Functional Divergence

Question

[Kartik Sunagar]

Dear all,

Is it appropriate to detect changes in evolutionary rates (theta) at sites in orthologous proteins belonging to different lineages and use it as a proxy of functional divergence? I know this can be done in Diverge, but I was wondering if it is only applicable to paralogous genes or even orthologous genes could be analysed in the same way. I personally think it should not be any different but I am not sure. Any suggestions are appreciated.

Thank you, Kartik

Answer 1

[2184687-1231-83-]

Even though homology doesn't imply isofunctionality, people use it for functional inferences, usually restricting to orthologous genes or loci. This is because paralogies predating the speciation events for your clade of species will have a chance to neofunctionalise, subfunctionalise or pseudogenise. This paper is a good start:

Fang G, Bhardwaj N, Robilotto R, Gerstein MB. (2010). "Getting started in gene orthology and functional analysis.". PLoS Comput Biol. 6. doi:10.1371/journal.pcbi.1000703. PMID 20361041.
http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000703

[Kartik Sunagar]

I totally agree with what you said. But, am I rite in thinking that when two sequences are separated by speciation event, the sites in them should keep evolving at similar evolutionary rates unless they are influenced by positive selection pressure and if they are, it is very much possible for them to acquire new functions or traits..? We expect one of the paralogous gene to evolve at different evolutionary rates at different sites as it is relieved of all the selection pressures after the duplication event and this could lead to neo-functionalization.

[Kartik Sunagar]

But because the orthologous genes are still maintained in a single copy in the new species, they will continue to have the same selection pressure as before and thus they should not accumulate variation. So, I was wondering if I could use tools like Diverge to calculate the theta parameter for different lineages and use it as a proxy of functional divergence between these proteins. I must add that I have found them to be evolving under the influence of positive selection and their actual functions are unknown.

[Larry_Parnell]

No, you cannot make the assumption that when two sequences are separated by speciation, the sites in those sequences should continue to evolve at similar rates unless they are influenced by positive selection pressures.

[Kartik Sunagar]

My point is.. because the two orthologs still exist in single copy in the respective species, they should continue to evolve under the same constraints, unless there is positive selection (or recombination: which is absent from my dataset); especially if they perform important functions. I understand that they can adapt to different conditions but the adaptations are again brought about by positive selection, recombination and/or similar evolutionary process..

[Kartik Sunagar]

So, in the absence of selective forces, the two-sequences should accumulate similar or proportional mutations under the neutral model.. I don't know if this is equivalent of evolving at similar or proportional rates. Could you please explain what am I overlooking here? Thank you very much.