Weak homology

David Jones David.Jones at brunel.ac.uk
Sun Jul 16 10:47:47 EST 2000


William R. Pearson <wrp at alpha0.bioch.virginia.edu> wrote:
> I strongly disagree with this statement.  With the exceptions of
> extremely biased sequences, like histones and low complexity regions,
> I know of no examples where "high sequence similarity" is misleading.
> In particular, all transmembrane helices do not look remarkably alike
> from the Blast/SW/Fasta perspective.  We routinely use various
> receptors with multiple transmembrane domains to test the FASTA
> package, and we never see statistically significant similarity to
> unrelated membrane proteins.  Dealing with highly biased sequence
> composition is an area of ongoing research, the latest version of the
> FASTA package (33t06) offers a statistical estimation option (-z 6)
> that includes a composition bias correction.
> 

Although I'm not going to argue with what Bill says here - it might be
worth noting that the above comment applies to "normal" Blast only.
Using iterated Blast (PSI-BLAST) with transmembrane proteins can produce
_apparently_ very significant matches to completely unrelated transmembrane
proteins after only two iterations. Given that PSI-BLAST is often used as
a black box for genome annotation, this is a serious problem. The underlying
problem is of course that in BLAST the E-value estimates are based on a
certain set of assumptions - even more assumptions in PSI-BLAST - and these
are not applicable in certain common cases.

Although in my lab we try to avoid using PSI-BLAST with transmembrane
proteins as far as possible - when we do use it for these cases we use a
much lower iteration E-value cutoff (1e-16 as opposed to the default 1e-3).
But, even this is not guaranteed foolproof.

- David -

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