Clustering proteins in multiple sequence alignments?

[Edward Wallace]

Hi Code Monkeys,
Any recommendations on best practice for clustering analysis of protein sequences? My MSc student Yuxuan says "I read something about doing the clustering and found there are many ways to do that (e.g. blastclust, CLUSS, AP)." Are there any particular recommendations for methods to use or avoid?

I'm not convinced that we need to do clustering rather than proper phylogenetic analysis, but it would be nice to get any advice!

For context, our proteins of interest have multiple conserved structured domains so we expect multiple sequence alignments, and clustering and phylogeny, to be quite informative. My major goal is to understand the evolution of the protein and especially of its RNA-binding sites, looking for clues to function.

Thanks!

Edward

 

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Edward Wallace

Tel: +44-777-914-7542

[OBBARD Darren]

Hi!

> I'm not convinced that we need to do clustering rather than proper
> phylogenetic analysis, but it would be nice to get any advice!

As always, I'd start out by asking "What's the question?"

(1) If you want to ask 'How similar are these proteins?' then clustering on a distance metric is describing similarity.
(2) If you want to ask 'How are these proteins related?' then formal alignment and model-based phylogenetic inference is the way forward.

Of course, (2) is quite likely to answer (1) as well, unless there's a lot of convergence. And you might use (1) on the way to (2), as a rough approximation to define the limits of the analysis (i.e. to guess at orthology)

I would only cluster based on distance if you explicitly expect similarity and phylogeny to be decoupled (e.g. lots of convergence, or many gained or lost domains) or if phylogenetic analysis is intractable either for computational requirements, or because evolutionary models can't be usefully applied (i.e. no meaningful alignment due to domain gains/ losses or re-ordering).

For (2), my current favourite would be t_coffee -mode 'accurate', followed by IQtree2

Regards!

D

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Darren Obbard
darren...@ed.ac.uk

Institute of Evolutionary Biology
University of Edinburgh
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[Edward Wallace]

Hi Darren,

Thanks, that is pretty much what I suspected, only clearer! I'll pass the message on to the student.

The last phylogenetic analysis that I did - successfully coached by Daniel Barker and Gemma Atkinson - mafft and IQ-TREE 2 worked extremely well. But that was a nice large well-behaved protein.

Best wishes,

Edward

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