all good points, and I've had some useful, interesting 
> offline exchanges with people about some of these issues.
>
> Certainly the current plan in place uses the evolutionary definition 
> of the term as described by Michelle, and will of course rely on 
> sequence similarity (OrthoMCL starts with BLAST) to find the 
> orthologous relationships.    I think/hope everyone would agree that 
> this is a good and necessary first step.  But, Val makes a good 
> point.  For the purposes of GO annotation, perhaps the bigger picture 
> is that we do not want to identify just putative orthologs but also 
> genes that are likely share the same function (many are orthologs, but 
> many are not, as Val points out in a subsequent email).  If that's the 
> case, we'd want to explore alternative methods that look at things 
> like conservation of interactions, gene expression, etc rather than 
> sequence similarity.  This is, of course, a much bigger job, and, not 
> to say it shouldn't be done, but we might want to stay off the 
> bleeding edge a bit longer and start with the simpler sequence based 
> approach as a start, keeping in mind the caveats that Val raises.
>
>
> On Feb 21, 2008, at 11:50 AM, Pankaj Jaiswal wrote:
>
>> This seems like a case for 'functional ortholog' based on the 
>> conserved assembly and interaction among subunits of a protein 
>> complex from two different species. We see these cases quite often.
>>
>> Here is an interesting paper on this theme
>> Systematic identification of functional orthologs based on protein 
>> network comparison. Genome Res. 2006 Mar;16(3):428-35.
>> PMID: 16510899
>> http://www.ncbi.nlm.nih.gov/pubmed/16510899?dopt=Abstract
>>
>> Pankaj
>>
>>
>> Gwinn Giglio, Michelle wrote:
>>> Hi Val,
>>> The definition of ortholog is that the two sequences arose from a 
>>> common
>>> ancestor and were separated by a speciation event.  The situation you
>>> describe sounds to me like there is good evidence that the two proteins
>>> carry out the same functions, however they could either be orthologs 
>>> that
>>> have diverged so much that no recognizable sequence similarity 
>>> remains or
>>> they have arisen due to convergent evolution and are NOT true 
>>> orthologs.
>>> Michelle
>>> On 2/21/08 8:54 AM, "Valerie Wood" <val at sanger.ac.uk> wrote:
>>>> In support of the final sibling arrangement of ISA/ISO, I came 
>>>> across an
>>>> example today where gene products are known to be orthologous but have
>>>> no sequence conservation which I thought I would share.
>>>>
>>>> Identification of the Proteins, Including MAGEG1, That Make Up the
>>>>  Human SMC5-6 Protein Complex
>>>> Elaine M. Taylor, Alice C. Copsey, Jessica J. R. Hudson, Susanne 
>>>> Vidot,
>>>> and Alan R. Lehmann
>>>> quote
>>>> "Nse6 contains ARM/HEAT repeats, but there is no sequence conservation
>>>> between these presumed orthologs from S. cerevisiae/ and /S. 
>>>> pombe/. In
>>>> /S. pombe/ they also appear to bridge the head domains of Smc5 and 
>>>> Smc6"
>>>>
>>>> where it is not even possible to detect the similarity between the 2
>>>> nse6 subunits in yeast and pombe but they are presumed orthologs from
>>>> other biological properties and position in the complex, binding
>>>> partners etc.
>>>> These are NOT reciprocal best hits, and although they can be aligned,
>>>> (you can align anything) it does not mean, that if I inferred any
>>>> experimental data from the S. cerevisiae ortholog it would come from a
>>>> sequence alignment.
>>>>
>>>> I should also add that this is very common which also has large
>>>> implications for the orthology prediction exercise.
>>>>
>>>>
>>>> Val
>>>>
>>>>
>>
>> -- 
>> Pankaj Jaiswal
>> G-15, Bradfield Hall
>> Dept. of Plant Breeding and Genetics
>> Cornell University
>> Ithaca, NY-14853, USA
>>
>> Ph. +1-607-255-3103 / 4199
>> fax: +1-607-255-6683
>>
>