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dN/dS spliced genes (Read 2031 times)
KBR
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dN/dS spliced genes
Feb 11th, 2008 at 9:49am
 
Hi  Smiley
Can someone explain to me why the PB1-F2 protein of influenza has a dN/ds ratio of between 9-13 while all other influenza genes have a ratio between 0.03-0.4?????
Some publications claim that the result is biased for PB1-f2 because this protein is dereived from a much larger protein from a +1 reading frame. I believe the protein is only 90 aa. It should also be very conserved. How is it then possible to have such a high score????
Should one believe that this small protein is regulated under extreme positive  selection pressure?? or what..I don't quite believe it.
How would you explain it....so that I understand.???

I also wonder about predicting individual positive selected sites from spliced genes. The NS and M genes of influensa are spliced into NS1/Ns2 and M1/M2, respectively. the M2 proteins have a higer dN/dS ratio than other proteins that we NOW are more prone to postive selection. Also several sites in M1 are selected as positive selection sites (this protein should not have been influenzed by selection pressure). Some excplain high dN/dS ratio for spliced genes as bias because dS is suppressed for overlapping regions. I don't understand this....if you have extracted the amino acids from an alignment  giving the M1 protein and run selection analysis on it....how can it then be biased by overlapping regions????

When i look at the HA protein as whole I find no positively selected sites, but when I only look at the HA1 region only, I find 25 sites. Why does SLAC suddenly identify these sites? is it only because the lenght of the alignment is shorter than the original one? If I shorten it further....will I then find more sites???
How can I then trust that the sites I find are truly under positive selection?

Please help  Embarrassed  Embarrassed  Embarrassed  Embarrassed
This is very hard!

KBR Wink
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Sergei
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Re: dN/dS spliced genes
Reply #1 - Feb 12th, 2008 at 7:26pm
 
Dear KBR,

Regarding PB1-F2, take a look at the note published by Eddie Holmes el al (Multimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to Login Login). The basic idea is that traditional dN/dS is meaningless in dual coding regions, because a synonymous mutation in one frame is almost always a non-synonymous mutation in another. I co-authored a paper which proposes a simple model to directly account for this effect (Multimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to Login Login). In other words, the very high dN/dS ratio in PB1-F2 can not be taken at face value.

SLAC/FEL/REL can correct for variable dS, so spliced genes should be handled correctly (unless you have dual coding). I am not sure one can say M1 is devoid of positive selection a priori, but generally speaking, higher average dN/dS does not automatically mean that the gene is under more/less selection. Indeed, consider a gene where all sites have dN/dS = 0.5, and another gene where dN/dS = 5 at 5% of sites and dN/dS = 0.1 at 95% of sites (mean dN/dS = 0.345). Clearly the second gene is under positive selection (at least some sites are), whereas the the first is under weak purifying selection.

The HA/HA1 results look very odd indeed; removing a part of the gene should not have such a drastic effect. Could you e-mail me the data (spond at ucsd dot edu) so that I can double check and get back to you.

Cheers,
Sergei

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